Research Paper Published:

1. Effect of Dehydroepiandrosterone (DHEA) on Monoamine Oxidase Activity, Lipid Per oxidation and Lipofuscin Accumulation in Aging Rat Brain Regions. Pardeep Kumar, Asia Taha, Deepak Sharma, R.K.Kale and Najma Z. Baquer. Biogerontology Aug;9(4):235-46,

Erratum: Aug;9(4):283-4 (2008). 2. A Metabolic and Functional Overview of Brain Aging Linked to Neurological Disorders.

Najma Z. Baquer, Asia Taha, Pardeep Kumar, P.McLean, S.M.Cowsik, R.K.Kale, R.Singh

and Deepak Sharma. Biogerontology (2009) 10:377-413. 3. Physiological and Biochemical effects of 17P estradiol in Aging female rat brain. Pardeep

Kumar, Asia Taha, R.K.Kale, S.M.Cowsik and Najma Z. Baquer. (Accepted in Experimental Gerontology, 201 0).

,Research Paper communicated:

4. Metabolic and Molecular Action of Trigonella foenum-graecum, fenugreek: Alternative therapies for Diabetes Najma Zaheer Baquer*, Pardeep Kumar, Asia Taha, R.K. Kale, S.M.Cowsik and P.McLean (Under review in Journal of Ethancopharmacology).

5. Beneficial effects of Trigonella foenum graecum and sodium orthovanadate on metabolic

parameters in experimental diabetes. Pardeep Kumar, Asia Taha, R.K. Kale , , S.M.Cowsik

and Najma Zaheer Baquer (Under review in Journal of Biosciences). 6. Hyperglycemia-induced alterations in activity of membrane bound enzymes, synaptosomal

membrane fluidity, neurolipofuscin and glucose transporter: Beneficial Effects of Trigonella

foenum-graecum seed powder in alloxan diabetic rat. (Under review in Life Sciences). 7. Neuroprotective effects of estradiol on altered age related neuronal markers in aging female

rats. Pardeep Kumar, Asia Taha, R.K. Kale , , S.M.Cowsik and Najma Zaheer Baquer (Under review in Neurotoxicology ).

8. Trigonella foenum-graecum seed powder improves calcium homeostasis, antioxidant status and glucose transporter in brain of alloxan induced diabetic rats. Pardeep Kumar, Asia Taha, R.K. Kale, and Najma Zaheer Baquer (Under review in Plant Foods for Human Nutrition.)

Book chapter:

I . Book chapter: "Effect of Estradiol administration in normalizing age related neuronal parameters in female rats." Pardeep Kumar, R.K.Kale and Najma Z. Baquer, In "Molecular mechanism of neurological and psychiatric disorders" volume 1, Publication Cooperation, Comenius University Jessenius Faculty of Medicine in Martin Institute of Medical Biochemistry, Mala Hora 4, Martin 036 01 SLOVAKIA (In press, 201 0) .

2. Book chapter: "DHEA and aging brain". Najma Z. Baquer, Pardeep Kumar, S.M.Cowsik

and R.K.Kale Publication by Taylor & Francis, USA (Under preparation, 2010).

'10" ' ~

ffl{orlf~tJof!s/C~,V!~~~:; ·.

1. Participated in the Theoretical Course of the Baltic Summer School 2009, 'Genetic basis of

medicine" 07th-19th September, 2009. University ofKiel, Germany.

2. Participation in "National Workshop on Advanced Analytical Instrumentation and Applications" (January 5-7, 2009) at Advanced Instrumentation Facility, University Science Instrumentation centre, Jawaharlal Nehru University, New Delhi, India.

3. Participated in the Theoretical Course of the Baltic Summer School 2008, "Basic and clinical aspects of cardiac arrhythmias" 17th-29th august 2008. Department of Biochemical Sciences University of Copenhagen Denmark.

1. Chronic 17P-estradiol administration improves membrane linked ATPases, membrane fluidity

and glucose transporter in brain of aging female rats. Pardeep Kumar, R.K. Kale,

S.M.Cowsik and N. Z. Baquer "The 9th International Conference on Brain Energy Metabolism (ICBEM) entitled "Mitochondrial-Cytosolic Interactions: From Energetics to Pathogenesis" , which will be held at Basic Medical Science Center of Semmelweis University in Budapest, Hungary on July 7-10, 2010. (Young investigator oral presentation award)

2. Neuroprotective effects of estradiol on altered age related neuronal markers in aging female rats Pardeep Kumar, R.K.Kale and Najma Z. Baquer._ 26th International Neurotoxicology Conference 'Unifying Mechanisms of Neurological Disorders: Scientific, Translational and Clinical Implications' to be held June 6-10, 2010 in Portland, Oregon, USA at the Portland Marriott Downtown Waterfront. (Abstract published in the NeuroToxicology).

3. Neuroprotective and Anti-aging Effects of Estradiol on Altered Membrane Functions m Aging Female Rat. Pardeep Kumar, Asia Taha, R.K.Kale and Najma Z. Baquer. ·International symposium on Endocrinology and Reproduction: Molecular Mechanisms to Molecular Medicine' and the '28th Annual meeting of the Society for Reproductive Biology and Comparative Endocrinology (SRBCE-2010)' being held in Jawaharlal Nehru University, New Delhi from 4-6th February, 2010.

4. Neuroprotective Effects of Trigonella foenum graecum seed powder on altered Membrane functions in Alloxan-induced Diabetic rats. Pardeep Kumar, Asia Taha, R.K.Kale and Najma z. Baquer. NSF-GEM4 Winter School, January, 4-14th 2010 at the University of

Texas at Austin, USA.

5. International Symposium on "Cancer Chemoprevention and Translational Research" December 21st, 2009, School of Life Sciences, Jawaharlal Nehru University, New Delhi,

India.

6. Effect of Trigo nella foenum graecum and insulin on altered membrane functions in alloxan

diabetic rat brains. Pardeep Kumar, Asia Taha, R.K.Kale and Najma Z. Baquer. 36th Annual conference of Clinical Biochemists of India (ACBICON 2009) November 5th to 7th, 2009. Amrita School of Medicine, Kochi, Kerala. (Abstract published in the Indian Journal of clinical biochemistry).

7. Anti-Aging Effect of Estradiol on Membrane Linked Functions and Glucose Transporter in

Aging Female Rats. Pardeep Kumar, Asia Taha, R.K.Kale and Najma Z. Baquer. The Baltic Summer School Programme. 06th- I 9th September 2009 in University of Kiel, Germany.

8. Estradiol treatment change the membrane linked functions in brain of different age groups of

naturally menopausal rats. Pardeep Kumar, Asia Taha, R.K.Kale and Najma Z. Baquer. The

22nd Biennial Meeting of the ISN/ APSN Joint Meeting August 23 - 28, 2009 BEXCO,

Busan, South Korea (Abstract published in the Journal of Neurochemistry).

9. BioEpoch 2009 I sr Annual Symposium of School of Biotechnology, 03-04 April, 2009,

School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.

I 0. Brain Antioxidant Status in Aging and Diabetes Linked to Neurological Disorders. Najma Z.

Baquer, Asia Taha, Pardeep Kumar, R.K.Kale and Deepak Sharma. International

Conferences on "Advances in Free Radical Research: Natural Products, Antioxidants and

Radioprotectors" (AFRR - 2009) & 8th Annual Meeting of the Society for Free Radical Research India, March 19th-21th, 2009 , Lucknow, India.

I 1. Altered membrane functions in alloxan diabetic rat brain. Effect of Trigonella joenum greacum and insulin. Pardeep Kumpr, Asia Taha, R.K.Kale and Najma Z. Baquer. 3rd International Congress on Prediabetes and the Metabolic Syndrome 5-7th February 2009 ,Nice, France.

12. Reversal of Membrane Functions in Diabetic Heart by Trigonella foenum graecum and

Insulin. Pardeep Kumar, Asia Taha, R.K.Kale and Najma Z. Baquer. 13th-15th, Feburary 2009. International Conference on "Genetic and Molecular Diagnosis in Modem Medicine (GMDMM 2009) " Kamineni Educational Society, Hyderabad, India

13. International Symposium on Novel Strategies for targeted prevention and treatment of cancer. December 19th-20th, 2008, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

14. Modulation of Age Related Neuronal Markers by Hormones in Rats. Pardeep Kumar, Asia Taha, Deepak Sharma, R.K.Kale and Najma Z. Baquer. International symposium on

"Molecular aspects of brain aging and neurological disorders" and annual meeting of society for neurochemistry (INDIA) (28th - 29th November, 2008). Guru Nanak Dev University,

Amritsar, INDIA.

15. Membrane linked functions in diabetic rat tissues and their reversal by insulin and antidiabetic

compounds. Pardeep Kumar, Asia Taha, M.R. Siddiqui, R.K.Kale and Najma Z. Baquer.

61h Annual World Congress on the Insulin Resistance Syndrome. 25th-27th September, 2008,

Hilton, Universal City, Los Angles, USA. (Abstract published in the Journal of Diabetes

and Vascular Disease, USA).

16. Effect of Trigonella foenum graecum on altered cardiac membrane function in diabetic rat

tissue. Pardeep Kumar, Asia Taha, R.K.Kale and Najma Z. Baquer. The Baltic Summer

School Programme. 17th-29th August, 2008 in University of Copenhagen, Denmark.

17. Anti-Diabetic Effect of Trigonella foenum graecum on Altered Membrane Functions in Alloxan Diabetic Rats. Pardeep Kumar, Asia Taha, Deepak Sharma, R.K.Kale and Najma Z.

Baquer. 2nd International Conference on Trends in Cellular and Molecular Biology. January 5-7, 2008, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

18. Antiaging Effect of Dehydroepiendrosterone (DHEA) on Membrane Functions in Aging Rat

Brain Regions. Pardeep Kumar, Asia Taha, Deepak Sharma, R.K.Kale and Najma Z.

Baquer. 34th Annual conference of Clinical Biochemists of India (ACBICON 2007) December 18th to 20th, 2007, Indian Habitat Center, New Delhi. (Abstract published in the

Indian Journal of Clinical Biochemistry). (Young investigator award+ BEST POSTER AWARD)

19. Regulation of Glucose Homeostasis in experimental Diabetes by Insulin and Antidiabetic

compounds Trigonella Foenum Graecum and Vanadium. Najma Z. Baquer, Asia Taha,

Pardeep Kumar, R.K.Kale and Deepak Sharma. 34th annual conference of Clinical Biochemists of India (ACBICON 2007) December 18th to 20th, 2007, Indian Habitat Center, New Delhi, India. (Abstract published in the Indian Journal of Clinical Biochemistry).

20. Effect of Experimental Diabetes on DNA Degradation, GLUT4 translocation and Membrane linked function in rat tissues and their reversal by insulin and antidiabetic compounds. Pardeep Kumar, Asia Taha, M.R. Siddiqui, R.K.Kale, D. Sharma, and Najma Z. Baquer. 76th Annual meeting of Society of Biological Chemists (India), 25th to 27th November 2007. Sri Venkateswara University, Tirupati, India.

21. Oxidative Stress Related Alterations in Alloxan Diabetic Rats: Reversal By Antidiabetic

Compounds. Asia Taha, Pardeep Kumar, Deepak Sharma and Najma Z. Baquer. 75th

Annual meeting of Society of Biological Chemists (India), New Delhi. 8th to 11th December

2006. School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

Biogerontology (2009) I 0:377-413

DOI I 0.1 007/s 10522-009-9226-2

A metabolic and functional overview of brain aging linked to neurological disorders

Najma Z. Baquer · Asia Taha · Pardeep Kumar · P. McLean · S. M. Cowsik · R. K. Kale · R. Singh • Deepak Sharma

Received: 6 February 2009 I Accepted: 2 April 2009 /Published online: 21 April 2009 © Springer Science+Business Media B.V. 2009

Abstract Close correlations have recently been shown among the late onset complications encoun­tered in diabetes and aging linked to neurobiological disorders. Aging in females and males is considered as the end of natural protection against age related diseases like osteoporosis, coronary heart disease, diabetes, Alzheimer's disease and Parkinson's dis­ease, dementia, cognitive dysfunction and hypema­tremia. Beside the sex hormones other hormonal changes are also known to occur during aging and many common problems encountered in the aging process can be related to neuroendocrine phenomena. Diabetes mellitus is associated with moderate cogni­tive deficits and neurophysiologic and structural changes in the brain, a condition that may be referred to as diabetes encephalopathy; diabetes increases the risk of dementia especially in the elderly. The current view is that the diabetic brain features many symp­toms that are best described as accelerated brain aging. This review presents and compares biochem­ical, physiological, electrophysiological, molecular,

N. Z. Baquer (1:81) · A. Taha · P. Kumar · S. M. Cowsik · R. K. Kale · R. Singh · D. Sharma School of Life Sciences, Jawaharlal Nehru University, New Delhi II 0067, India e-mail: nzbaquer@gmail.com

P. McLean Division of Infection and Immunity, University College London Medical School, London WIT 4JF, UK

and pathological data from neuronal tissue of aging and hormone treated control and diabetic animals to arrive at the similarities among the two naturally occuring physiological conditions. Animal models can make a substantial contribution to understanding of the pathogenesis, which share many features with mechanism underlying brain aging. By studying the pathogenesis, targets for pharmacology can be iden­tified, finally leading to delay or prevention of these complications. Antiaging strategies using hormone therapy, chemical and herbal compounds were car­ried out for reversal of aging effects. Neuronal markers have been presented in this review and similarities in changes were seen among the aging, diabetes and hormone treated (estrogen, DHEA and insulin) brains from these animals. A close correla­tion was observed in parameters like oxidative stress, enzyme changes, and pathological changes like lipofuscin accumulation in aging and diabetic brain.

Keywords Brain aging · Diabetes · Endocrine · Glucose homeostasis · Neuronal markers · Neurodegenerative diseases · Pentose phosphate pathway

Introduction

Aging is the underlying cause of almost all major human diseases, and the optimal treatment for each

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378

and every disease is to prevent or delay the onset of these age related diseases by intervening in the basic process of aging, may be the ideal solution for monitoring/or improving the quality of life. Recently Rattan and Singh (2009) have reviewed and evaluated the scientific basis for developing potential therapies and modes of intervention in the process of aging, with special reference to involving gene therapy, the authors have also discussed the biological under­standing of aging, a well understood problem in biology. Age related neurological disorders like Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM) are conditions that affect a large number of people, both conditions are on the increase and finding novel treatments to cure or prevent them are a major aim in research. AD and T2DM share several molecular processes that underline the respec­tive degenerative development. Disturbance in insu­lin signaling appears to be the main common impairment. Insulin signaling affects blood glucose levels and also acts as a growth factor for all cells including neurons in the CNS. The common patho­logical processes in AD and T2DM have recently been reviewed by Li and Holscher (2007). Harman ( 1956, 1981) was the first to propose free radicals vital role in aging and reported an age dependent decrease in antioxidant defense system. The brain is especially vulnerable to oxidative damage as a result of its high oxygen consumption rate, its abundant lipid content, and relative paucity of antioxidant enzymes as compared to other tissue. The biological system possesses defense mechanism against the removal of reactive oxygen specie (ROS). Endoge­nous reactive oxygen species that are generated from aerobic metabolism are probably the most important causes of age related neuronal damage. Under normal physiological conditions, a balance exists between the production of ROS and the systems antioxidant mechanism. The toxic 0 2- and OH- radicals have been implicated in age related disorders, diabetes and many other disease like cancer, atherosclerosis and others by causing non specific glycation of protein, peroxidation of membrane lipid and cross linking of proteins, causing loss of organelle function and cell death.

Aging of the normal brain is accompanied by changes in its structure, function and metabolism. There are significant gender differences in brain aging e.g., brain atrophy starts earlier in men than

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Biogerontology (2009) I 0:377-413

women (Kaye et al. 1992), however, once started it is relatively more rapid in women, than the age matched men (Takeda and Matsuzawa 1985). These gender differences occur in regions essential to cognitive function and are implicated in neurological disorders. The consequences of aging of the neuroendocrine system have been incriminated in the development of various age dependent conditions such as insulin resistance, osteoporosis, muscular atrophy and abnor­malities of fat deposition. Aging effects the endocrine system by altering endocrine cells, the hormones produced by these cells and hormone receptors or post receptor processes in the target cells (Veiga et al. 2004). The sex hormones androgens, estrogen and progestins are among the peripheral signals that modulate neuronal function and development; they act on the neurons and glial cells regulating differ­entiation, survival and neuronal connectivity both in the brain and spinal cord. They act in the adulthood modulating neurotransmitter synthesis, neurotrans­mitter receptor expression and synaptic transmission and remodeling.

The implication for brain function in aging and diabetes has been reviewed by Biessels eta!. (2002b). Diabetes is associated with moderate cognitive def­icits and neurophysiologic and structural changes in the brain. Emerging view is that the diabetic brain features many symptoms that can be described as accelerated brain aging. Authors have explored and discussed the neurological complications of diabetes focusing on brain particularly the metabolic and pathogenic mechanism, and the possible interactions of diabetes and aging. Aging being the progressive and gradual accumulation of detrimental changes in structure and function over time would also be evident in nervous electrical activity of the brain. Electrical activity will not only be a reflection of the aging of some baseline process of the nervous system but its alteration may contribute to physiological and behavioral changes associated with aging (Nygard et al. 2005)1eading to decrement in neurological function (Singh and Sharma 2005).

In this review an attempt has been made to evaluate and present data highlighting the similarities among physiological; biochemical, electrophysiolog· ica1, and molecular changes associated with aging, diabetes and steroid hormone therapies to aging animal models, also discussing some potential anti aging strategies used.

Biogerontology (2009) 10:377-413

Glucose utilization by the brain

The brain utilizes approximately 20% of all the glucose metabolized by the entire body at rest (Sacks 1965) mainly via the two major alternative pathways of carbohydrate metabolism that is glycolysis coupled to the tricarboxylic acid cycle and pentose phosphate pathway. The largest proportion of glucose consumed is via the energy producing glycolytic and tricarboxylic acid pathway (Fig. 1). The pentose phosphate path­way, although quantitatively a minor route of glucose metabolism, appears to provide essential function in cerebral tissue depending on the stage of development (Baquer et al. 1977) or the region of the brain (Lowry 1964). The role in the brain of the glycolytic pathway and the tricarboxylic acid cycle and the route by which glucose carbons are incorporated into glutamate and GABA (}'·amino butyric acid) through the action of these pathways have been amply reviewed (Baquer

Fig. 1 Interrelationships of pathways of glucose metabolism. The glucose carbon from which the C02

of each pathway originates is shown in brackets. Calculation for each pathway contribution is shown in Table I. Adapted from Baquer et al. (1975)

379

et al. 1977; Balazs 1971; Mcilwain and Bachelard 1985; Himwich 1974; Zubairu et al. 1983).

Pathways of glucose metabolism

The pattern of glucose metabolism in brain during development and aging changes both in enzyme profile (Wilson 1973; Mac Donnell and Greengard 1974; Leong et al. 1981; El-Hassan et al. 1981) and the proportioning of glucose among different path­ways (Baquer et al. 1973, 1975; Zubairu et al. 1983) of its metabolism. Age related changes have been reported to occur in the rate of glucose utilization (Smith and Thompson 1987), oxygen uptake (Peng et al. 1977), lipid synthesis (Mcilwain and Bachelard 1985), and monoamine metabolism (Carlsson et al. 1980; Leong et al. 1981 ). Hence corresponding changes in the pathways of glucose metabolism will occur to meet the shifting requirements of aging

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380 Biogerontology (2009) 10:377-413

Table 1 Alternative pathways of glucose utilization in aging rat brain using differentially labelled 14C substrate

Labeled substrate 20 days 4 months 12 months 26 months % Decrease 26/ 4 months x 100

C02 yields

[1 .14C]glucose 4.41 ± 0.20 4.0 ± 0.22 3.41 ±0.15 2.17 ± 0.05 54

[1-14C]glucose + PMS 31.0 ± 1.8 26.2 ± 0.9 23.0 ± 0.9 13.4 ± 1.1 51

[2-14C]glucose 8.65 ± 0.48 9.07 ± 0.48 6.95 ± 0.43 5.76 ± 0.22 64

[3,4-14C]glucose 15.4 ± 0.70 15.6 ± 0.9 15.8 ± 0.5 11.8 ± 1.1 76

[6-14C]glucose 3.69 ± 0.14 3.26 ± 0.21 3.12 ± 0.08 2.53 ± 0.19 78

[6-14C]glucose + PMS 3.8 ± 0.37 3.5 ± 0.3 2.94 ± 0.17 2.76 ± 0.29 79

[1- 14C]pyruvate 33.2 ± 0.24 27.3 ± 1.5 28.1 ± 2.1 30.9 ± 2.2 113

Pathway estimates

Glycolysis + TCA 4.17 ± 0.50 4.78 ± 0.35 5.06 ± 0.44 4.66 ± 0.6 97 14C02 .... c3,JC6

Pyruvate dehydrogenase 33.2 ± 0.24 27.3 ± 1.5 28.1 ± 2.1 30.9 ± 2.1 113 14C02 .... Py-1

Pentose phosphate pathway (PPP) 0.71 ± 0.13 0.74 ± 0.17 0.30 ± 0.09 0.36 ± 0.10 Not detected 14COz .... C1-C6

Activated + PPP 26.9 ± 2.1 22.3 ± 0.9 20.4 ± 1.1 10.6 ± 0.9 48 14C02 .... C1-C6

Glutamate: GABA pathway 5.17 ± 0.45 6.12 ± 0.37 3.88 ± 0.32 3.23 ± 0.22 53 14COz .... Cz-C6

Biodata

Body weight (gm) 40.8 ± 1.4 396 ± 18 687 ± 13 630 ± 19

Brain weight (gm) 1.23 ± 0.06 2.15 ± 0.14 2.27 ± 0.07 1.92 ± 0.04 Protein mg/g WH 108 ± 8.0 224 ± 19.0 240 ± 26 188 ± 18.0

The values are given in 11moles/g/h and are mean± SEM of 4-6 values. Table derived from Zubairu eta!. (1983) and ail procedures and calculation of pathways are as described there. The PMS concentration was 0.1 mM. Subscripts designate the position of the 14C label in glucose and pyruvate

brain. The pattern of glucose metabolism in the brain of rats has been elucidated in ages ranging from 20 days to adult (Hothersall et al. 1979; Zubairu et a!. 1983). The glucose flux through glycolysis, the tricarboxylic acid cycles, pentose phosphate pathway and glutamate-y-amino butyrate pathway had been carried out by earlier described procedures (Table I).

Experimental approaches to study of metabolic pathways

The nature and metabolic function of the component pathways can be achieved and arrived at by using three different types of experimental approaches each of which contribute a different type of information. These may be summarized.

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a. Enzyme studies which yield information on the presence or absence of enzymes, the maximal potential activity of the enzymes present and the existence or appearance of enzymes of special significance to the tissue, from an analysis of the occurrence of constant and specific proportion enzymes (Pette 1966; Baquer et a!. 1973 ). Such studies can be extended by histochemical inves­tigation of the regional and subcellular location of important enzymes.

b. The measurement of the actual flow of substrates through pathways or segments of pathways (utilizing labeled 14C-substrates) which in com­bination with (a) yield information on the existence of control mechanisms either regulat­ing the flow of such substrates through a pathway

Biogerontology (2009) I 0:377-413

or apportioning substrates between pathways (Zubairu et al. 1983).

c. Measurements of the standing concentration of the metabolic intermediates of pathways usually before and after a particular treatment which pinpoint the location of the control points indicated in (b) and help define the factors which regulate such control points (Exton 1975). Such measurements have been done under ischemia, anaesthesia and hypo and hyperthermia and during intoxication such as fluoroacetate or indoacetate poisoning (Kauffman et al. 1969), ammonia intoxication and 6-aminonicotinamide poisoning (Kauffman 1972; Hothersall et al. 198 I). This approach has also been used in the study of changes in the brain in experimental diabetes and following insulin treatment (Thur­ston et al. 1975). The time sequence according to which the brain taps the reserve supply of energy has been revealed in this way (Lowry 1964 ).

The extension of these approaches to human studies present considerable ethical and technical problems. Isotope studies have been carried out using arterio-venous difference (Sacks 1965). Specialized micro techniques for enzyme determination on microgram quantities of tissue developed by Lowry and his collaborators (Kauffman 1972; Kato and Lowry 1973) may possibly be applied to biopsy samples or the possibility of parallel changes which mirror brain enzyme lesions occurring in other, more readily available cells-such as leucocytes, may pro­vide a useful probe for the study of brain disorders of genetic origin. It is important to note that metabolic derangements can arise not only from enzyme deletions but also from a modification of the control elements regulating enzymes and their pathways.

Elucidation of pathways of carbohydrate metabolism using 14C labeled substrates

The oxidation of differentially labeled glucose pyru­vate, and glutamate measured in brain slices from cerebral hemispheres of aging rat has been studied by Zubairu et al. ( 1983). Pathways calculated using this study over aging from 20 days to adult brain were measured and their contribution calculated.

The glycolytic and tricarboxylic acid pathway, the pentose phosphate pathways and the Glutamate

381

GABA shunt (latter very specific to the brain) have been calculated and the percentage changes over the age span have been shown in Table 1. Results showed that over 4-26 months there was an approx­imately 20% decrease in the production of 14C02 via the glycolytic tricarboxlic acid cycle route, the Glutamate GABA pathway falls by about 50% over this same life span. The broad activity of the pentose phosphate pathways falls rapidly and cannot be detected in the brain of rats aged 18 months or more, whereas the fully stimulated pathway, i.e., in the presence of artificial electron acceptors, phenazine methosulphate decline only marginally over this period. The pentose phosphate pathway is stimulated by the presence of 5-hydroxytyptamine and this stimulation appears to increase with age, the latter effect on the pentose phosphate pathway has been described in detail elsewhere (Hothersall et al. 1982; Table 1).

Pentose phosphate pathway

Baquer et al. (1977) discussed the connection between pentose phosphate pathway activity and the presence of the neurotransmitters, that it could be related either to the process of transmission itself or to the metabolism of the neurotransmitters. It was proposed that the aldehydes produced by the action of MAO on the catecholamine were reduced to the corresponding alcohols by NADPH-linked aldehyde reductase. Baquer et al. (1975) also suggested that NADPH produced by the pentose phosphate pathway also served an additional function, i.e., the protection of membrane lipids, from peroxidative damage resulting from the appearance of the monoamine degradation product hydrogen peroxide. The pentose phosphate pathway does protect the brain from peroxidative damage via the glutamate peroxides and glutathione reductase The significance of the role of pentose phosphate pathway in brain during aging has been reviewed by Baquer et al. (1975, 1988; Fig. 2) the presence of these enzymes in synapto­somes and their linkage with peroxidative mecha­nisms, monoamine oxidase and glutathione pathway suggested that they may be serving an important role in the brain in vivo (Hothersall et al. 1982). Saggerson (2009) in a classic paper series has recently shown that research into the pentose phos­phate pathway has arisen from the realization that

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382

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Biogerontology (2009) 10:377-413

GLUTATHIONE REDUCTASE

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NADPH is essential for the protection of cells against reactive oxygen species through coupled actions of glutathione peroxidase and reductase and that glucose 6 phosphate dehydrogenase gene, through this adap­tivity to oxidants appears to act as a sentinel against potential damage by these agents (Fig. 2).

Glutamate: GABA pathway

The activity of the glutamate: GABA pathway falls sharply between 4 and 8 months and very slowly thereafter (Zubairu et al. 1983), in 26 months the pathway exhibits only about 50% of the activity of the young adult. Calculation of the partition of the oxidation of glutamate through either the TCA or through glutamate decarboxylation (Hothersall et al. 1979; Zubairu et al. 1983), shows that neither of these pathways change appreciably over the time range of 20 days to 26 months, indicating that the inhibitors of the glutamate: GABA route arise earlier in the metabolic sequences, agreeing with the earlier obser­vation (Epstein and Barrows 1969) that glutamate

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phosphate pathways linked to the degradation of biogenic amines by monoamine oxidase (MAO) through the formation of H20 2• Adapted from Baquer et al. ( 1977)

decraboxylase, the rate limiting enzyme of the glutamate GABA pathway, does not change with age (Table 1 ).

Ketone body metabolism

Though we are talking about and discussing the significance of carbohydrate metabolism (mainly glucose), it must, however, be emphasized that the ketone bodies also constitute a major source of energy and substrate for the brain, particularly in periods of high fat utilization, e.g., during suckling of the young, or in the starving or diabetic adult. During such periods changes in the enzymes profile reflect the adaptation to high ketone body utilization (Klee and Sokoloff 1967). Interactions between ketone body and glucose metabolism have also been reviewed (Buckley and Williamson 1973).

By the time adult stage is reached the normal brain uses carbohydrate almost exclusively. This almost total dependence of the brain on the utilization of glucose carries a significant corollary for clinicians

Biogerontology (2009) 10:377-413

investigating nervous disorders, that any major defects in the pathways of glucose degradation are likely to be lethal. It is only in the subsidiary pathways of glucose utilization, or in pathways which partially depend on an aberration could produce a nonfatal condition.

It is clear that a tissue which has so many specialized functions must also have a variety of metabolic pathways which are either unique to the tissue, or of special significance in it, nevertheless it is true that the major pathways of glucose metabolism are the same in brain as they are in other tissues. The importance of these main pathways of glucose utilization and the specialized role they play, how they are controlled and integrated and how these change with development, through the stages of growth and aging myelination and the onset of neurotransmission in the brain have been amply reviewed (Baquer et al. 1975, 1990; Hothersall et al. 1979; Mcilwain and Bachelard 1985). A knowledge of these basic processes is essential to the study of brain disorder and brain aging in which aberrations of certain routes of glucose metabolism may occur.

Developmental changes in carbohydrates metabo­lism and the regulatory features of key control reactions have of necessity been investigated mostly in experimental animals and it is from these sources that our main evidence on the detailed biochemical knowledge of the regulation of glucose metabolism in the brain has come.

Age related changes in brain parameters

Enzyme changes in whole brain

The effect of aging on brain enzymes has been studied by many investigators (El-Hassan et al. 1981; Hothersall et al. 1981; Zubairu et al. 1982; Baquer et al. 1990; Kaur et al. 1998, 200 I, 2003; Kaur and Lakhman 1994 ). Measurements had been made of the enzymes of the glycolytic, pentose phosphate and lipogenic pathways and some marker enzyme of TCA cycle in brains of rats between 20 days and 24 months. In general, the activity of most enzymes remained unchanged; except that there was an

. increase of hexokinase, glucose-6-phospahate dehy­drogenase and malic enzyme and decrease of A TP citrate-lyase, acetyl Co-A carboxylase and fatty acid

383

synthetase (El-Hassan et al. 1981 ). The enzymes of glutathione metabolism and NADPH generation showed a differential pattern, controlling the redox state of the brain, the role of glutathione related enzymes in controlling the hydrogen peroxide metab­olism and suppressing peroxidative damage to the brain was discussed (Hothersall et al. 1981 ). The flux of glucose in the pathways of acetyl group formation and disposal and the activities of a range of enzymes related to these were measured in aging rats up to 24 months. The pattern of enzyme changes in system involving hydrogen transfer system appears to increase disproportionately relative to the glycolytic flux in the brain. Results suggested that these increases are an essential corollary to the need for a maintained glycolytic flux in a tissue dependent upon glucose as a fuel and one in which alternative routs of NADPH oxidation diminish with age (Zubairu et al. 1982; Baquer et al. 1988).

Synaptosomal and membrane linked enzymes

Baquer et al. (1988, 1990) had studied a number of soluble and membrane associated enzymes of gly­colysis, pentose phosphate pathways, and other related enzymes from three different brain regions of aging animals and enzymes utilizing and synthe­sizing peroxides. Increasing levels of peroxidative products are known to accumulate in the brain with age. The membrane associated enzymes were found to be the primary focus of damage. Phosphofructo­kinase and glucose 6 phosphate dehydrogenase exhibited an unusual pattern when measured in whole homogenates. A progressive decrease in the synap­tosomal bound hexokinase was found with increasing age. The synaptosomal phosphofrucktokinase also showed a significant decrease with aging. Significant decrease in the incorporation of myoinositol into phospholipids and a loss of activity of membrane bound adenylate cyclase must be occurring in the structure of the brain and the loss of cerebral competence in the senescent brain may arise from peroxidative damage to membranes (Table 2; Fig. 3).

Baquer et al. (1990) had shown a clear decrease in myoinositol incorporation into phospholipids with aging. The result was important since it is known that phospholipids are the most rapidly renewed components of the nerve sheath, that they bind Ca2+, one of the source of fatty acid precursors of the

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Table 2 Effect of aging on glycolytic NADP linked and other membrane linked enzymes in rat brain cerebral hemispheres

Myoinositol incorporation is given as pmoles/glh at 37°C. Values are given as mean SEM each group not less than six. Detail described in Baquer et al. (1990). Units are 1-1 moles substrate converted per minutes at 25°C, with the exception of adenylate cyclase which is in nmoles/ g/min/g/min

WH whole homogenate

Fig. 3 Synaptosomal enzymes in Aging rat brain cerebral hemispheres. Percentage changes in the activities of NADP linked, glycolytic and membrane associated enzymes from synaptosomes prepared from cerebral hemispheres of aging rat brain taking 20 days old as 100%. Figure derived from Baquer et al. (1990)

Enzymes

Glycolytic

HK

PFK

Gly-3-P-D

Membrane linked

Na+K+ ATPase

Adenylate cyclase

Myoinositol incorporation

Glutamate dehydrogenase (NAD)

NAPD-linked

G 6 P dehydrogenase

6 P G dehydrogenase

Malic enzyme

Glutamate dehydrogenase

Antioxidant

Glutathione peroxidase

Glutathione reductase

Biodaw

Brain weight (CH)

Protein (mg/g)

Whole homogenate

Synaptosomes

so

Biogerontology (2009) 10:377-413

Age (months) (~ moles/g/min)

0.7 6 12 30

11.5 ± 0.3 18.6 ± 3.1 18.5 ± 1.9 16.8 ± 1.5

17.54 ± 1.55 18.75 ± 1.4 21.03 ± 1.4 18.8 ± 2.8

0.93 ± 0.15 1.42 ± 0.3 1.78 ± 0.21 2.03 ± 0.09

15.3 ± 0.15 10.3 ± 2.3 11.3 ± 4.5 11.5 ± 1.6

68.9 ± 7.5 87.7 ± 13.2 84.0 ± 16.0 75.4 ± 1.0

4.34 ± 0.64 2.71 ± 0.3 1.75 ± 0.14 1.06 ± 0.11

28.5 ± 8.0 36.3 ± 7.0 62.3 ± 9.0 32.0 ± 2.8

1.11 ± 0.1 1.3 ± 0.07 1.21 ± 0.05 1.2 ± 0.08

0.75 ± 0.06 0.55 ± 0.07 0.75 ± 0.09 0.60 ± 0.07

0.97 ± 0.08 1.51 ±0.12 1.55 ± 0.09 1.78 ± 0.03

22.3 ± 2.6 25.6 ± 2.5 23.3 ± 6.8 15.0 ± 1.4

1.4 ± 0.14 1.93 ± 0.13 2.22 ± 0.19 4.23 ± 1.39

0.98 ± 0.07 1.06 ± 0.13 1.18 ± 0.15 1.63 ± 0.21

0.99 ± 0.02 1.28±0.12 1.25 ± 0.04 1.38 ± 0.1

76.3 ± 3.3 82.3 ± 4.1 78.5 ± 3.2 61.0 ± 5.0

16.3 ± 4.9 19.4 ± 2.8 24.5 ± 3.6 17.0 ± 2.0

2Sil

12 18 24 200AV$ 6 12 18 24

AGE (monthS)

prostaglandin and are associated with transport phenomenon. This fall in the myoinositol incorpora­tion would be reflected in changes in the structure and fluidity of the membranes (Mantha et al. 2006) and hence would produce wide spread changes in aspects of nerve behaviour.

The formation of C' AMP by adenylate cyclase is one of the key steps in neurotransmission and has been

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AGE (monthS!

implicated as an essential step in the mechanism of action of noradrenalin and dopamine and to a lesser, but still important extent of serotonin. The decrease in the activity of adenylate cyclase with age is notable in the cerebral hemispheres, but is very large in the cerebellum and the brain stem, latter not shown in Table 2 (Greengard and Kebabian 1974; Baquer et al. 1983, 1990; Hothersall et al. 1983; Table 2).

Biogerontology (2009) 10;377-413

Earlier work and ample evidence has shown that peroxidative damage to lipid and protein occurs with the aging process and the products of these reactions accumulate in the brain with age (Bondereff 1964; Mann and Yates 1974; Davison and Wright 1980; Baquer et al. 1990; Moorthy et al. 2004a, 2005a, b; Bala et al. 2006; Sinha et al. 2005, 2008).

The changes observed in the activity of enzymes in isolated synaptosomes seemed to be more severely affected with aging in brain region. These changes (decrease) could be due to the extreme complexity of brain structure and the compartmentalization of vari­ous modulators for enzyme activities. For example the concentration of the allosteric activator of phospho­fructokinase, namely fructose 2, 6, bisphosphate may decrease with age, or it may be in some other cellular compartment, unavailable to the enzyme. The concen­tration of glucose-6-phosphate or NADPH may also modulate hexokinase and glucose-6-phosphate dehy­drogenase activities, respectively (Fig. 3).

The significance of the pentose phosphate dehy­drogenases in brain fractions has been discussed in detail in earlier section of the review (Baquer et al. 1975, 1977, 1988). Among the factors that could be important in relation to the apparent age-related decrease in the activity of the pentose phosphate pathway are two prominent ones (1) possible decrease in the activity of hexokinase and the two oxidative enzymes of the pathway glucose-6-phos­phate dehydrogenase and 6 phosphogluconate dehy­drogenase (2) a decrease in the availability of NADP. The synaptosomal hexokinase also decreased with aging (Fig. 3). The flux through the pathway may also be decreased or shut off by increase in the concentration of NADPH, a very strong inhibitor of the two pentose phosphate pathway dehydrogenases since three systems utilizing NADPH, i.e., the lipogenic route: glutamate, GABA synthesis and antioxidant system (glutathione) are depressed with aging, leading to a concomitant fall in the expressed activity of the pentose phosphate pathway (Hothersall et al. 1981; Zubairu et al. 1983; Table l ).

Changes in membrane linked en?ymes with age

As lipid and protein are essential components of membranes, a change in the enzymes linked to membrane may occur during the aging process. Baquer et a!. (I 990) measured membrane linked

385

enzymes, namely adenylate cyclase, synthesizing C' AMP, involved in neurotransmission in the brain (Greengard and Kebabian 1974) and Na+K+ ATPase (Baquer et al. 1990; Moorthy et al. 2004a, 2005a, b; Siddiqui et al. 2005) both enzymes controlling the polarization of neurons.

A number of glycolytic and other soluble enzymes were found to be bound to the membrane (Baquer et al. 1975, 1990). It has been reported (Svoboda and Mosinger 1981) that the microsomal brain Na+K+ ATPase can be selectively inactivated by an endog­enous system (Ascorbic acid and Fe2+) which appears to act via a mechanism identical with the free radical induced phospholipid peroxidation. Sim­ilar results had been reported by Sun and Samorajiski (1975). This conclusion together with the results of Logan and George 1982, Logan and Newland 1982 and Logan et al. (1982) on the catecholamine inhibition of Na+K+ ATPase elucidates and shows changed neurotransmitter sensitivity with age.

Moorthy et al. (2005a, b) and Mantha et al. (2006) had also shown that the activity of AChE decreased with increasing age in different regions of the brain and also in peripheral nerve. The decline in the activity of the enzyme in old age may be due to loss of neuron/or a decrease in protein synthesis and a decrease in the number of synapse with aging, making synaptic transmission less effective (Table 3).

The role of the enzyme acetyl choline esterase (AChE) has been recently reviewed in the nervous system and other tissues. AChE inhibitors have been clinically used in neurodegenerative disease (Tripa­thy and Srivastava 2008). These disorders are neu­romuscular disorders like Myasthenia Gravis and glaucoma, and the cholinergic deficient glaucoma associated with AD. Clinically, moderate inhibitors of AChE are given in the treatment of these diseases to prolong the effect of acetylcholine (ACh) on the receptor, such treatments are desirable either if there is reduced concentration of ACh, as shown in AD, or if there are fewer receptors for acetylcholine as in the case of Myasthenia Gravis.

Mantha et al. (2006) also showed changed neuronal markers with aging in female rat brain synaptosomes. AChE and Na+K+ ATPase activity in synaptosomes decreased with age as compared to young rats. A decreased activity of Na+K+ ATPase with aging has been reported in female rat brain synaptosomes and its significance discussed (Fraser and Arieff

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386 Biogerontology (2009) I 0:377-413

Table 3 Changes in neuronal markers in aging brain cerebral hemispheres

Age/treatment AChE SOD GOT GPT MDA Na+K+ ATPase

3 months

Control 75.1 ± 2.2 8.64 ± 0.64 38.66 ± 2.79 68.73 ± 4.05 0.23 ± 0.03 9.03 ± 0.12

12 months

Control 43.1 ± 2.6 5.12 ± 0.04 32.91 ± 1.56 48.67 ± 3.21 0.30 ± O.ot5 3.59 ± 0.22

C+E 52.6 ± 2.1 7.69 ± 0.09 27.9 ± 3.9 27.01 ± 3.9 0.22 ± 0.25

C+E+P 55.5 ± 1.9 8.82 ± 0.8 23.05 ± 1.3 25.21 ± 3.5 0.20 ± 0.30

18 months

Control 30.0 ± 1.1 3.03 ± 0.55 24.37 ± 1.06 30.95 ± 2.6 0.40 ± 0.035 0.97 ± 0.18

C+E 36.9±1.8 6.94 ± 0.4 21.56 ± 1.43 22.15 ± 3.2 0.29 ± 0.025

C+E+P 40.1 ± 1.9 7.15 ± 0.6 17.56 ± 1.6 17.83 ± 2.7 0.25 ± 0.02

24 months

Control 24.0 ± 1.1 1.86 ± 0.2 20.98 ± 1.25 23.93 ± 2.11 0.45 ± 0.028 0.61 ± 0.03

C+E 29.9 ± 1.3 3.56 ± 0.36 16.59 ± 1.41 18.12 ± 2.7 0.37 ± 0.02

C+E+l> 33.1 ± 2.2 4.28 ± 0.41 14.75 ± 1.07 16.93±3.05 0.34 ± 0.31

Effect of estradiol and progesterone. Each value is a mean SEM of six or more values. The concentrations of MDA are given as nmoles/mg protein. Units are defined as AChE is micro-units/mg protein and SOD as mu/mg protein. GOT and GPT are defined as described in Moorthy et at. (2005a, b)

E estrogen, P progesterone

2001). A decreased Na+K+ ATPase activity with age could result in neurotoxicity resulting in neuronal vulnerability to excitotoxic insults to the neuronal cells. The authors also showed changes in the fluidity of membrane lipids during aging and lipid peroxida­tion. Vitorica and Satrustegui (1986) had earlier evaluated the influence of an altered lipid phase in rat brain mitochondria with aging. Changes in neuro­nal markers with aging have been presented in Table 3.

Changes in membrane structure with aging

The changes in myoinositol incorporation, showing a clear decrease in the myoinositol incorporation into phospholipids with aging and the loss of activity of adenylate cyclase with aging indicate that changes must be occurring in the structure of the brain membrane, particularly the integrity of the membrane associated hormone binding site and the linking of these sites to their effectors system in the membrane in aged rats, can these deleterious effects be pre­vented? For example, by dietary regime or hormonal administration to aging animals to suppress formation of free radicals. Moorthy et al. (2005a) have shown that administration of estradiol and progesterone

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reverse some of the aging effects in older animals. Mantha et a!. (2006) had shown the changes in membrane fluidity in synaptosomes with age. Effects of estrogen and DHEA administration have recently been shown on aging brain in female and male aging animals (Moorthy et al. 2004b; Kumar et al. 2008; Sinha et al. 2008; Tables 3, 6).

Aging and effect of hormone interactions, peptide and steroid

Aging is an important event in the life of mammals, including human beings, during which a number of metabolic and hormonal changes take place. In the female rat the concentration of circulating hormones, estrogen (E2) and progesterone (P) decrease with age (Lapolt et al. 1988; Moorthy et a!. 2005a; Fig. 4) leading to various health problem such as diabetes, cardiovascular complications, osteoporosis and oth­ers. Veiga et al. (2004) have reviewed the changes in the sex hormones and brain aging, and the authors have discussed the role of these hormones in modulating neurotransmitter synthesis, neurotrans­mitter receptor expression and synaptic transmission and remodeling, emphasizing that the nervous system

Biogerontology (2009) I 0:377-413

Fig. 4 Estradiol and progesterone levels in aging 80 female rats. Levels of Estradiol and progesterone 70 in different stages of 3, 12, e 60 18 and 24 months old rats. -Each value is a c::n

mean ± SEM of six c. 50 .5

separate values. Table c adapted from Moorthy et al. 0 40

"(i; (2005b) ... ....

30 c Cl) () c 20 0 u

10

0

20

18

~ 16

14 c::n c .5 12 c 0 10 :; ... 8 .... c Cl)

6 () c 0 4 u

2

0

is a target for sex hormones and a source of sex steroids (Koricanac et al. 2004; Table 5).

The physiological variations in the concentration of sex hormones could affect the insulin receptor action and their interaction with glucose, thereby altering the carbohydrate metabolism (Valdes et al. 1991 ). Various clinical and experimental data suggest that insulin and sex hormones interact and affect the carbohydrate metabolism. The rate of glucose trans­port into the cells is regulated by both peptide and steroid hormones, IRS-1, insulin receptor substrate is down regulated with a high concentration of 17 p estradiol in menopausal women which could be responsible for the upregulation of IRS-1, increasing insulin sensitivity in muscle and adipose tissue, Glut 1 is the glucose transporter expressed in most of the tissues including uterus, the largest being in brain

387

Estradiol

1§11 Proestrous fiDEstrous

I! Metaestrous

[J Diestrous

ID12 months

818 Months

18124 Months

Progesterone

il Proestrous fiDEstrous

EIJMetaestrous

[]Diestrous

ID12 months

ei18Months

18124 Months

cells (Roy and Jack 1999). Earlier report on the effect of age and insulin showed that pancreatic insulin secretion at the plasma membrane level is impaired in older animals probably regulating the flux of glucose into the brain, thus affecting glucose metabolism (Draznin et al. 1985).

Variations in the physiological concentration of E2 also control and regulate the glycolytic pathway required for the additional energy and/or metabolites for the neurotransmitters (Fig. 4). Thomas et a!. (1986) had previously reported that the serum insulin and glucose levels were increased by E2 administra­tion and combined treatment of estrogen and proges­terone, when compared with the ovariectomy and intact groups. Reduced glucose uptake has been shown to occur early in AD prior to neuronal degeneration (Jay et al. 1994 ). The decreased rate of both glucose

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388

and ketone body utilization have been observed in aged brain, but energy requirement remains the same when compared with young animals (Smith et a!. 1987; Mcilwain and Bachelard 1985). The decreased utilization of glucose in the brains of AD patients may be related in part with reduction in the activity of enzymes related to acetylcholine synthesis, the sensi­tivity of this transmitter to dysfunction of glucose metabolism has been reported (Dash et al. 1991; Gupta et al. 1992a). Changes in acetylcholine esterase activity have been shown to occur in brain of diabetic and aging animals (Khandkar et a!. 1995; Moorthy et al. 2005a, b; Mantha et al. 2006; Table 4).

Meier-Ruge et a!. (1984) have reported signifi­cantly lower levels of activity of glycolytic enzymes HK and PFK in sample taken from patients with confirmed Alzheimer's disease compared with age matched control subjects. Dena and Phyllis (200 1) have reported that estradiol plays a neuroprotective role in the injured brain of both young and middle aged rats and data suggest, as reported by Moorthy et a!. (2004b) also, that older women might also benefit from the protective effects of HRT(hormone replacement therapy) that uses a relatively lower concentration of hormones. Keller et a!. (1997) have demonstrated that estradiol can directly act on the synapse and protect critical membrane transport systems from oxidative impairment particularly Na+K+ ATPase. Steroid hormones are also known to affect the sensitivity of cells to insulin.

Estrogen has been shown to rapidly activate several components of signal transduction pathway including those associated with glucose transport translocation, such as MAP Kinase (Morley et al. 1992; Aronica et al. 1994; Migliaccio et al. 1996). Results of Moorthy et a!. (2004b), showed that treatment of older rats with estrogen/progesterone alleviate the glucose transport in the tissues of older rats treated with the hormone. Results showed (Moorthy et a!. 2005a) that the hormone levels used are at lower doses, than that given for HRT treatments. The amount of estrogen levels taken were equivalent to those found in 3 months old, adult rat (Fig. 4). Estrogen and combined, estrogen and pro­gesterone given to aging rats caused a series of growth related responses, such as increase uptake of glucose, increased protein levels, increased glucose oxidation and decreased gluconeogenesis (Birge 2003; Veiga et al. 2004).

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Effect of aging and estrogen on neuronal enzymes

Oxidative stress and neuronal damage in aging

Brain is susceptible to oxidative stress which is associated with age related brain dysfunction, due to its high content of key compounds for oxidative damage and the relevant scarcity of antioxidant defense systems (Poon et a!. 2006). Protein oxidation, which results in functional disruption, appears to be associated with increased oxidation in specific pro~ teins and has been implicated in the progression of aging and age related neurodegenerative disorders such as AD. Protein carbonyls, a marker of protein oxidation are increased in Alzheimer's brain (Caste­gna et al. 2002; Poon eta!. 2006). Oxidative damage can lead to several events such as loss in specific protein function, abnormal protein clearance, deple­tion of cellular redox-balance and interference with the cell cycle and ultimately to neuronal death. Further it has b~en reported that creatine kinase BB and {J-actin are specifically oxidized in Alzheimer's brain. However, recently the powerful technique, emerging from application of proteomics to neuro­degenerative disease, revealed the presence of spe­cific targets of protein oxidation in Alzheimer's brain: creatine kinase BB, glutamate synthase and ubiquitin carboxy terminal hydrolase L-1 (Castegna et a!. 2002; Sultana et a!. 2006; Butterfield and Castegna 2003; Butterfield et al. 2006).

Recently it was shown that in aging tissues from female and male animals the oxidative stress increases due to decreased activity of antioxidant enzymes and proteolysis increases due to decreased activity of aminotransferase (Moorthy et al. 2005a, b; Sinha et a!. 2005; Bala et al. 2006). Oxidative stress as well as gene expression profile has been identified as causal factors in the aging process (Harman 1981; Ames et al. 1993; Sohal et al. 2000).The brain is especially vulnerable to the oxidative damage as a result of its high oxygen consumption rate, its abundant lipid content and the relative paucity of anti-oxidant enzymes compared to other tissues. The effect of estrogen and DHEA on aging brain enzymes are presented in (Tables 3, 6).

Endogenous reactive oxygen species (ROS) that are generated from aerobic metabolism are probably the most important cause of age related neuronal damage. ROS are continually produced within the

Biogerontology (2009) I 0:377-413 389

Table 4 Changes in cerebral enzymes in experimental diabetes: effect of insulin

Enzyme/pathway Control Diabetic Diabetic + Insulin Reference

Carbohydrate metabolism

Hexokinase (T)

(a) Brain 5.8 4.59 8.59 Ali et at. (1980a) and Sochor et at. (1990)

(b) Sciatic nerve 0.87 0.60 0.76 Preet et at. (2005)

Phosphofructokinase 11.6 10.4 11.5 Srivastava and Baquer (1984)

Pyruvate kinase 67 75.2 66.5 Srivastava and Baquer (1984)

Lactate dehydrogenase 39.5 42.1 40.1 Ali et at. (1980a), Mohamad et at. (2004)

Pyruvate dehydrogenase (T) 1.26 1.04 1.08 Murthy and Baquer (1980)

Glucose-6-phosphatase" 0.4 0.45 0.46 Kaur (unpublished, 1983)

Fructose I ,6 diphosphatase" 0.27 0.38 0.36 Kaur (unpublished, 1983)

Amino acid metabolism

Ornithine decarboxylase 0.183 0.086 Sochor eta!. (1977)

Arginase 54 83 42.2 Murthy et a!. (1980)

Creatine kinase 2.98 1.82 2.89 Genet et a!. (2000)

Glutamate dehydrogenase (NADP) 100 50 160 Ali et at. (1980b)

Neurotransmitter/membrane associated

Monoamine oxidase• 41.6 48 40.5 Mayanil eta!. (1982a)

Na+K+ ATPase" (~-tmollmg protein) 2.05 1.46 2.01 Siddiqui et al. 2005

Acetylcholine esterase 2.6 1.7 2.0 Dash et al. (1991)

NADH oxidase 45 62 63 Askar and Baquer (1994)

Insulin receptor

Insulin receptor kinaseb 2.50 4.21 3.80 Gupta et a!. (1992b)

Insulin degrading enzyme• 0.41 0.43 0.44 Azam et al. (1990a)

Insulin receptorsd

(a) Brain 0.54 0.45 0.64 Azam et al. (1990b)

(b) Choroid plexus 0.53 0.051 0.140 Ansari et al. (1993)

Malate aspartate shuttle

(a) Alanine aminotransferase

Soluble 1.01 1.18 0.98 Kazmi and Baquer (1985)

Particulate 1.03 1.21 1.10 Kazmi and Baquer (1985)

(b) Aspartate aminotransferase

Soluble 32 28.5 27.6 Kazmi and Baquer (1985)

Particulate 50 51 43 Kazmi and Baquer (1985)

(c) Malate dehydrogenase

Soluble 230 238 219 Kazmi and Baquer (1985)

Particulate 206 173 159 Kazmi and Baquer (1985)

Catecholamine levels (nglg tissue)

(a) Epinephrine 17.3 23.0 19.0 Gupta et at. (1992a)

(b) Norepinephrine 190 290 210 Gupta et al. (1992a)

(c) Dopamine 206 390 323 Gupta et al. (1992a)

Hexose monophosphate pathway 14C02 _. C-t-C-6c 0.95 0.80 0.85 Sumathy (unpublished 1988)

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Table 4 continued

Enzyme/pathway

Glutamate-GABA pathway 14C02 -+ C-2-C-6c

Antioxidant enzymes/metabolites

Glutathione peroxidase

Glutathione reductase

Catalase•

Superoxide dismutase•

Malondialdehydec (lipid peroxidation)

Control Diabetic

0.21 0.13

1.16 2.52

0.96 1.30

4.99 3.0

8.63 6.5

0.228 0.350

Biogerontology (2009) I 0:377-4 I 3

Diabetic + Insulin Reference

0.15 Sumathy (unpublished 1988)

1.21 Siddiqui et al. (2005)

1.03 Taha (unpublished 2006)

4.29 Siddiqui et ~1. (2005)

8.26 Siddiqui et al. (2005)

0.280 Genet et al. (2002)

Units: J.imoles/gm tissue, a J.imollmg protein, b cprniJ.ig protein, c nmoles/mg protein, d nglmg protein, • fmol/mg. The hexosemonophosphate shunt and Glutamate GABA pathway are estimated using 14C-labelled substrates and 14C02 measurements as described in Table I. The table is derived from values in the respective reference as given

Ttotal

body from normal oxidative metabolism. Sources of ROS are mainly the mitochondrial electron transport chain, and also the arachidomic acid cascade or nitric oxide (Miguel 1992). During evolution living organ­isms have been found with the compulsion to inactivate these free radicals, and they have devel­oped several ways to protect themselves from oxida­tive attacks. These defense mechanism include a variety of anti-oxidant enzymes like superoxide dismuatase (SOD) or glutathione reductase, which catalyze the NADPH-dependent reduction of gluta­thione disulfide (GSSG) oxidised form, to glutathione (GSH) reduced form. This reaction is essential for the maintenance of glutathione levels.

Glutathione itself plays a major role as a reductant in detoxification (Carlberg and Mannerik 1985). Leutner et al. (2001) have studied in detail the formation of ROS, lipid peroxidation and anti­oxidant enzymes Cu-Zn-superoxidase dismutase and glutathione reductase activities and found that the two enzymes increased in brain with age, whereas glutathione peroxidase remained unchanged. The group also showed that the basal levels of LPO (lipid peroxides) measured as malondialdehyde increased gradually with a significant delay in mouse brain homogenate. There was a significant delay in the time course of ROS generation in brain cells from old mice. Similar results have also been reported in brain aging in female and male rats (Moorthy et al. 200Sa, b; Bala et al. 2006; Sinha et al. 2008).

A clear pattern emerges when analyzing the relationship between the aging process and the gen­eration and detoxification of oxygen free radicals.

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Oxidative stress develops when the well regulated balance between pro-oxidant and protective antioxi­dant gets out of control, this seems to happen in the brain of aged mice even if the activities of anti-oxidant enzymes SOD and OR are considerably increased. Any imbalance between pro-oxidant and antioxidant factors can lead to a chronic accumulation of damag­ing effects like lipid peroxidation (Leutner et al. 200 l ).

Antioxidant status in aging: effect of hormones

It can be reiterated that oxidative stress is one of the most important mechanisms behind age related changes in anti-oxidative enzymes and increased apoptosis in aged rats (Kokoszka et al. 200 l ). Most of the evidences indicate that SOD contributes in the protection of cells from oxygen toxicity by catalyzing the dismution of oxygen and it can be modified by sex hormones in various tissues. Results of Pajovic et al. (1993); Laloraya et al. 1989; D' Almeida et al. (1995) showed that the activity of SOD (Mn) is increased in the brains of proestrous rats, indicating that estradiol and progesterone can modulates the activity of SOD in tissues through its receptors. In aging the levels of estradiol and progesterone were reduced as compared to the normal cyclic rats, therefore, aging rats treated with estradiol and progesterone can reduce or delay the burden of free radical induced aging disease as shown by Moorthy et al. (2005a, b; Table 3). Beside the sex hormones other hormonal changes are also known to occur during aging. As reported by Rehman and Masson (2001) many common problems encountered in the

Biogerontology (2009) I 0:377-413

Table 5 Changes in the levels of hormones/re~;eptors with aging

Hormone/receptor Change

Increase Decrease None

Dopamine + Dopamine receptor 1 + + Dopamine receptor 2 + Monoamine oxidase A + + Monoamine oxidase B + Noradrenaline + Serotonin + + y-Aminobutyric acid + Muscarinic receptor + Nicotinic receptor + Choline acyltransferase + {3-Endorphin + IX-Melanocyte-stimulating hormone - + Adrenocorticotrophic hormone + /3-Lipotropin + Follicle stimulating hormone + Luteinising hormone + Inhibin + Testosterone + + Luteinizing hormone-releasing +

hormone

Aldosterone + Growth hormone + Insulin + Thyroid stimulating hormone + + Thyroxin + Tri-iodothyronine + Antidiuretic hormone + + Oxytocin + Prolactin + + + Melatonin +

aging patients can be related to neuroendocrine phenomena (Table 5). These include AD, dementia and cognitive dysfunction, depression, Parkinson's disease, hyponatraemia and the post menopausal increase in both vascular risk and osteoporosis.

Effect of aging on the neuroendocrine system

The consequences of aging of the neuroendocrine system have been incriminated in the development of various age dependent conditions such as insulin

391

resistance, osteoporosis, muscular atrophy and abnor­malities of fat deposition. Aging affects the endocrine system by altering endocrine cells, the hormones produced by these cells and hormone receptors or post receptors processes in the target cells. Rehman and Masson (2001) have reported some of the changes in the hormones and their receptors and elaborated the effects of aging on the hypothalamic neuroendocrine system in detail. Age related deficits in neurotransmit­ters may be functionally important in relation to compensatory capability in response to pharmacolog­ical challenges. Authors concluded that aging results in a decline in neuroendocrine function, strength and quality of life. Changes in hormone levels and receptors are summarized in Table 5 and Fig. 4.

Alterations in electrophysiological parameters with aging

Electrical signals and action potential

The processing of information in the brain (such as sensory detection, higher mental functions, and consciousness) has its basis in electrical signals produced by changes in voltage across the plasma membrane of particular collections of neurons (Fain 1999). Even during neural development, electrical activity occurring in the developing brain guides the formation of neural connections (Aamodt and Con­stantine-Paton 1999). Electrical activity of the ner­vous tissue (synaptic potentials, action potentials, membrane potentials, single channel current, poten­tiation and depression, electroencephalogram etc.) thus may reflect intricacies of a variety of physio­logical, biochemical and behavioral phenomena. Thus relationship between neural function including cognitive function and brain electrical activity are of considerable importance in the objective assessment of normality or impairment of neural function including intellectual function (Pelosi et al. 1992).

Aging being the progressive and gradual accumu­lation of detrimental changes in structure and functions over time would thus also be evident in nervous electrical activity. Electrical activity will not only be a reflection of the aging of some baseline processes of the nervous tissue but its marked alteration may contribute to physiological and behavioral changes associated with aging. For example, alteration in the pattern of

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firing spontaneous action potentials in the suprachias­matic nucleus neurons in old age may disturb endog­enous biological rhythm (Nygard et al. 2005), and increased action potential firing rate in prefrontal cortex of aged subjects appeared to be associated with age-related prefrontal cognitive dysfunction (Chang et al. 2005). Changes occurring with aging in neuronal electrophysiologcal parameters such as action poten­tials, synaptic potentials, spontaneous field potentials (EEG), multiple unit and unit activities constitutive electrophysiological aging of the nervous tissues, these alterations would signify aging-related impairment and disorganization of electrical signals leading to decrement in neurological functions (Singh and Shar­ma 2005). Since information in the nervous system is conducted and integrated as electrical signals, the disorganization of electrophysiological activity would result in derangement of neural functions. For exam­ple, deficiency of, or absence of synchronous action potential bursts may alter presynaptic neurotransmitter release consequently influencing synaptic plasticity and information processing (Apartis et al. 2000; Lisman 1997). The decline in spontaneous multiple unit activity with age can be considered as a measure of neuronal impairment and thus as an important param­eter of elctrophysiological aging.

The resting membrane potential of neurons is generally not affected by normal aging (Frolkis et al. 1984; Potier et al. 1992, 1993; Chang et al. 2005) after it has acquired its normal value during early postnatal days (Zhang 2004 ). The synaptic resting membrane potential, however, exhibits decrease with aging (Tanaka and Ando 1990). A significantly increased input resistance was found in aged monkey's hippocampal granule cells compared with cells from the young monkeys (Luebke et al. 2004 ). Elevated input resistance was also observed in aged monkey's layer 2/3 pyramidal cells of the prefrontal cortex (Chang et al. 2005).

The action potential is a membrane event consist­ing of a series of sequential transient changes in the membrane potential: threshold, a rising phase (spike), a falling phase (overshoot-amplitude) and an after hyperpolarization. These changes (components of the action potential) occur over a small period of time that constitute the duration of the action potential. Some components of the action potential are affected by the aging process. For instance, while the action potential amplitude generally shows no age change, the spike duration may be enhanced with aging (Barnes and Me

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Naughton 1980; Potier et al. 1992). After hyperpo­latlzation following a single spike may not show an age-related change, but the afterhyperpolarization following a burst of spikes may exhibit age-related changes (Potier et al. 1992): repetitive action potential firing rates were significantly increased in aged cells, which may be responsible for age-related prefrontal cortex dysfunction. The rhythmic bursting activity appears to be necessary for memory and attention purposes. Interestingly, while the rhythmic bursting activity is impaired by aging, the nonrhythmic activity is not affected by aging (Apartis et al. 2000). Some neurons are endowed with the ability to change their pattern of firing action potentials during different states of arousal. Those neurons, which fire nonrhyth­mically during slow wave sleep, adopt burst-firing patterns during waking and rapid eye movement sleep. This functional plasticity (ability to shift from one pattern of activity to the other), however, may decrease with aging (Apartis et al. 2000).

Structural changes in synapses and neurotransmitter sensitivity with age

Structural and neurochemical alterations in synapses during aging, which may have profound effects on synaptic transmission, are potential candidates for age-related impairment of brain function and cogni­tion (Monti et al. 2004; Marrone et al. 2004). The synaptic resting membrane potential decreases with aging (Tanaka and Ando 1990). Postsynaptic poten­tials (both excitatory and inhibitory) which are produced upon excitation of the postsynaptic mem­brane by neurotransmitters may exhibit age-related changes. Normal aging is likely to involve decreased synaptic excitation and increased synaptic inhibitory processes that may contribute to age-associated cognitive impairment (Luebke et al. 2004), postsyn­aptic potentials were decreased in aged rats.

Alterations in postsynaptic potentials (responses) will depend on the presynaptic neurotransmitter release mechanism, and on the number of binding sites (receptor density). In age-associated synapse elimination without pre and post synaptic death, there is a loss of synaptic input in cells, and in such cases in aged individuals there is an attenuation of EPSP amplitude together with an attenuation of both the amplitude and frequency of miniature excitatory postsynaptic potentials (Coggen et al. 2004).

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The postsynaptic sensitivity to neurotransmitters may be affected in aged subjects, and as a conse­quence the inhibitory and excitatory postsynaptic potentials (IPSP and EPSP) are likely to show age­related alterations. Changes will depend upon the number of binding sites (receptor density) available and presynaptic release mechanisms (Shen and Barnes 1996; Taylor and Griffith 1993). An age­related decrease in the amplitude and duration of y-amino butyric acid (GABA)-related IPSP was found in CA I neurons in three strains of rats although glutamate-related EPSP's were not significantly altered in aged rats (Potier et al. 1993). Aged synapses may also show deficient synaptic plasticity (impaired long-term potentiation) (Almaguer et al. 2002).

Changes in excitability and molecular mechanism of aged neuron

Molecular mechanisms of electrogenesis are complex and involve ion movements through membrane channels and pumps. At synaptic junctions interac­tion of neurotransmitter molecules with their recep­tors precedes generation of postsynaptic potentials. The membrane pumps, channels, receptors and protein molecular entities are a part of the biological structure and functional organization. Therefore, alteration in molecular functions resulting from changes in genetic expression/genes may be causal to changes in electrophysiological signals. Because channel currents contribute to action potential gener­ation, age-related alterations in the genetic expression of channels (number of channels) and their subunit composition (Murchison and Griffith 1995) may affect action potential signaling. Molecular changes are well documented in cholinergic, glycinergic and GABA-ergic channels and receptors (Murchison and Griffith 1995).

There may be an alteration in the excitability of aged neurons. For example, aged neurons may show a decrease in excitability, hippocampal CAl pyramidal neurons from aged animals have enhanced voltage­gated Ca2+ entry and post-burst after hyperpolariza­tion, and as a result there is a decrease in their intrinsic excitability (Hemond and Jaffe 2005; Cingo­lani et al. 2002; Disterhoft and Mathew 2006) which leads to age-associated impairments in cognitive functioning (such as learning) and modulation of

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firing properties of neurons (Cingolani et al. 2002). The axonal excitability also shows age-related alter­ations and could be due to changes in nodal and internodal ion channels, nodal width, electrical iso­lation between the internodal and nodal compart­ments, altered myelination, and membrane potential (Nodera et al. 2004 ).

Sensory stimulus-evoked responses consisting of averaged short train of waves (representing changes in EEG recorded from the scalp and corresponding to dendritic actions in the cerebral cortex, called evoked potentials) provide a picture of information (impulse) flow through synaptic tracts of the brain. This involves: sensory processing, axonal conduction, synaptic transmission, and cognitive processing (Crowley and Colrain 2004). The components of evoked potentials (event related potentials both audi­tory and visual) reveal both early and late electrical brain processes associated with behavioral/physiolog­ical functions. With increasing age there is likely to be a decline in the performance of tasks and there are multiple and varying effects of age on both auditory and visual responses. Advancing age thus may be associated with an elevated amplitude of early positive waves (PIOO-auditory and pl45-visual) and there may be significant delays of the major late positive wave in the old subjects (Pelosi and Blumhardt 1999). The components of evoked potentials can thus be used as process-specific time markers in young adult and aged subjects (Pfutz et al. 2002; Boutros et al. 2000). The alcohol use-related accelerated aging caused changes in P300 latency and amplitude similar to those of normally-aging human subjects (Boutros et al. 2000). Parkinson disease patients showed lower N400 ampli­tudes than normal elderly subjects showing impaired delayed recognition memory in aging and Parkinson's disease patients (Minamoto et al. 2001). In normally­aging demented patients, Yaney et al. (2002) did not find age-related changes in the latency and amplitude of P3. However, in this study Vitamin E supplemen­tation appeared to lower the latency of the P3 amplitude but increase its amplitude indicating that antioxidant therapy by decreasing the oxidative stress may lead to improvement in cognitive pool of generator neurons of P3. However, in several human studies vitamin E has not been found to provide cognitive benefits (Kang et al. 2006; Dunn eta!. 2007).

In the aged striatum of Fisher 344 rats, there is an increase in the activity of non-locomotor-related

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neurons (Standford and Gerhardt 2004). This increased activity because of its influence on basal ganglion output nuclei may contribute to age-related or Parkinson's disease-related hypokinesia and move­ment disorders (Standford and Gerhardt 2004). The suprachiasmatic nucleus of mice is subject to marked electrophysiological changes (Nygard et al. 2005), in old animals for example, there were more silent cells (i.e., not rhythmically firing cells) than in young animals.

Electrical changes in the cortex and synapse plasticity

Electrical changes of the brain cerebral cortex are recorded as the surface or cortical electroencephalo­gram (EEG). The EEG is made up of a compounded wave form consisting of multiple frequencies, and is derived from summation of the synaptic activity in cerebral cortex pyramidal cells (Salek-Haddadi et al. 2003). Spectral content of the EEG do reflect changes occurring in the brain subcortical structures, and several electrophysiological measures appear geneti­cally heritable (Winterer and Goldman 2003). The human EEG may undergo significant age-correlated changes (Duffy et al. 1984) as the human EEG tends to show reduced alpha activity with age; increased dyscronization with age consisting of reduction in slow activity and augmentation of fast activity. Topographically the greatest change was found to occur in the temporal lobes, and the right hemisphere seemed to differ from the left (nonsymmetrical nature of the aging process). Furthermore, topographically temporal correlations were found to be stronger in alpha than in beta oscillations and ·were largely unaffected by age (Nikulin and Brismar 2005). In general, the effect of age on the EEG may be frequency specific and topographically variable (Landolt and Borbely 2001).

Long-term potentiation (LTP) is considered a form of synaptic plasticity and has been indicated as a cellular mechanism of learning and memory. Aging appears to be associated with an impaired ability to maintain LTP, and alterations in the balance of protein kinase/phosphatase activities may be respon­sible for these impairments (Hsu et al. 2002). LTP is a Ca2+ -dependant process and is altered with age (lsomura and Koto 1999; Foster and Kumar 2002). Ca2+ dysregulation with age and consequent changes

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in Ca2+ signaling pathways underlie the impairment of LTP with age (Biessels et al. 2002b). Studies concerning LTP have mostly focused on the hippo­campus and particularly CAl cells, as hippocampus­dependant memory appears to be age-sensitive (Foster and Kumar 2002). The age-related cognitive decline is also associated with disruption of Ca2+ homeostasis. The aged CA3 cells were also found to fail to rapidly encode new spatial information com­pared with young CA3 cells (Wilson et al. 2005).

Electrophysiology changes in aging

Electrophysiological changes in the aging brain can also be assessed by measuring cellular-level electro­physiological activity i.e., unit and multiple-unit action potentials. Multiple-unit activity (MUA) i.e., action potentials simultaneously derived from many neurons represents an electrophysiological marker of cellular firing activity of the concerned neuronal population. Its alterations may reflect the biochem­ical, physiological and behavioural changes of the neurons (Mizumori et al. 1996; Barnes et al. 1987; Malmo and Malmo 1982). Therefore, age-related change in spontaneous (basal) neuronal firing is of interest as one of the neuroelectric indicator of electrophysiological functional alteration in the brain. Age-related declines in spontaneous neuronal firing have been found to occur in several brain areas: inferior and superior colliculi of rat (Malmo and Malmo 1982), locus coeruleus neurons of rat (Olpe and Steinmann 1982), forebrain neurons of rat (Jones and Olpe 1984 ), the cerebral cortex of rat (Roy and Singh 1988; Abdulla et al. 1995), the hippocampus, thalamus, and striatum of rat (Kaur et al. 1998, 2001, 2003; Sharma et al. 1993). Age related decline in MUA in four brain regions of rats during aging from 6 to 24 months of age is shown in Fig. 5.

Diabetic brain features symptoms like accelerated brain aging

Diabetes mellitus (DM) is a heterogeneous metabolic disorder characterized by hyperglycemia resulting from defective insulin secretion, resistance to insulin action or both (Gavin et al. 1997). Type 1 diabetes is the consequence of an autoimmune destruction of pancreatic beta cells, leading to insulin deficiency.

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Fig. 5 Electroencephalograms and multiple unit action potentials (MUA) showing age­related changes. Figure adapted from Sharma et al. (1993). Derived from Rehman and Masson (200 I)

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Insulin administration is required for survival. Type 2 diabetes is characterized by insulin resistance, and relative, rather than absolute insulin deficiency. DM is associated with moderate cognitive deficits and neurophysiologic and structural changes in the brain, a condition that may be referred to as diabetic encephalopathy, diabetes increases the risk of demen­tia especially in elderly. The emerging view is that the diabetic brain features many symptoms that are best described as accelerated brain aging. Animal models can make a substantial contribution to the understanding of the pathogenesis, which shares many features with the mechanisms underlying brain aging. By unraveling the pathogenesis, targets for pharmacology can be identified. This may allow treatment or prevention of the diabetic complications.

The effect of experimental diabetes on cerebral enzymes has been evaluated by many authors (Kaur and Lakhman 1994; Lakhman and Kaur 1997; Khandkar et al. 1995; Siddiqui et al. 2005; Azam et al. 1990a, b). Table 4 shows the changes in these enzymes and effect of insulin. Khandkar et al. (1995) had measured the activity of AChE from brain of alloxan diabetic rats. The results suggested that membrane binding and membrane alteration in dia­betes can significantly influence the kinetic properties of AChE. The results show that Km and Vmax of the membrane bound enzyme, but not the soluble AChE increased in the diabetic state, and is possibly related to the delayed nerve transmission and impaired brain function in the diabetic brain. Lakhman and Kaur (1994, 1997) showed that acute hyperglycemia

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caused an increase in the activity of AChE suggesting that the dysfunction of the cholinergic system may be involved in diabetes associated CNS complications; they also showed an increase in MAO, with reversal of the activity after insulin administration. Na+K+ ATPase also showed a decrease in activity in the brain which was normalized after insulin administra­tion (Kaur and Lakhman 1994).Changes in brain Na+K+ ATPase and MAO have been earlier reported from diabetic brain by Mayanil et al. 1982b and latter, i.e., MAO more recently also (Siddiqui et a!. 2005) Reversal of the enzyme activity was shown by insulin administration (Table 4).

The study of receptor subtypes, second messenger system, and protein kinase may account for the alteration in synaptic plasticity, together with the possible role of cerebrovascular changes, oxidative stress, non-enzymatic protein glycation, insulin and alteration in neuronal calcium homeostasis are some of the parameters that have been recently discussed in a review by (Biessels eta!. 2002a, b; Biessels and Gispen 2002). DM is often associated with complications such as cardiovascular disease, kidney failure, retinopathy and peripheral and autoimmune neuropathy. Proper metabolic control, especially the hyperglycemia, reduces the development of these complications.

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Deficient signaling by insulin, as occurs in diabetes is associated with impaired brain function, and diabe­tes is associated with an increased prevalence of AD. Alteration in the insulin receptor signal transduc· tion pathway found in aging and AD are shown in Fig. 6.

One of the hallmark and pathological characteris­tics of AD is the presence of neurofibrillary tangle containing hyperphosphylated tau, a microtubule associated protein. Recently Clodfelder-Miller et al. (2006) have demonstrated a massive and wide spread increase in the phosphorylation of the microtubule binding protein tau in mouse brain after depletion of insulin by administration of streptozotocin. Tau phosphorylation is a key regulator of the ability to bind and stabilize microtubules (Johnson and Stoot­hoff 2004 ), suggesting that this function is impaired by insulin insufficiency, actually tau hyperphoryla­tion is a key early event in the pathogenesis of AD raising the possibility that the reported association between diabetic and AD could in point be due to increased phosphorlation of tau caused by insulin deficiency. This hyperphosphorylation may sensitise neurons to subsequent or concomitant insults associ­ated with AD to promote progressive neurodegener­ation. Authors also show ·that streptozocin induced

Fig. 6 Alteration in the insulin receptor signal transduction pathways found in aging and Alzheimer's disease showing the diverse roles and functions that insulin receptor plays, showing insulin receptor desensitization effects on neuronal metabolism and on the development of Alzheimer's disease. Figure adapted from Fulop et al. (2003) and Li and Holscher (2007)

Effects of Insulin Receptor Desensitization in Alzheimer's Disease

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insulin deficiency shares with AD two common outcomes, reduced pp2A activity and increased tau phosphorylation.

Recently a review by Nelson et al. (2009) included a description of cerebral neuropathology of Type 2 diabetes mellitus (CNDM2) patients. It is believed that in the absence of a known pathogenomic anatomic substrate for cognitive dysfunction in diabetic patients, there are no definitive histopathol­ogical changes in diabetic brains. Many metabolic disorders induce mental changes out of proportion to known neuropathological changes. These disorders may be induced by fluxes in blood levels of insulin, glucose and other metabolic parameters in DM2. Other diseases like hypoxia can produce brain atrophy and cell death. Thus delirium or a disease with entirely nonspecific pathology may partly con­tribute to diabetic neuropathy. This clearly shows that several associations between DM2 and brain pathol­ogy appear to exist. Evidence has been described for and against the link between (CNDM2) and AD pathogenesis. The authors concluded that in diabetics, cerebrovascular pathology was more frequent and Alzheimer-type pathology was less frequent than in non diabetics (Nelson et al. 2009).

Diabetic neuropathy-peripheral and central nervous system

Peripheral neuropathy is a frequent complication of DM. Kamal et al. (2000) studied the role of hippo­campus in certain types of learning and memory where the function and synaptic plasticity has been studied as plastic changes in synaptic strength are assumed to be involved in learning and memory (Bliss and Collingridge 1993). Animal models have been used to examine the relation between memory deficits and changes in synaptic plasticity in diabetes (Shafrir I 997; Kumagai I 999). Like diabetic patients, STZ­diabetic rats develop end organ damage affecting the eyes, kidney, heart, blood vessels, and peripheral and central nervous system.

Aging and diabetes both affect cognition, synaptic plasticity and glutaminergic neurotransmission in rats, hence the effects of diabetes and aging interact, this was examined by Kamal et al. (1999), and the results suggested that there was an interaction between aging and diabetes cerebral dysfunction. Kamal et al. (2000) and Hoyer (1998) put forward the

397

concept that hyperinsulinemic brain glucose utiliza­tion and insulin signal transduction in the brain play an interconnected role in the patho-physiology, also suggesting that Sporadic AD may reflect the brains of Type 2 diabetes mellitus. Clinical and experimental studies indeed show that altered glucose regulation impairs learning and memory (Messier and Gagnon I 996) and defects in insulin action both in peripheral and brain, and these have recently been implicated in the pathogenesis of sporadic AD. Ryan and Geckle (2000) came to the conclusion that the increased risk· of cognition dysfunction in elderly Type 2 patients is the consequence of a synergistic interaction between diabetic related metabolic derangements and struc­tural and functional cerebral changes in normal aging process due to changed insulin receptor function (Fig. 6).

Regional cerebral blood flow changes occur in response to alteration in metabolic demand of brain regions. Kalaria ( 1996) has described the morpho­logical and vascular changes with aging. Studies on the effect of DM on cerebral blood flow has been conflicting (Mankovsky et al. 1997; Sabri et al. 2000). Many uncertainties still exist about the patho­physiologic mechanisms. It can be concluded, how­ever, that both in aging and diabetes vascular changes occur that may have consequences for the cerebral circulation.

Aging, diabetes and Alzheimer's disease, age related disorders

A common theory for aging and for the pathogenesis of AD relates cell death to oxidative stress mediated by free radicals (Beckman and Ames 1998). Accu­mulation of damaged, oxidized, dysfunctional protein seems to result from a combination of age related increase in the rate of oxygen free radical mediated damage and a loss of the ability to degrade oxidized protein (Facchini et al. 2000). Indeed increased levels of oxidized protein and reduced activity of antioxi­dant enzymes have been demonstrated in the brains of aged individuals with and without AD (Gsell et al. 1995; Troni et al. 1984), and in diabetes (Table 4).

Diabetes is associated with increased oxidative stress as reflected in an increased presence of lipid peroxidation products (Jennings et al. 1987; Rosen et al. 2001; Siddiqui et al. 2005; Genet et al. 2002). Like in aging increased oxidative stress appears to be

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the result of increased formation of ROS, reduction in ROS scavengers or both (Moorthy et al. 2005a, b; Baquer et al. 1990). Increased ROS production in diabetes is a consequence of the process of glucose auto oxidation. This process in which glucose is oxidized in the presence of free metal ion, leads to superoxide and hydroxyl radical release, and finally causes protein oxidation (Wolff et al. 1991 ; Wolff and Dean 1987). The activity of ROS scavenger compounds like glutathione, catalase and superoxide dismutase may be affected by diabetes (Wohaieb and Godin 1987; Genet et al. 2002). Decrease in ROS scavenging compounds may be due to the direct affect of diabetes and aging on scavenger production or activity, like enhanced protein glycation may be responsible for the reduced enzymatic anti-oxidant activity of superoxide dismutase (Siddiqui et al. 2005; Mohamad et al. 2004). Alteration of glutathi­one levels may be related to an increased polyol pathway (Preet et al. 2005) activity as this leads to a depletion of NADPH which is necessary for the enzymatic reduction of oxidized glutathione (Fig. 2). A local decreases in endogenous ROS scavenging compounds may be due to increased consumption by ROS, like the generation of increased amount of hydrogen peroxide (Hothersall et al. 1981; Ikebuchi et al. 1993). Increased concentration of lipid perox­idation byproducts have been demonstrated in the brain of diabetic rats and in aging rat brain (Kumar and Menon 1993; Mooradian and Smith 1992; Genet et al. 2002; Siddiqui et al. 2005; Leutner et al. 2001; Sinha et al. 2005; Kumar et al. 2008). The activity of SOD and catalase, enzymes involved in antioxidant defense of the brain, appears to be decreased in (STZ) diabetic rats (Kumar and Menon 1993;Makar et al. 1995), whereas in Type 2 diabetic mice increased brain superoxide dismutase activity has been reported (Huang et al. 1999; Table 4 ).

In tissues affected by diabetes the amount of AGE's are generally increased, leading to structural changes in the extracellular matrix, as well as to modifications of cell membranes and intracellular components (Brownlee 2000; Singh et al. 2001; Siddiqui et al. 2005). Increased levels of AGE's have been reported in central and peripheral nervous tissue from diabetic animals (Pekiner et al. 1993; Ryle et al. 1997; Vlassara et al. 1983).

Age related disorders, like AD and T2DM affect a large number of people, AD and T2DM share several

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molecular process that underline the respective degenerative development. Disturbance in insulin signaling appears to be the main common impairment that affects cell growth and differentiation, cellular repairs mechanisms, energy metabolism, and glucose utilization. Insulin not only regulates blood sugar levels but also act as growth factors on all cells including neuron in the CNS. Impairment of insulin signaling, therefore, not only affect blood glucose levels but also causes numerous degenerative pro­cess. Other growth factors signaling systems such as insulin growth factors (IGFs) and transforming growth factors (TGFs) also are affected in both conditions. Also misfolding of protein plays an important role in both diseases, as does the aggrega­tion of amyloidal peptides and hyperphosphorylated protein. More general physiological process such as angiopathic and cytotoxic developments, the induc­tion of apoptosis, or of non-apoptotic cell death via production of free radicals, greatly influence the progression of AD and T2DM. In a recent review Li and Holscher (2007) have outlined and discussed in details the two metabolic, diseases, T2Dm and AD and showed similarity between the physiological process, epidemiological links, similarities in forma­tion of amyloid peptides in the brain. Other similar­ities were discussed between NFrs (neurofibrillary tangles) and growing evidence that impairments in insulin signaling is partly responsible for the cogni­tion decline in AD. One impairment that has been described repeatedly is the observation that in AD, insulin resistance in the CNS develops due to alterations of insulin receptors sensitivity, affecting the expression and metabolism of amyloid beta and tau protein. Insulin receptor signal transduction pathway in aging and Alzheimer's brain is shown in Fig. 6.

Recently Khan and Ballard (2008) have reviewed the main mechanisms thought to underpin the devel­opment of AD and the treatments that are being developed based upon it. The hallmarks of AD are mainly two fold, as discussed earlier in the review the formation of extra-cellular P-amyloid plaques, intra­cellular neurofirillary tangles and shrinkage of the brain. Deficits Amyloid processing are the main genetic predisposition leading to the amyloid hypoth­esis. The authors have discussed a range of approaches that are currently under investigation for the disease modifying treatment of Alzheimer. These

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range in their targets from anti-amyloid treatment to neuroprotective agent and neurogenerative therapies.

The anti-amyloid therapies are aimed at slowing down or halting the production of the amyloid peptide by together targeting the secretase enzymes which cleave amyloid from APP presenting the aggregation of the amyloid into plaques or using immunotherapies to completely remove amyloid from the brain.

Since aging and diabetes are also now included as a neurodgenerative physiological phenomena, the treatments used for AD may also be used for the delaying of neuronal complication associated with aging and diabetes. Mantha et a!. (2006) have recently shown the neurotoxic effect of synthetic amyloid peptide in isolated synaptosomes from aging rat brains together with changes in neuronal markers. Kumar et al. 2008 have measured the lipofuscin changes in aging brain and effect of DHEA on it together with effects of diabetes and insulin treatment of diabetic brains (latter unpublished).

Changes in neuronal markers, diabetes, aging

Lipofuscin is a morphological structural entity and is mainly accumulated in post-mitotic cells of brain. The accumulation of lipofuscin in cells occurs because it is undegradable and cannot be removed from the cells via exocytosis. As age progresses, the lipofuscin content per neuron as well as the number of pigmented neurons has been shown to increase in a linear fashion in many regions of the brain (Sharma et a!. 1993; Drach et al. 1994; Moorthy et a!. 2005a, b). Intraneuronal accumulation of lipofuscin is considered to be a marker of neuronal aging, and its formation appears to be integrative and proportional to the occurrence of lipid perox­idation. In addition, an age-related increase in lipid peroxidation has been shown to be directly corre­lated with the gross level of lipofuscin accumulation and thus, as reported by earlier workers, intraneu­ronal accumulation of lipofuscin is considered to be a marker of neuronal aging (Sohal and Brunk 1989; Sharma et al. 1993).

Aging increases accumulation of fluorescent "lip­ofuscin" or "wear and tear" pigments in post-mitotic cells such as neurons and muscle cells (Terman and Brunk 2006). DM is one of the diseased model for aging (Cerami et al. 1987) and its complications

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include peripheral neuropathies that exhibit axonal degeneration, demyelination and impaired axonal transport that would affect cell body functions. Hellweg et al. (1994) also showed that autoftuores­cent pigments such as lipofuscin/ceroid could be increased in neurons of rats that have experimentally induced diabetes. Lipofuscin is well known to increase during aging of neurons of humans and some animals, and is an important bio-marker of aging. It has been shown that DM significantly increased the fluorescent pig-ments in the neurons of experimentally induced DM, with the possibility that the induction of DM makes some functional changes due to the accumulation of the fluorescence materials in neurons (Sugaya et al. 2004). The authors therefore concluded that experimentally induced DM by alloxan increases the production of autofluorescent pigments "lipofuscin" in the neurons; that this change is thought to correlate with aging. This result suggests the possibility that the DM could make the functional change in several types of neurons.

Phosphorylation and dephosphorylation of pro­teins (enzymes and receptors), are known to regulate numerous aspects of cell function and abnormal phosphorylation is causual in many diseases and aging. Pyruvate Dehydrogenase genome complex (PDC) is central to the regulation of glucose homeo­stasis. McLean et al. (2008) have recently presented and discussed the regulation of pyruvate dehydroge­nase (PDH). Their results showed that the putative insulin mediator inositol phosphoglycan P type (IPG­P) has a sigmoidal inhibitory action on the PD kinase, together with a linear stimulation of PD phosphatase, suggesting a powerful regulatory function, involving phosphorylation (kinases) and dephosporylation (phosphatase) thereby regulating the active and inactive form of PDH. The IPG;s are released from cell membranes by insulin, very significant in the case of diabetes. Synthetic inositol hexose amine analogues were shown to have similar effects as natural IPG's suggesting their potential for their use in treatment of metabolic disorders including diabe­tes. Unpublished observations by Baquer and McLean's from McLean laboratory on changes in rat brain, IPG's with age, also show results correlat­ing with the diabetic data, reiterating the similarities and complications occurring with diabetes, aging and neurological disorders, contemplating the probable use of synthetic IPG analogues for reversing some

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changes associated with neurological disease and aging.

Insulin effect on brain

Recent data implicate insulin itself in the pathogen­esis of age related memory decline and diabetic encephalopathy (Gispen and Biessels 2000; Schulingkamp et al. 2000). Insulin and its receptors are known to be present in the brain (Havrankova et al. 1978a, b; Azam et al. 1990a, b). Insulin receptors are concentrated in specific brain region, particularly abundant in the hypothalamus and olfac­tory bulb. The physiological function of insulin in brain region is still a controversy, and glucose uptake by brain is considered to be mainly insulin insensitive (Kumagai 1999). Insulin does affect cerebral glucose utilization to some extent (Schulingkamp et al. 2000), analogous to its role in the periphery. In addition brain insulin does seem to play a role in the regulation of food intake and body weight (Schwartz et al. 1999), and it may act as a neuromodulator influencing the release and reuptake of neurotrans­mitters, and probably also learning and memory (Zhao et al. 1999).

Impairment of insulin signaling pathway in the periphery and brain have been implicated in AD, diabetes and aging (Frolich et al. 1998). In AD the age-related reduction in cerebral insulin levels appears to be accompanied by functional disturbances of the insulin receptor qualifying AD as an Insulin Resistant Brain State. Chronic hyperinsulinemis is associated with cognitive decline. Acute insulin administration, in these individuals while keeping glucose at fasting levels, actually improves memory in individuals with AD, as well as in healthy controls (Craft et al. 2000). Morever, the brain insulin/IR signal transduction, beside the regulation of glucose metabolism, delivers signals necessary for synaptic activity and plasticity, of memory formation and for memory storage as well as for cell differentiation (Kremerskothen et al. 2002). Recently insulin levels have been measured in aging and show a decrease with age (Koricanac et a!. 2004), insulin levels are also decreased in DM as well as experimental diabetes in animal models (Fulop et al. 2003; Biessels et a!. 2002b; Taha et al., unpublished).

Insulin degrading enzyme (IDE) has been mea­sured in diabetic brain and diabetic treated with

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insulin (Azam et al. 1990a, b; Table 4). IDE is a metalloendopeptidase also involved in the degrada· tion of amyloid beta protein (Qiu et a!. 1998) the latter is involved in the pathology of AD and has been shown to induce apoptosis invitro (Forloni 1993; Watt et al. 1994 ). It has been reported that in vitro insulin, inhibits insulin degrading enzyme (IDE) activity and proteosomal function competitively (Bennett et a!. 2000; Hamel et a!. 1998; Qiu et a!. 1998) impairing protein turnover, thereby facilitating the gradual accumulation of oxidized protein. Dia­betes and its treatments with insulin are likely to affect cerebral insulin levels and insulin signaling. It is different, however, to separate the direct effect of alterations in insulin homeostasis on the brain from the consequence of the accompanying alteration in peripheral and control glucose homeostasis, which in themselves can affect the brain.

Aging brain, hyperglycemia and calcium hypothesis

It is generally assured that aging is one of the most important and consistent risk factors for AD. The calcium hypothesis of brain aging and dementia has been put forward to account for a number of the phenomena in the pathogenesis of dementia (Khach­aturian 1994 ). A cellular mechanism that regulates the homeostasis of calcium plays a critical role in brain aging. Small changes in free calcium (Ca2+) sustained over a period of time results in cellular damage. A close relation between Ca2+ homeostasis, the production of ROS, ischemia and brain cell death has been reported (Finkel and Holbrook 2000; Kristian and Siesjo 1996). Disturbed (Ca2+) regula­tion and Ca2+ channel activity have been described in various diabetic tissues, like myocardium, arteries and muscle and have been implicated as secondary complications of diabetes (Levy et a!. 1994 ). Con­sidering the peripheral nerve as target for diabetic damage, there are several direct and indirect mech­anisms through which diabetes related disturbance in Ca2+ homeostasis may lead to impaired nerve function (Biessels et al. 1996a, b).

It has been discussed in earlier section in this review that diabetes appears to be an important risk factors for significant cognitive decline and dementia in aging. Preliminary studies in experimental models of diabetes and aging provide evidence that

Biogerontology (2009) 10:377-413

treatments aimed at the pathogenesis factors may be fruitful, for example with anti-oxidants or Ca2+ channels antagonist may restore defects in synaptic plasticity in STZ diabetes rats (Biessels et al. 2002a, b; Biessels and Gispen 2002). As shown recently, treatments with antidiabetic agents, and hormones to aging animals, reducing blood glucose levels in the diabetic animals, ameliorate altered antioxidant status and membrane linked function, like Na +K+ ATPase activity and membrane fluidly in alloxan diabetic and aging rat brain, cause significant reversal of the aging and diabetic induced effects (Moorthy et al. 2005a, b; Siddiqiui et al. 2005).

Metabolic disorders associated with diabetes and Alzheimer's disease

Type 2 DM is one of the most common metabolic disorders, and its prevalence increase with age. Insulin resistance or T2DM is often associated with the most common occurring metabolic and physiological prob­lems, including elevated blood pressure, cardiovascu­lar disease, dyslipidemia and high cholesterol levels, this clustering of risk factors are known as the metabolic syndrome (Ahmed and Goldstein 2006; Levine 2006). Recent evidence has identified T2DM as a risk factor for AD. AD a progressive neurode­generative disorders of either unknown etiology leading progressively to serve incapability and death, has been described as the pandemic of the twenty-first century ()ellinger 2006). Familial AD is caused by mutations in the amyloid precursor protein (APP) and presenelin genes, both linked to Amyloid beta systems. The etiology of the sporadic form of AD is common with an interaction of both genetic and environment risk factors (Blennow et al. 2006). A key event in AD pathogenesis is the conversion of Amyloid beta from soluble monomeric form into various aggregated forms in the brain. A therapeutic strategy will be therefore to prevent aggregation of the soluble form (Liu et al. 2006).

Using aging animals models of AD and T2DM Lester-Coli et al. (2006) showed that Sporadic Alzheimer's disease (SAD) can be recognized as an insulin resistant brain state. It was further shown that the brains of STZ-injected rats were reduced in size and exhibited neurodegeneration, associated with cell Joss, gliosis and other characteristics similar to AD brain (Lester-CoB et al. 2006). Additionally STZ

401

mJection produces oxidative stress in the brain of treated rats (Sharma and Gupta 2001). The impair­ment of insulin signaling in the brain results in the development of neuropathy, rat model therefore can be a valuable tool for basic research of the biochem­ical process that underlines neurodegeneration (Grun­blatt et al. 2006, 2007). While there were obvious difference between the two conditions, the similar signaling impairment and cytotoxic process are important to obtain detailed knowledge about them.

Antiaging strategies

Possible antiaging strategies may involve reduction of oxidative stress and prevention of lipofuscin accumulation (Terman and Brunk 2006). Pharmaco­logical intervention, besides many other types of interventions, to reduce oxidative stress, and to prevent lipofuscin formation is an interesting approach to slow the aging process. There is tremendous public interest in the development of antiaging therapy and the idea that the aging process can be reversed by approaches such as antiaging medicine is emerging (de Grey 2003) although limitations (Ohlansky et al. 2004) are there. A variety of substances and drugs have been investigated for their antiaging influences.

Chemical antiaging compounds therapy

Acetyl-L-Carnitine (ALC) is an ester of L-carnitine, and is normally synthesized in tissues from the reversible acetylation of carnitine (Shigenaga et al. 1994). In experimental studies it has been found to reduce age-related cognitive and neural changes (Markowska et al. 1990; Caprioli et al. 1995; Davis et al. 1993). It has cholinergic and cholinoprotective effects because of its ability to increase acetylcoen­zyme A levels (Szutowiez et al. 2005). It reduces lipofuscin accumulation and has antioxidative action (Dowson et al. 1992; Kaur et al. 2001). Kaur et al. (200 1) have further shown that ALC treatment activates glutathione-s-transferase and Na+K+ -ATP­ase, and reduces lipid peroxidation in the brain. It has been proposed as a therapeutic agent for several neurodegenerative disorders (Calabrese et al. 2006). ALC activates EEG in elderly human patients (Herrmann et al. 1990) and augments multiple unit

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activity in brain regions of aged experimental animals (Kaur et al. 2001; Singh and Sharma 2005; Fig. 7). ALC was,however, not found to show cognitive benefits in Down syndrome (Pueschel 2006) Alzhei­mer disease patients (Thai et al. 2000, 1996) and in dementia (Hudson and Tabet 2003).

L-Deprenyl (phenylisopropyl-N-methylpropynyl­amine, also known as selegiline), a selective inhibitor of monoamine oxidase B, is used as an adjunct to the pharmacotherapy of Parkinson's disease. L-deprenyl is of interest to biogerontologists as it shows bene­ficial effects against aging-related parameters (Kitani et al. 2002; Kaur et al. 2003), and is considered as a putative antiaging drug. The drug has antioxidative effects (Kaur et al. 2003) and its effects on antiox­idative enzymes are unrelated to the monoamine oxidase and uptake of catecholamine effects of the drug (Knoll 1998). A continuous administration of deprenyl improves the performance of patients with AD (Knoll 1993); it improves memory impairment mediated by the cholinergic system (Takahata et al.

Fig. 7 Effect of acetyi-L­camitine and L-deprenyl on electroencephalogram and multiple unit action potential (MUA). Figure derived from Kaur et al. (2001)

CORTEX

Biogerontology (2009) 10:377-413

2005), reverses age-related deficits in long-term memory (Kiray et al. 2004), protects against cogni­tive impairment induced by neonatal administration of iron and in cerebral ischemia (Maia et al. 2004 ). Deprenyl augments multiple unit activity in brain regions indicating that it reverses the aging-related decline in brain electrophysiological activity (Kaur et al. 2003).

Centrophenoxine has been widely studied for its antiaging effects (Sharma et al. 1993; Fig. 8). It augments the activity of antioxidant enzymes and inhibits lipofuscin formation (Roy et al. 1983; Sharma et al. 1993 ), also improves synaptic plastic­ity. Centrophenoxine stimulates multiple unit activity in aged rat brain cerebral cortex and hippocampus (Roy and Singh 1988; Sharma et al. 1993).

Herbal antiaging neuroprotective compounds

Curcumin (a yellow pigment extracted from the rhizome of the plant Curcuma longa (turmeric) is also

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Fig. 8 Effect of centrophenoxine on hippocampal MUA and electroencephalogram in 24 month-old rat. Figure derived from Singh and Sharma (2005)

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30-days centrophenoxine-treated

of interest as an antiaging substance because of its antilipidperoxidative, antilipofuscinogenic effects. It also counters aging-related decrease in membrane­linked Na +K+ ATPase activity in aging rats (Bala et al. 2006; Sharma et al. 2008; Goel et al. 2008).The plant herb Bacopa monniera (called Brahmi in Sanskrit) is also of interest for neuroprotective antiaging properties and extract of the plant has beneficial effects on cognitive functions (Singh and Dhawan 1997). The extract also counteracts alumi­num-induced oxidative stress in the hippocampus (Jyoti and Sharma 2006; Jyoti et al. 2007). Curcumin was, however, not found to have beneficial effects on lipid profiles in humans (Baum et al. 2007). Further­more, some studies indicated that other mechanisms than the antioxidant activities could be involved in the neuroprotective effects of ALC and curcumin (Mancuso et al. 2007).

Steroids, as antiaging compounds

Dehydroepiendrosterone (DHEA) is a neuroactive steroid and can regulate neural functions through its influence on neurotransmitter-gated ion channel and

gene expression; DHEA is synthesized denovo in the brain and accumulates in the nervous system (Racchi et al. 2001). DHEA's substantial fall with age has been shown to be associated with neuronal vulnera­bility to neurotoxicity process. Thus, DHEA is considered to be a neuroactive pharmacological substance with potential antiaging properties. Cal­cium-phospholipid-dependant protein kinase C (PKC) is involved in the induction and maintenance of long­term potentiation of signal transduction and thus has a key role in learning and memory. With brain aging there is alteration (impairment) of mechanisms involving the activity of PKC, and administration of DHEA to aging male animals can modulate the age­associated impairment of PKC signal transduction (Racchi et al. 2001). DHEA may thus indirectly restore age-associated impairment in cognitive func­tions and has been received as a pharmacological antiaging substance (Kumar et a!. 2008; Sinha et a!. 2005) Administration of DHEA to aging animals was found to significantly decrease the increased mono­amine oxidase activity, lipid peroxidation and lipo­fuscin accumulations in the brain. DHEA was also found to counter the age-related decline of superoxide

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dismutase and Na+K+ ATPase activity in the brains of old rats (Sinha et a!. 2008; Taha et a!. 2008; Table 6). The effect of estrogen on aging parameters in animal models has been discussed in earlier section (Table 3).

A controlled maintenance/achievement of normal hormone levels, increasing the sensitivity of insulin receptors, control of blood glucose levels to near normal values, are some of the physiological param­eters to be achieved after the above pharmacological interventions, which can be tried, leading to a better management of age related disorders and diabetic complications, delaying their onset considerably.

Table 6 Percentage changes in SOD, Na~·K+ ATPase, lipid peroxidation and MAO activity from aging rat brain in dif­ferent subcellular fractions after DHEA treatment

Enzymes/fractions Brain regions Percent increase

Age

12 months 22 months

Superoxide dismutase (SOD) activity

Cytosol Cortex 40 63

Cerebellum 16 66

Hippocampus 16 56

Medulla 15 20

Mitochondria Cortex 48 63

Cerebellum 26 65 Hippocampus 30 66

Medulla 32 63

Na+Je+- ATPase activity

Synaptosome Cortex 89 46

Cerebellum 75 59

Hippocampus 87 58

Medulla 70 28

Enzymes/fractions Brain regions Percent decrease

Monoamine oxidase (MAO) activity

Synaptosome Cortex 18 44

Supernatant 13 48

Lipid peroxidation

Whole homogenate Cortex 35 54

Cerebellum 15 52

Medulla 21 29

The percentage changes have been calculated taking age matched controls for each age. All procedures are as described in the references. Table adapted from Sinha et al. (2008) and Kumar et al. (2008)

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Thus, by identifying and understanding functional dimensions of these natural physiological conditions, timely interventions will be effective in prevention of complications to a healthier life span of the individuaL

Acknowledgments The authors gratefully acknowledge the financial support in the form of projects from University Grants Commission, and Indian Council of Medical Research, India. Pardeep Kumar is the recipient of SRF from Council of Scientific and Industrial Research, New Delhi, India. This work was in part supported by a grant for International Scientific Cooperation. This review is dedicated to late Prof. A. L Greenbaum, Professor of Biochemistry, University College of London, UK for appreciation of his wide knowledge of teaching biochemistry and excellent communications and writing skills of scientific work to make it easily understood by students, scholars and researchers.

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