[ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY] The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease Volume 595 || NEUROPROTECTIVE EFFECTS OF CURCUMIN

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SVNY332-Aggarwal January 19, 2007 15:7

NEUROPROTECTIVE EFFECTS OF CURCUMIN

Greg M. Cole, Bruce Teter, and Sally A. Frautschy

Abstract: Neurodegenerative diseases result in the loss of functional neurons andsynapses. Although future stem cell therapies offer some hope, current treatmentsfor most of these diseases are less than adequate and our best hope is to prevent thesedevastating diseases. Neuroprotective approaches work best prior to the initiationof damage, suggesting that some safe and effective prophylaxis would be highlydesirable. Curcumin has an outstanding safety profile and a number of pleiotropicactions with potential for neuroprotective efficacy, including anti-inflammatory,antioxidant, and anti-protein-aggregate activities. These can be achieved at sub-micromolar levels. Curcumin’s dose–response curves are strongly dose dependentand often biphasic so that in vitro data need to be cautiously interpreted; manyeffects might not be achievable in target tissues in vivo with oral dosing. However,despite concerns about poor oral bioavailability, curcumin has at least 10 knownneuroprotective actions and many of these might be realized in vivo. Indeed, accu-mulating cell culture and animal model data show that dietary curcumin is a strongcandidate for use in the prevention or treatment of major disabling age-relatedneurodegenerative diseases like Alzheimer’s, Parkinson’s, and stroke. Promisingresults have already led to ongoing pilot clinical trials.

1. INTRODUCTION

Many neurodegenerative diseases of aging involve the accumulation of protein ag-gregates, oxidative damage, and inflammation. Curcumin has multiple desirablecharacteristics for a neuroprotective drug, including anti-inflammatory, antioxi-dant, and anti-protein-aggregate activities that we have previously reviewed.1,2

Because of its pluripotency, oral safety, long history of use, and inexpensive cost,curcumin has great potential for the prevention of multiple neurological conditionsfor which current therapeutics are less than optimal. Examples reviewed includeAlzheimer’s, Parkinson’s, Huntingtin’s, head trauma, aging, and stroke. Despitethe widely held belief that curcumin’s poor systemic bioavailability precludes ther-apeutic utility outside of the colon,3,4 there is ample animal model evidence forvery effective neuroprotection in a variety of disease models. Conversely, many ofcurcumin’s reported toxic effects are achieved only at doses that will not be reachedin systemic tissues with oral dosing. One of the key obstacles with curcumin, aswith other compounds lacking adequate patent protection, is that there has beenno push for development from the private sector. What is needed is preclinical and

197

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198 COLE, TETER, AND FRAUTSCHY

clinical development support from either government or philanthropic support.One example of this might be support from the US NIH Aging and Complemen-tary and Alternative Medicine Institutes. In the following pages, we review some ofthe literature supporting the neuroprotective utility for curcumin, beginning withAlzheimer’s disease.

2. BIPHASIC OR DOSE-DEPENDENT RESPONSES TO CURCUMIN

As reviewed elsewhere in this volume, curcumin is both a potent antioxidant andanti-inflammatory agent and has a long history of use, both as a food preser-vative and in traditional Indian and Asian medicine, often as an oral or topicalextract for conditions where Western medicine might employ a nonsteroidal anti-inflammatory drug and/or vitamin E. Curcumin’s activity and structure–functionrelation as a radical scavenger, metal chelator, and antioxidant has received con-siderable attention . It clearly reduces mRNA production for pro-inflammatorymediators, including cytokines, inducible nitric oxide synthase (iNOS), and cy-clooxygenase (COX)-2.5,6 Apparently, this is due to limiting activator protein(AP)-1 and nuclear factor (NF)-�B-mediated gene transcription7,8; however, thedirect molecular targets at low doses are not entirely clear. Curcumin inhibitionof AP-1 and NF-�B-mediated transcription occurs at relatively low (<100 nM)doses and might be due to inhibition of histone acetylase (HAT) or activationof histone deacetylase (HDAC) activity.9 At high doses (>3 �M) that are rel-evant to colon cancer but unlikely achievable with oral delivery in plasma andtissues outside of the gut, curcumin can act as an alkylating agent,10 a phase IIenzyme inducer,11 and stimulate antioxidant response element-mediated protec-tive gene expression.12 Some of the effects of curcumin at high in vitro dosesare clearly toxic and undesirable beyond its use in cancer therapy. For example,inhibition of proteasomal function and potentiation of huntingtin toxicity can beachieved with dosing >3 �M in vitro.13 Proteasomal inhibition would clearly beundesirable in neurodegenerative disorders, which often have protein aggregateaccumulation, whereas proteasome stimulation would be protective. However, thedose dependence of curcumin’s effects on the proteasome is biphasic with dosesup to 1 �M (e.g., achievable in vivo) causing 46% increased proteasomal activityand higher doses leading to proteasome inhibition.14 Proteasome activation wouldpresumably be a useful response in neurodegenerative diseases with accumulatingaggregates.

As discussed below, many protective effects, including anti-amyloid, antiox-idant, and anti-inflammatory activities, can be obtained with doses at or below1 �M. For example, low-nanomolar doses can inhibit histone acetyltransferase15

and JNK-stimulated AP-1 activity, suggesting that these functions are likely centralto many in vivo effects,16,17 including central nervous system (CNS) neuroprotec-tive activity.18 Also as reviewed below, low-dose curcumin can limit the aggrega-tion of multiple forms of amyloid-forming peptides that lead to intraneuronal orextracellular aggregates in a variety of neurodegenerative diseases.

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NEUROPROTECTIVE EFFECTS 199

3. ALZHEIMER’S DISEASE

Alzheimer’s (AD) is the most prevalent form of age-related dementia, with ADrisk doubling every 5 years after age 65. Thus, AD risk for persons living intotheir eighties rises to 20–40% depending on the population. There are millions ofAD patients in the United States today and this number is expected to double anddouble again with the demographic shift toward a more aged population, leadingto over 10 million expected cases, unless preventive measures can be achieved.19

The classical pathology of AD involves neurodegeneration and the accumulationof protein aggregates to form two major lesions: neurofibrillary tangles (NFTs)and senile plaques. The senile plaques consist of abnormal neuronal proceses(“dystrophic neurites”) and activated glial cells surrounding and penetrating amore central proteinaceous deposit of amyloid fibrils made up of �-amyloid (A�)peptide. The A� peptide is typically 40–42 amino acids in length and is derivedfrom a larger single membrane spanning “amyloid precursor protein” (APP) byendoproteolytic cleavage. The N-terminus is exoplasmic and cut by a rate-limiting�-secretase enzyme (BACE 1). The final secreted amyloid peptide product isamphipathic with the 12–14-amino-acid C-terminal hydrophobic amino acid tailcut from within the membrane by a “� -secretase” enzyme complex. A� peptideis, thus, normally rapidly produced and equally rapidly degraded. However, atelevated concentrations, it has a strong tendency to self-aggregate to form poorlydegradable, �-pleated sheet-rich oligomers, protofilaments, and, finally, filamentsthat have the histochemical staining properties of amyloid. These A� filamentsdeposited in plaques can be visualized with the amyloid dyes thioflavin S andCongo red. The 2-amino-acid longer A�1–42, typically a minor species, formsaggregates more than a thousand times faster than A�1–40. A large number ofdifferent autosomal-dominant AD mutations have been found in APP and the“presenilin” component of the � -secretase complex and all of these cause moreA�1–42 to be made, resulting in early-onset AD. Thus, the genetics of AD clearlyimplicate an etiopathogenic role for increased A�1–42. Further, because mutationsin A� itself can also increase the aggregation rate and cause AD, most researchersare convinced that A� aggregates initiate pathogenesis.20,21 Transgenic mousemodels that overexpress human mutant APP develop neuritic amyloid plaquesthat closely resemble the senile plaques in AD patients,22,23 but although theyshow hyperphosphorylated tau, they do not develop neurofibrillary tangles. Morerecently, tangle pathology has been achieved by expressing high levels of mutanthuman tau or wild-type human tau on a mouse tau knockout background, butcurcumin effects have not been reported on in these models.

3.1. Amyloid Reduction

We initially tested curcumin in a mutant APP transgenic plaque-forming animalmodel and found that it not only reduced indices of oxidative damage and inflam-mation, but it also reduced amyloid plaques and accumulated A�.24 We also foundthat curcmin reduced oxidative damage, inflammation, and cognitive deficits in

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rats receiving CNS infusions of toxic A�.25 Tests on cultured HEK or 293 cellstransfected with human APP and producing measurable A� failed to show anyevidence of secretase inhibition and reduced A� production. However, becausecurcumin structurally resembles the amyloid-binding dye Congo red, we testedthe ability of curcumin to bind amyloid and inhibit A� aggregation and found thatit dose-dependently blocked A� aggregation at submicromolar concentrations.1

A more extensive report on these observations showed that curcumin not onlystained plaques and inhibited A� aggregation and fibril formation in vitro; butcurcumin also inhibited the formation of A� oligomers and their toxicity andreadily entered the brain to label plaques in vivo.26 More significantly, we foundthat curcumin appeared to reduce preformed amyloid in vitro and to markedlysuppress A� accumulation and plaques in vivo even when the drug treatment wasbegun when the mice were old enough to already have well-established amyloidburdens at levels similar to AD patients. This efficacy in late stages of amyloiddeposition is in marked contrast to other antioxidants and other treatments thatfail to reduce amyloid in the same Tg2576 model mice when treatments are begunlate.27,28 Curcumin’s in vivo capacity to reduce �-amyloid accumulation mightderive from multiple activities beyond this first mechanism: (1) direct bindinginhibition of A� aggregate formation. Amyloid formation has been shown to belimited by five additional mechanisms: (2) metal chelation,29 (3) the antioxidant vi-tamin E,28 (4) lowering cholesterol30,31 and reducing expression of the �-secretaseenzyme BACE1 by reducing its induction by both (5) pro-inflammatory cytokines[interleukin (IL)-1� and tumor necrosis factor (TNF)-�)32 and (6) the lipid perox-idation product 4 hydroxynonenal acting on JNK-mediated transcription.33 Cur-cumin might work to limit amyloid production by direct inhibition of aggregatesand control of all five of these pathways, including chelating metals,34 limitingoxidative damage better than vitamin E,35,36 lowering cholesterol,37,38 reducingpro-inflammatory cytokines,24,38,39 lipid peroxidation,25and protein oxidation24

and JNK-mediated transcription39 to control BACE1 expression. For example,treatment with curcumin reduced BACE1 mRNA in cultured primary rat neuronsand in aging Tg2576 (Morihara, Ma, and Cole, unpublished data). Iron chela-tion is another activity that also has in vivo support.40 Further, although it is notclear whether it can do so in vivo because the dosing seems to require >3 �M,11

curcumin can induce phase II enzymes in astrocytes and heme oxygenase-1 in neu-rons in vitro.41 Two additional mechanisms might contribute to amyloid reduction:(7) Amyloid aggregates can be cleared via phagocytosis by brain macrophages,curcumin at dosing as low as the 100–500-nM range can stimulate microglialphagocytosis, and clearance of amyloid in vitro and curcumin appears to promotephagocytosis in vivo (Yang, et al., unpublished data). (8) Finally, one of the ma-jor defenses against intraneuronal protein aggregate formation is the induction ofheat shock proteins (HSPs) that function as molecular chaperones to block proteinaggregate formation.42 Increased HSP expression from transgenes clearly protectsfrom neurotoxicity arising from intraneuronal protein aggregates.43 Like severalother nonsteroidal anti-inflammatory drugs (NSAIDs), curcumin can potentiate theproduction of HSPs in response to cellular stress in vitro and in vivo44. Curcumin

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potentiates the in vitro and in vivo HSP response to infused (in vivo) or appliedsoluble A� aggregates on neurons in culture (Frautschy et al., unpublished results).Thus, there are eight known ways for curcumin to limit �-amyloid accumulationand protect against amyloid peptide-mediated toxicity.

A very recent report using direct in vivo multiphoton microscopy to repeatedlyobserve the same amyloid plaques in AD model mice showed the ability of cur-cumin to enter the brain, bind plaques, and reduce amyloid plaque size by 30%, andto significantly reduce soluble A� in vivo.45 These data encourage the continueddevelopment of curcumin as an anti-amyloid agent and efforts to understand itsmechanisms of action.

3.2. Inhibition of Amyloid Toxicity

The mechanisms by which �-amyloid peptide aggregates act to cause AD re-main unclear, but they appear to include induction of oxidative damage46,47

as well as inflammation4,49 and neurotoxicity, the latter mediated through JNKactivation.50,51 Thus, curcumin might act not only by limiting amyloid aggregatesbut also by suppressing their pro-oxidant, pro-inflammatory, and JNK-mediatedtoxic amyloid aggregate effects. Further, high doses of curcumin can also inhibitamyloid toxicity in vitro and neurotoxic p75 neurotrophin receptor signaling.52

AD pathogenesis also involves the accumulation of other protein aggregates, in-cluding intraneuronal tau amyloid as NFTs and �-synuclein aggregates (discussedbelow), which curcumin could potentially suppress. Tau dimerization is initiatedby oxidative damage53 and at least some tau kinases, notably mitogen-activatedprotein kinase (MAPK), are activated by oxidative damage.54 Further, tau pathol-ogy appears to induce oxidative stress and mitochondrial dysfunction, suggest-ing antioxidants might protect.55 Finally, like all amyloids, tau aggregates con-tain a core �-sheet domain that plays a central role in aggregation and mightbe blocked by natural and synthetic amyloid-binding dyes, potentially includingcurcumin.

In summary, curcumin’s known activities target at least eight anti-amyloid mech-anisms relevant to AD pathogenesis, suggesting that it might be useful in preventingor treating AD. Although there is no epidemiology isolating curcumin intake as avariable, age-adjusted AD prevalence and incidence in an area with high curcuminintake (rural India) was surprisingly low compared to the United States and otherWestern countries.56 Collectively, available evidence warrants the exploration ofcurcumin in clinical trials for AD treatment and prevention; a pilot trial in early ADevaluating dosing and efficacy with clinical end points and biomarkers is currentlyunderway at UCLA’s Alzheimer’s Disease Center.2

4. PARKINSON’S DISEASE

Another prevalent, age-related neurodegenerative condition, the movement dis-order Parkinson’s disease (PD), involves relatively selective vulnerability to the

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neuromelanin-bearing dopaminergic neurons of the pars compacta region of thesubstantia nigra and their terminals in the striatum. In Western populations, sig-nificant age-related loss of pigmented neuromelanin-bearing neurons commonlyoccurs in the this region, but symptoms of PD do not manifest until 60–80% neuronloss.

4.1. Oxidative Damage and Inflammation

Of the age-related neurodegenerative conditions, PD has long had the strongestassociations with elevated oxidative damage, including that associated with auto-oxidative dopamine breakdown and related semiquinone metabolism to superox-ide, as well as monoamine oxidase production of hydrogen peroxide.57 Low dosesof curcumin can inhibit dopamine toxicity in vivo.18 More recently, mitochondrialelectron transport defects at complex I and increased free-radical production havebeen identified in PD brain and peripheral sites, whereas oxidative damage tovulnerable dopaminergic neurons and a PD syndrome can be produced in humanand animal models by the MPTP toxin (reviewed in Ref. 58). MPTP toxicity ismediated by MPP+, and curcumin can directly inhibit MPP+ toxicity to the PC12neuronal cell line.16

Further, support for a free-radical role in PD comes from evidence that selectiveneuron loss, aggregation of �-synuclein, and clinical symptoms resembling PDcan be produced by the pesticide toxin rotenone that targets mitochondrial electrontransport and causes increased free-radical production.59 Although not as closelyassociated with inflammation as AD, recent studies have shown chronic microglialactivation in PD and that a single pro-inflammatory stimulus results in sustainedmicroglial activation around dopaminergic neurons that can contribute to their lossin animal models.60 These data provide some rationale for protection from PD withthe polyphenolic antioxidant/ NSAID curcumin.

4.2. Synuclein Aggregation

Although rare, some genetic cases of PD are linked to mutations in a synaptic pro-tein called �-synuclein that was originally identified from smaller peptides isolatedin amyloid-containing fractions of AD brains.61 The �-synuclein protein is anotheraggregating, fibril-forming protein that is a major component of the Lewy bodylesions characteristic of PD as well as certain cases of AD and several other neu-rodegenerative conditions. Synuclein aggregates show evidence of nitration-basedoxidative damage62 that might play a critical role in aggregate formation.63 Recentstudies have shown that curcumin can reduce the aggregation of �-synuclein,64

and administration to cultured cells with �-synuclein aggregate formation resultsin fewer aggregates.65

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5. OTHER NEURODEGENERATIVE DISEASES WITH PROTEINMISFOLDING

5.1. Mad Cow Disease

“Mad cow” involves the aggregation of infectious prion proteins that form protease-resistant toxic species with a �-sheet core. Low doses (IC50 ∼ 10 nM) of curcumineffectively inhibited protease-resistant prion protein aggregation and accumulationin neuroblastoma cells in vitro, but an initial trial to delay scrapie pathogenesis invivo was unsuccessful.66 The reasons for the failure in the animal model remainunclear and should be further explored, but one likely explanation would be thefailure to obtain adequate curcumin blood levels with oral administration.

5.2. Huntington’s Disease and Other CAG Repeat Diseases

These diseases have extended C-terminal CAG repeats coding for polyglutamine,which causes protein aggregates to form at a rate determined by the repeat length.Because curcumin resembles Congo red and its chrysamine G homologue Congored, its anti-amyloid-binding protein properties are generic and should extend toother protein-misfolding diseases with a �-pleated sheet, including the polyglu-tamine dieases like Huntington’s disease (HD).67 Evidence for a protective effectin an HD transgenic model has been recently obtained by a UCLA investigator,68

leading to a pilot curcumin clinical trial with HD patients at UCLA. Marie-CharcotTooth disorder is another example of a similar protein-misfolding neuropathy andcurcumin protects against this disorder in vitro69 ( and in vivo in a transgenic model(Lupski, personal communication).

5.3. Tauopathies

Aggregates of the microtubule-associated protein tau are present in neurofibrillarytangles in AD and tau mutations have been genetically linked to neurodegenera-tion in some forms of frontotemporal dementia (FTD), which can be modeled inFTD mutant tau transgenic mice.70 There is currently intense interest in the neuro-toxicity of soluble tau aggregates because of a recent report using a doxycycline-regulated tau transgenic that showed that turning off tau transgene expression inolder tangle-bearing mice fails to reduce tangles, but markedly protects againstneurodegeneration.71 Curcumin might protect against the formation of these solu-ble tau aggregates because the initial tau dimerization step can be driven by oxida-tive damage, notably lipid peroxidation53 or redox-regulated disulfides.72 Further,as discussed earlier, the induction of HSPs should also protect against aggregates.Although an abstract report claimed that curcumin can reduce tau pathology in oneof the tau transgenic models, as far as we are aware there are no peer-reviewed pub-lications on this topic. Nevertheless, in a model of CNS A� infusion into genomicwild-type tau transgenic mice, dietary curcumin appeared to limit A� infusion

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and tau transgene-related cognitive deficits (Frautschy et al., unpublished data).Based on this suggestive data, ongoing studies are further examining the impactof curcumin on tau pathology.

6. CEREBROVASCULAR DISEASE AND STROKE

Cerebrovascular and cardiovascular disease risk factors overlap AD risk factors andmany dementia cases are mixed. Therefore, if confirmed in larger trials, curcumin’sreported ability to lower total cholesterol and raise high-density lipoprotein (HDL)cholesterol in humans should be relevant to dementia prevention.73 To provide an-other example, homocysteinuria appears to be an important risk factor for both ADand cardiovascular disease.74 Curcumin effectively protects against homocysteine-induced endothelial damage.75 Free-radical damage and inflammation contributeto ischemic damage after a stroke. Prior and even delayed curcumin treatmentreduces this damage. For example, curcumin injections i.p. reduced damage tovulnerable hippocampal CA1 and preserved antioxidant enzymes and glutathione,even when initiated 3 and 24 h after ischemia76 Further, curcumin has been shownto protect in a standard middle cerebral artery occlusion rat model for stroke.77.

7. HEAD TRAUMA

Head trauma is a stringent test of neuroprotective activity and a validated en-vironmental risk factor for AD.78,79 ;epeated head trauma is also the cause ofboxer’s dementia (dementia pugilistica), which involves both tangles80 and A�42deposition.81 ApoE4, the major genetic risk factor for AD and brain trauma, syn-ergistically increases the risk of AD and A� deposition.82 Further, in an APPtransgenic animal model for AD, brain trauma and the APP transgene act syner-gistically to increase both cognitive deficits and neurodegeneration.83 Thus, pro-tection against head trauma by curcumin, as shown in an animal model,84 is anothermechanism for potential AD prevention by curcumin.

8. ALCOHOL-INDUCED NEUROTOXICITY

Ethanol-induced toxicity involves lipid peroxidation, inflammation, and otherwell-established curcumin targets. Not surprisingly, curcumin can effectively pro-tect against ethanol-induced oxidative damage, inflammation, and resulting liverdamage6 and ethanol-induced CNS neurodegeneration in vivo.85 These reportsshow that despite claims of poor bioavailability, properly delivered , curcumin orits metabolites are effective in protecting tissues from oxidative damage outsideof the gastrointestinal tract.

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9. THE AGING BRAIN

Curcumin is one of the few drugs likely to slow aging rates, as evidenced by the abil-ity of its major metabolite, tetrahydrocurcumin, to increase the life span in middle-aged mice.86 Evidence for an impact on aging brain has been recently produced inaging rats, where chronic curcumin treatment was shown to result in reduced lipidperoxidation and accumulation of the age-pigment lipofuscin and to increase theantioxidant defense enzymes glutathione peroxidase and superoxide dismutase aswell as sodium potassium ATPase, which normally declines.87 Curcumin resem-bles another biphenolic antioxidant, resveratrol, that is believed to have antiagingactivity via induction of sirtuins and HDAC activtion, so curcumin’s ability tolimit HAT and promote neurogenesis15 might also impact longevity, promotinga sirtuin-like effect on HAT-regulated transcription. These results are intriguing,consistent with other measures of normal brain aging, including protection againstCNS oxidative damage, and support the hypothesis that curcumin might slow nor-mal aging of the brain and presumably other tissues in which age-related oxidativedamage is an issue.

10. STEM CELL NEURODIFFERENTIATION AND ADULTNEUROGENESIS

Although still controversial, adult neurogenesis appears to be both modulatableand therapeutically significant.88 It would be of obvious utility to functionally re-place lost neurons in neurodegenerative diseases. Curcumin has been reported tostimulate neuronal differentiation of stem cells in vitro and adult neurogenesis invivo, notably in the striatum.15 Although this is a single report that needs confirma-tion and extension, it shows additional potential for curcumin in conditions withCNS injury and neurodegeneration.

11. OBSTACLES FACING THE CLINICAL DEVELOPMENTOF CURCUMIN

As summarized in Table 1, curcumin has at least ten neuroprotective effects and itcan apparently act at nanomolar or even picomolar doses. For example, curcumin’ski for amyloid binding is 200 picomolar.89

Curcumin is neuroprotective in multiple animal models and has great potentialfor the prevention or treatment of age-related dementia arising from AD or car-diovascular disease, Parkinson’s disease, other diseases of aging, and aspects ofaging itself. Like any drug, it needs preclinical development to establish dosing,formulation, pharmacokinetics, therapeutic windows, and potential toxicity. Nor-mally, these issues are the concern of drug companies, but in the absence of patentprotection, this is unlikely to occur. Further, large clinical trials will be requiredto establish efficacy for any of curcumin’s many disease indications. Primary

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Table 1. Ten neuroprotective effects of curcumin.

LIMITS MECHANISM

Pro-inflammatory cytokine induction Inhibition of AP-1, NF-�B, HAT, HDAC stimulation?

Reactive oxygen species (ROS) Scavenger, metal/Fe chelator, induces AO defense

enzymes

A� production Suppresses cholesterol, BACE1 induction

Amyloid aggregates Congo red mimetic/aggregate inhibitor

Misfolded protein accumulation Potentiates HSPS

Neurotoxicity JNK pathway

Excitotoxicity COX-2 induction via AP-1, NF-�B

Toxicity Phase II inducer, HO-1

Particulate toxins Increases phagocyte clearance

Neuron loss Stimulates neurogenesis

Note: References are reviewed in the text.

prevention of age-related neurodegeneration would be the eventual goal, but thisis even less likely to ever be tested in clinical trials. Government or philanthropicsupport will likely be required to realize curcumin’s potential for amelioratingage-related neurodegeneration and other debilitating conditions with enormouspersonal and economic costs.

12. CONCLUSION: RATIONALE FOR MULTITARGET APPROACHTO AGE-RELATED DISEASE

Most chronic age-related conditions are not caused by foreign pathogens, but thefailure to repair or resist chronic age-related lesions arising from naturally oc-curring damage or imbalances. They involve prolonged multistep cascades thatinduce slow degeneration that would best be dealt with by long-term preventionwith very inexpensive and safe interventions rather than new drugs with unknownor unacceptable costs and side-effect profiles. This is a huge issue because in theabsence of a foreign pathogen, most of the targets will involve essential phys-iological pathways, where major inhibition will predictably lead to sideeffects.With modest efficacy from multiple beneficial activities, a pleiotropic drug likecurcumin can be efficacious without side effects. Further, the original cause mightbe superseded by subsequent steps in the cascade and no single pathway mightbe responsible for ongoing degeneration. For example, most of these diseases in-volve inflammation and oxidative damage, which are known curcumin targets.Atherosclerosis and stroke, colon cancer, and Alzheimer’s are prime examples.Furthermore, Alzheimer’s and other neurodegenerative diseases of aging typi-cally involve amyloidogenic protein misfolding and aggregation that can be di-rectly combated by curcumin’s anti-amyloid activity and possibly by potentiatingHSP synthesis. Curcumin’s favorable effects on cholesterol metabolism are alsolikely to reduce vascular disease and mixed dementia that cause dementia and fre-quently overlap AD. There are other likely beneficial effects. Finally, stimulation

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of neurogenesis might facilitate functional replacement of lost neurons, and cur-cumin has been reported to stimulate adult neurogenesis. With so much potential,the argument for curcumin’s further development for neurodegenerative and otherdiseases of aging is compelling.

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[ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY] The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease Volume 595 || NEUROPROTECTIVE EFFECTS OF CURCUMIN