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Behavioural Brain Research302 (2016) 35–43

Contents lists available at ScienceDirect

Behavioural Brain Research

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b b r

Research report

Oral administration of d-galactose induces cognitive impairments andoxidative damage in rats

Josiane Budnia,b,∗, Robson Pachecoa,b, Sabrina da Silvaa,b, Michelle Lima Garceza,b,Francielle Minaa,b, Tatiani Bellettini-Santosa,b, Jesiel de Medeirosa,b,Bruna Constantino Vossa,b, Amanda Valnier Steckerta, Samira da Silva Valvassori a,c, João Quevedoa,d,e,f

a Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidadedo Extremo Sul

Catarinense, Criciúma, SC, Brazilb Laboratóriode Doenças Neurodegenerativas, Programa de Pós-Graduação em Ciências da Saúde,Unidade Acadêmica de Ciências da Saúde,Universidade

do Extremo Sul Catarinense, Criciúma, SC, Brazilc Laboratório de Sinalização Neural e Psicofarmacologia, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde,

Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazild Translational Psychiatry Program, Department of Psychiatry andBehavioral Sciences, TheUniversity of Texas Health Science Center at Houston

(UTHealth), McGovern Medical School, Houston, TX, USAe Center of Excellence onMood Disorders, Department of Psychiatry and Behavioral Sciences, TheUniversity of Texas HealthScience Center at Houston,

McGovernMedical School, Houston, TX,USAf Neuroscience Graduate Program, Graduate School of Biomedical Sciences, TheUniversity of Texas HealthScience Center at Houston, Houston, TX,USA

h i g h l i g h t s

• d-Galactose by oral route induces novelty habituation deficit.• d-Galactose by oral route induces spatial memory impairment.• d-Galactose by oral route induces high thiobarbituric acid reactive species levels.• d-Galactose by oral route induces increase of carbonyl group content.

a r t i c l e i n f o

Article history:

Received27August 2015

Received in revised form

20December2015

Accepted25 December2015

Available online 31December2015

Keywords:

Oral d-galactose

Aging

Cognitive impairment

Oxidative damage

a b s t r a c t

d-Galactose (d-gal) is a reducing sugar that can be used to mimic the characteristics of aging in rodents;however, the effects of d-gal administration by oral route are not clear. Therefore, the aim of this study

was to elucidate if the oral administration of d-gal induces cognitive impairments, neuronal loss, andoxidative damage, mimicking an animal model of aging. Male adultWistar rats (4 months old) received

d-gal (100mg/kg) via the oral route for a period of 1, 2, 4, 6 or 8 weeks. The results showed cognitiveimpairments in the open-field test in the 4th and 6th weeks after d-gal administration, as well as an

impairment in spatial memory in the radial maze test after the 6th week of d-gal administration. Theresults indicated increase of levels of thiobarbituric acid reactive species—TBARS—and carbonyl group

content in the prefrontal cortex from the 4thweek, and in allweeks of d-gal administration, respectively.An increase in the levels of TBARS and carbonyl group content was observed in the hippocampus overthe entire period of d-gal treatment. In the 8th week of d-gal administration, we also observed reduc-

tions in synaptophysin and TAU protein levels in the prefrontal cortex. Thus, d-gal given by oral routecaused cognitive impairments which were accompanied by oxidative damage. Therefore, these results

indicate that orally administeredd-gal can induce the behavioral and neurochemical alterations that areobserved in the natural aging process. However, oral d-gal effect in rats deserve further studies to be

better described.© 2015 Elsevier B.V. All rights reserved.

∗ Corresponding author at: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do

Extremo Sul Catarinense, 88806-000Criciúma, SC, Brazil.

E-mail address: [email protected] (J. Budni).

http://dx.doi.org/10.1016/j.bbr.2015.12.041

0166-4328/© 2015 Elsevier B.V.All rights reserved.

http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.bbr.2015.12.041http://www.sciencedirect.com/science/journal/01664328http://www.elsevier.com/locate/bbrmailto:[email protected]://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.bbr.2015.12.041http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.bbr.2015.12.041mailto:[email protected]://crossmark.crossref.org/dialog/?doi=10.1016/j.bbr.2015.12.041&domain=pdfhttp://www.elsevier.com/locate/bbrhttp://www.sciencedirect.com/science/journal/01664328http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.bbr.2015.12.041

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36 J. Budni et al. / Behavioural Brain Research 302 (2016) 35–43

1. Introduction

d-Galactose (d-gal) is a reducing sugar or monosaccharidewhich is abundantlypresent inmilk products, fruitsand vegetables[1], and is usually converted intoglucose by galactose-1-phosphate

uridyltransferase and galactokinase [2]. However, d-gal adminis-tration over long periods of time canlead toanenzymaticoverload,which impairs the body’s natural ability to catalyze galactose intoglucose, so causing an increase of galactitol and an activation of

aldose reductase. This in turn causes a depletion in NADPH, whichleads to an accumulation of hydrogen peroxide and other free rad-icals (Lai, 2009), causing oxidative damage to the cells [3,4]. Inaddition, at high levels, d-gal may react with the amino groups

of proteins and peptides to form advanced glycation end products(AGE) in vivo [5]. AGE are increased during aging and have beenassociatedwith thepathogenesis ofmanydiseases,such asdiabetes[6], amyotrophic lateral sclerosis [7], andAlzheimer’s disease [8].

Therefore, it has beenpostulated that d-galmay induce behav-ioral alterations that reproduce the natural aging processes in ratsand mice [9,10]. Several studies have suggested that chronic sys-temicadministration of d-gal could be used asamodel of cognitive

disorders and aging [11–14]. Aging is a natural process of changesthat culminates in a progressive decline in both physiological and

behavioral ability. The progression of aging tends to compromisethe entire organism, showing particular severity within the cen-

tral nervous system [15,16]. It is characterized by a gradual lossof cognitive performance, memory, and spatial ability [17]. Thesesymptoms are accompanied by structural and functional changeswithin the brain, such as a decline in mitochondrial function [18]

characterized by a decrease inATPsynthesis andoxidativedamage[19]. These changes play a crucial role in the neurodegenerativedisorders associatedwith the pathogenesis of age-relateddiseases.

According to data from studies, d-gal leads the field in cre-

ating biochemical abnormalities in experimental animals, suchas; accumulations of reactive oxygen species, reductions of antioxidant enzymes, mitochondrial deficits and neuroinflamma-tion/apoptosis. These changes in rodents are similar to those that

occur in the aging human brain [11,13,20–22].Moreover, chronic systemic (intraperitoneal or subcutaneous)

administrations of d-gal can induce alterations like the onesobserved in Alzheimer’s disease (AD) [23,24]. Lin et al. [24] f ound

that d-gal given via intraperitoneal administration significantlyincreased the content of amyloid beta (A) in the hippocampusof mice. A previous study showed that intraperitoneal adminis-trations of d-gal also increased the expression of the brains Aprecursor protein [25]. It has beenwell described in literature thatthe aggregation and deposition of A in the brain is a key step inthe pathogenesis of AD, and that this process elicits a cascade of cellular events that ultimately leads to neuronal loss anddementia

[26]. In addition, intraperitonealor subcutaneousinjectionsof d-gallead to spatial learning impairments, oxidative stress andneuroin-

flammation, aswell as activation of the NFB signaling pathway inthe brain of rodents [11,27–30]. -Amyloid peptide, as AGEı́s, can

activate the receptor for advanced glycation end products (RAGE),leading to oxidative stress and to the activation of the transcrip-tion factor NF-B signaling pathways, causing the transcription of

inducible nitric oxide synthase and a variety of cytokines [8].On the other hand, there is compelling evidence showing that

the oral administration of d-gal induces protective effects in ananimal model of AD induced by streptozotocin. A recent study

compared both systemic andoral chronic administrationsof d-gal,and the results demonstrated that the oral administration route,unlike the systemic method, can reverse cognitive deficits in astreptozotocin-induced model of AD, thus the protective effects

of this sugar may well be concentration or administration route

dependent [31]. Therefore, there is some controversy surrounding

the use of d-gal via the oral route.Considering that many studies related to aging focus on the

animal model of d-gal administered by the intraperitoneal andsubcutaneous routes, the administration of this carbohydrate by

the oral route has not received sufficient attention. Therefore, inthis study we are investigating if the oral administration of d-galinduces cognitive and biochemical abnormalities, since the oralroute can be used as an alternative way of administrating d-gal

over longer periods of time.

2. Material andmethods

2.1. Animals

4 month old adult maleWistar rats, (weighing350–500g) wereused in this research (total of 150 rats). The animals were accli-

matized to the laboratory conditions at room temperature prior toany experimentation. The animals were kept under standard labconditions of a 12h light/dark cycle,with food and water available

ad libitum, and were housed in plastic cages with soft bedding. All

manipulations were performed between 8:00 a.m. and 5:00 p.m.

The project was approved by the ethical committee of the Univer-sidadedo ExtremoSulCatarinenseand allexperimental procedureswere performed according to the NIH Guide for the Care and Use

of Laboratory Animals, as well as under the Brazilian Society forNeuroscienceandBehavior recommendations foranimalcare. Thisstudy was approved by the local ethics committee (Ethics Com-mittee on Animal Use—CEUA of the Universidade do Extremo Sul

Catarinense).

2.2. Drugs and treatment

d-Gal (d-galactose, Sigma–Aldrich, St. Louis, MO, USA) solutionwas used. Itwas dissolvedinwater foradministrationat thedose of 100mg/kg [9,14,32,33] of body weight, and given by oral gavage,

once a day, over a period of 1, 2, 4, 6 or 8 weeks. Animals wererandomized into two groups: control animals (receiving water byoral gavage) or d-gal animals (receiving d-gal by oral gavage). Thebehavioral tests andbiochemical analysis were undertaken on the

1st, 2nd, 4th, 6th and 8th weeks after the last administration of

d-gal. Twenty-four hours after the last administration of d-gal ineach periodof treatment, the animals wereweighed andsubjectedto the behavioral tests. After the completion of the open field task,

or72h after thelast administrationof d-gal, therodentswerekilledby decapitation without the use of anesthesia (the procedure wasapproved by the Ethics Committee) and their brain tissues werecollected for use in themolecular studies.

2.3. Open-field test

Long-term retention of habituation in a novel environment canbe considered a non-associative, non-aversive type of learning,which can bemeasuredby a decrease in the amountof exploratoryactivity undertaken by the test subject. In rodents, it is assessed by

thenumber of rearings performed in a test session carried out 24hafter the first exploration session [34]. This apparatus consists of a45cm×60cmbrownplywood arenawhich is surroundedby50cmhigh wooden walls and fitted with a frontal glass wall. The floor

of the open field was divided into nine rectangles (15cm×20cmeach) by black lines. The animals were gently placed on the leftrear quadrant and then left to explore the arena. To investigate theeffects of any drug treatment on spontaneous locomotor activity,

the numbers of horizontal (crossings) and vertical (rearings) activ-

itiesperformed byeach rat during a 5min observationperiodwere

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J. Budni et al. / Behavioural Brain Research 302 (2016) 35–43 37

counted by an expert observer. Twenty-four hours after the train-

ing session, one new exposition (test session) to the openfieldwascarried out for a period of 5min.

2.4. Radial maze

Trainingwas conducted in an elevated plastic mazewith a cen-ter platform(40 cm indiameter) that was connectedto eight 60cmby 9 cm arms extending radially. Twenty-four hours after the last

administration of d-gal in each period of treatment, the animalswere subjected to the maze, but only for the purpose of habitua-tion to the apparatus. Subsequently, food-rewarded training trialsbegan on day 2 [35]. During the habituation sessions, the animals

were allowed to explore the eight maze arms for 10min, and thenreturnedtotheir homecages.Afterthis,10 fruit loopsper cageweregiven overa periodof2h.On the secondday,eachratwas returnedto themazewith all eight armsopen, and fruit loopswereplaced in

only fourofthe arms.The animalswereplacedin thecentralportionof themaze and allowed to find the rewards, the test period eitherlasting a total of 10min, or endingwhen the animal had found thefood in all 4 arms. The training periods were performed over four

consecutive days. The total time to find the food in the 4 armswasrecorded. Entries into arms that did not contain fruit loops, or into

arms inwhich the animal had previously consumed the foodwererecorded as total errors.

2.5. Thiobarbituric acid reactive species levels

The hippocampus and prefrontal cortex were mixed with 1mL

of trichloroacetic acid 10% and 1mL of thiobarbituric acid 0.67%,and then heated ina bathofboilingwater for 30min.Malondialde-hyde equivalents (amarkerof lipidperoxidation)were determinedspectrophotometricallyat 532nm.Formationof thiobarbituric acid

reactive species (TBARS) duringan acid-heating reaction wasmea-sured as previously described [36].

2.6. Carbonyls protein content

The oxidative damage to proteins was assessed by thedetermination of carbonyl groups content based on a dinitro-phenylhidrazine (DNPH) reaction [37]. The hippocampus and

prefrontal cortex were precipitated by the addition of 20%trichloroaceticacid,and resuspendedinDNPH.The absorbancewasmonitored spectrophotometrically at 370nm.

2.7. Immunoblot analysis

The hippocampus and prefrontal cortex were removed forimmunoblot analysis 72h after the last administration of d-gal.

Protein samples of hippocampal tissue were separated by SDS-PAGE,usingpolyacrilamidegels (10%), followedbytransfer toPVDF

Immobilon-FL transfer membranes (Millipore, USA). Protein load-ing and blot transfer efficiency were monitored by staining with

Ponceau S (0.5%ponceau:1%aceticacid).Membraneswere blockedfor 1h with TBS-T (tris-buffered saline and 0.1% Tween-20; pH7.4) andmilk (0.5%).Membrane blotswere incubatedwith primary

antibody anti--actin (1:1000; Sigma–Aldrich, USA; cod. A5441);anti-TAU(1:1000;Millipore Temecula,USA;cod.#05-348); or anti-synaptophysin (1:750; Millipore, USA; cod. #MAB368) diluted inTBS-T and stored overnight at 4 ◦C. After washing, themembranes

were incubated for 1h with goat anti-mouse (1:5000; Santa CruzBiotechnology, USA) horseradish peroxidase (HRP)—conjugatedsecondary antibodies. Immunocomplexes were visualized usingthe enhancing chemiluminescence detection system (GE Health-

Care,UK)asdescribedby themanufacturer. Densitometric analysis

was performed using ImageJ software (version Java 1.6.0 20,

USA). The total protein concentrations were determined using the

method described by Lowry et al. [38].

2.8. Statistical analysis

Statistical analyses were performed using SPSS 20.0 for Win-

dows. Data from the habituation test and immunoblot analysiswere reported as means±SEM. Oxidative damage was reported

as means±SD. These data were analyzed using the paired Stu-dent’s t -test. Data from the radial maze tests were analyzed using

repeated-measures analyses, followed by the Bonferroni post-hoctest when the Mauchley’s test of sphericity result was signifi-cant (assumption of sphericity violated). The data was reportedas means±SEM, and p values

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Fig. 1. Theeffect of d-gal (100mg/kg) administration via theoral route in male rats subjected to theopen-field habituation task. Theopen-field test was carried 24h after

the last training session, and lasted for a period of 5min.The tests were performed on the 1st, 2nd, 4th, 6th and 8th weeks of treatment. Dataare the mean±SD number of

crossings (A) andrearings(B). Thecontrolratsin alltreatmentprotocols in the1st,2nd,4th and 6thweeks of treatmentwereobservedto havea reduced numberof crossings

(A) and rearings (B), when re-exposed 24h later (test) to the apparatus. The animals that received d-gal administration produced the same pattern of response in the 1st,

2nd and 8thweeks. However, in the4thand 6thweeks there were no statistical differenceswhen observing thenumberof crossings, and in the4thweek when observing

the number of rearings(suggestingimpairments in thehabituationmemory).Datawere analyzedby paired-samples t -testto compare the test sessionwith trainingsession,

and compare the control test with d-gal test, n=9 animals per group.* p

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Fig. 2. Theeffects of d-gal (100mg/kg, v.o)administration via theoral route inmale rats subjected to theradial maze oneday afterhabituation. (B)The same apparatus wasused forthe training sessions andtesting.When thetestswereinitiated, each rathad 10min tofind the food, the tests being performed in the end of4th, 6th and 8th weeks

of treatment. Therewas a decrease in the latency time to find foodwhen comparing the first day to the subsequent days in the animals that receivedwater, exceptwhen

comparing thefirst dayto the2nd dayduring week 6 of treatment. In theanimals that receivedd-gal,therewere no differences between thefirst andthe 2nddays,and the

4th day, demonstrating that these animals did not learn the location of food when analyzing the total errors, however, the animals treated with d-gal showeddecreasesin

the errors to find food only in the 3rd and 4th days when compared to the first day after 4 weeks of treatment, and showed no reduction of errors in any of the test dayswhen compared to the first day in the 6th weekof testing. Dataare the mean±SEM of latency timeto find food (A), and total errors tofind food (B). Datawere analyzedby

repeated-measures analyses followedby the Bonferroni post-hoc test,n=9–10 animals per group.* p

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Fig. 3. Theeffects of d-gal (100mg/kg, v.o)administration via theoral route onmale rats showing thelevels of oxidativedamage in theprefrontal cortexand hippocampus.

Data arethe mean±SD of thehippocampusand prefrontal cortex taken from animals treated with either water or d-gal at the end of 1, 2, 4, 6 and 8 weeks. Thiobarbituric

acid reactive species levels (TBARS) are shown in (A) and carbonyl protein content in (B). (A) The TBARS levels were found to have increased in the prefrontal cortexwith

d-gal treatment when comparedto thecontrol group after four, sixand eightweeksof treatment, and d-gal also induced increasesin TBARS levelsin thehippocampus after

one, two, four andsixweeks. (B) The levels of carbonyl groupsin theprefrontal cortexand hippocampus were increased in rats treated with d-gal compared to the control

group in everyweek of treatment, indicating that d-gal treatment can lead to oxidativedamage in lipids and proteins.Data were analyzedusing thepaired-samples t -test.

n=7 animals per group. * p

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Fig. 4. The effect of d-gal (100mg/kg, v.o) administration via the oral route on male rats subjected to immunoblot analysis. The hippocampus and prefrontal cortexwere

removedfromanimalsfor immunoblot analysis48h followingoralwater ororald-gal administrationat theendof 1,2, 4,6 and8weeksof treatment. Dataarethemean±SEM

of theoptical density (D.O) of thesynaptophysin (A)and TAUtotal protein bands(B) divided by-actin protein. (A)8 weeks after treatment with d-gal, therewas a decrease

of synaptophysin protein in the prefrontal cortex and (B) TAUcontent. Data were analyzed using the paired-samples t -test. n=4 animals per group. * p

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related diseases, the generation of reactive oxygen species leads to

central nervous systemoxidativestress,microvasculardysfunctionandneuronal damage [53,54].

The animal model of aging has also shown an increase inthe levels of oxidative stress in various brain regions [21,55–59].

Specifically, chronic systemic d-gal administration induces neu-rodegeneration, oxidative damage andmitochondrial dysfunctionin both mice and rats [10,11,14,46]. The present study showedincreases in lipid and protein oxidation, indicative of oxidative

stresslikeaging.In fact, themostoxidativedamageoccurredafter4and 6weeks of treatmentwithd-gal, which can help to explain thecognitive and memory impairments observed after 4 and 6 weeksof d-gal treatment.

Therefore, additional investigations were performed to eluci-date the effect of d-gal administeredvia the oral route. For this, thepresent study evaluated the protein content of synaptophysin andtotal TAU. However, our results showed a reduction in the synap-

tophysin and TAU total contents only in the prefrontal cortex after8 weeks of d-gal treatment. TAU protein is abundant in neuronsand plays an important role to the assembly and stabilization of microtubules, and maintains the cytoskeletal structure [60]. The

microtubule-associated protein TAU promotes axonal outgrowth,and it is also necessary for maintaining axonal morphology and

axonal transport [61]. Similarly, synaptophysin is oneof majorpro-tein components that are present in the synaptic vesicles possibly

responsible for neuronal transmission [62]. Robinson et al. [63]observed that synaptophysin wasreduced in aged individualswithcognitive impairments anddementia, suggesting that synaptic lossis a major contributor to dementia in the elderly [63]. Ullah et al.

also show that d-gal (120mg/kg/day intraperitoneally for 60 days)induces reductions of synaptophysin in the hippocampus of rats[21]. Our results indicate that d-gal administeredvia theoral routedoesnotaltersynaptophysinafter4 or6 weeksof treatment.There-

fore, in this case, thebehavioral abnormalities arenot accompaniedby a decrease in synaptophysin.

In conclusion, thepresent study showed for thefirst time someof the changes induced byd-gal administeredvia the oral route.d-

Gal given byoral routefor a periodof 4 or6 weeks induced noveltyhabituationand spatialmemory impairments, respectively. Oxida-tive damage was observed during each period of treatment. Theseresults indicated that d-gal administered via the oral route over

long periods of time can induce thebehavioral and neurochemicalalterationsobservedin aging.However,furtherstudiesarerequiredto betterunderstand theeffectsof oral d-gal administration in rats.During thenext study,we intend to add different ages and include

a washout period to detect if the changes are reversible. In addi-tion, we will be using antioxidants to try to reverse the changesobserved.

Conflict of interest

The authors declare that there is no conflict of interests regard-ing the publication of this paper.

Acknowledgments

This study was supported in part by grants from the ‘ConselhoNacional de Desenvolvimento Científico e Tecnológico’ (CNPq-

Brazil—JQ), from the ‘Instituto Cérebro e Mente (JQ)’ and UNESC(JB, JQ and SSV). JQ is a recipient of the CNPq (Brazil) ProductivityFellowship.

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on/tmp/scratch_1/dx.doi.org/10.1007/s00210-009-0442-8http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00210-009-0442-8http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00210-009-0442-8http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00210-009-0442-8http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00210-009-0442-8http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00210-009-0442-8http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00210-009-0442-8http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00210-009-0442-8http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neurobiolaging.2009.04.016http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neurobiolaging.2009.04.016http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neurobiolaging.2009.04.016http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neurobiolaging.2009.04.016http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neurobiolaging.2009.04.016http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neurobiolaging.2009.04.016http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neurobiolaging.2009.04.016http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neurobiolaging.2009.04.016http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neurobiolaging.2009.04.016http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neurobiolaging.2009.04.016http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neurobiolaging.2009.04.016http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuroscience.2011.02.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuroscience.2011.02.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuroscience.2011.02.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuroscience.2011.02.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuroscience.2011.02.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuroscience.2011.02.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuroscience.2011.02.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuroscience.2011.02.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuroscience.2011.02.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuroscience.2011.02.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuroscience.2011.02.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.3389/fnagi.2015.00209http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.3389/fnagi.2015.00209http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.3389/fnagi.2015.00209http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.3389/fnagi.2015.00209http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.3389/fnagi.2015.00209http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.3389/fnagi.2015.00209http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.3389/fnagi.2015.00209http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.3389/fnagi.2015.00209http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.3389/fnagi.2015.00209http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-010-0777-yhttp://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-010-0777-yhttp://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-010-0777-yhttp://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-010-0777-yhttp://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-010-0777-yhttp://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-010-0777-yhttp://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-010-0777-yhttp://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-010-0777-yhttp://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-010-0777-yhttp://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-010-0777-yhttp://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuint.2015.07.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuint.2015.07.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuint.2015.07.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuint.2015.07.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuint.2015.07.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuint.2015.07.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuint.2015.07.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuint.2015.07.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuint.2015.07.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuint.2015.07.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1016/j.neuint.2015.07.001http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-003-0017-9http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-003-0017-9http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-003-0017-9http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-003-0017-9http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-003-0017-9http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-003-0017-9http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-003-0017-9http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-003-0017-9http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-003-0017-9http://localhost/var/www/apps/conversion/tmp/scratch_1/dx.doi.org/10.1007/s00726-003-0017-9http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0010http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005http://refhub.elsevier.com/S0166-4328(15)30350-8/sbref0005

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