curcumin and neurodegenerative diseases
TRANSCRIPT
Review Article
Curcumin and Neurodegenerative Diseases Adriana Monroy1
Gordon J. Lithgow2
Silvestre Alavez2*
1Direcci�on de Investigaci�on, Hospital General de M�exico,M�exico D. F., M�exico2Buck Institute for Research on Aging, Novato, CA, USA
Abstract
Over the last 10 years curcumin has been reported to be effec-
tive against a wide variety of diseases and is characterized as
having anticarcinogenic, hepatoprotective, thrombosuppres-
sive, cardioprotective, antiarthritic, and anti-infectious proper-
ties. Recent studies performed in both vertebrate and
invertebrate models have been conducted to determine
whether curcumin was also neuroprotective. The efficacy of
curcumin in several preclinical trials for neurodegenerative
diseases has created considerable excitement mainly because
of its lack of toxicity and low cost. This suggests that curcu-
min could be a worthy candidate for nutraceutical interven-
tion. As aging is a common risk factor for neurodegenerative
diseases, it is possible that some compounds that target aging
mechanisms could also prevent these kinds of diseases. One
potential mechanism to explain several of the general health
benefits associated with curcumin is that it may prevent
aging-associated changes in cellular proteins that lead to pro-
tein insolubility and aggregation. This loss in protein homeo-
stasis is associated with several age-related diseases.
Recently, curcumin has been found to help maintain protein
homeostasis and extend lifespan in the model invertebrate
Caenorhabditis elegans. Here, we review the evidence from
several animal models that curcumin improves healthspan by
preventing or delaying the onset of various neurodegenerative
diseases. VC 2013 BioFactors, 39(1):122–132, 2013
Keywords: curcumin; model organisms; mammals; neurodegenerative
diseases
1. Introduction
Curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is the main component of Curcumalonga, generically known as turmeric, a perennial plant of thefamily Zingiberaceae that grows naturally in southeast Asia.Turmeric is a spice present in Indian curries and many dishesin south Asia. It has also been used for thousands of years inIndian and Chinese medicine [1]. The main components of tur-meric extracts (curcumin, demethoxycurcumin, and bisdeme-thoxycurcumin) are commonly known as curcuminoids. Multi-ple beneficial effects of curcumin, which could be linked to itsability to act as a strong antioxidant and anti-inflammatory,
have been reported during the last 10 years (please see Dr.Shehzad’s paper in this issue). In studies performed on cellcultures and in different animal models, curcumin has beenreported to provide a number of beneficial effects. These stud-ies have led to the identification of several pharmacological tar-gets of curcumin and have shed some light on the molecularmechanisms activated by this compound. Interestingly, andmaybe because of its lack of toxicity and inexpensive cost, someclinical trials have also been conducted with this compound.Curcumin has been reported to be effective against a wide vari-ety of diseases such as cancer [2,3], cardiovascular disease [4],obesity [5,6], liver disease [7,8], inflammatory disease [9–11],and even aging [12–14] (for a comprehensive review of thesetopics, please see the appropriate chapters in this issue).
In addition to the age-related pathologies noted above,curcumin may have beneficial effects on specific kinds of dis-eases characterized by the formation of aggregated fibrillarproteins deposits. Collectively known as conformational dis-eases [15,16], they are responsible for tremendous social andeconomic burden. Especially under neurodegenerative condi-tions, the aggregation of aberrant forms of specific proteinssuch as a-synuclein (Parkinson’s disease, PD) [17], b-amyloid(Alzheimer’s disease, AD) [18], and huntingtin (Huntington’sdisease, HD) [19] may contribute to the onset and/or progres-sion of the disease. Initially, the protein aggregates themselves
VC 2013 International Union of Biochemistry and Molecular Biology, Inc.Volume 39, Number 1, January/February 2013, Pages 122–132*Address for correspondence to: Silvestre Alavez, PhD, Buck Institute forResearch on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA.Tel.: þ1 415 209 2298; Fax: þ1 415 209 2232;E-mail: [email protected] 27 August 2012; accepted 2 October 2012DOI: 10.1002/biof.1063Published online 10 January 2013 in Wiley Online Library(wileyonlinelibrary.com)
122 BioFactors
were considered to be the toxic insult leading to cell death.However, more recent studies suggest that soluble aggregateprecursors such as soluble oligomers or fibrils may initiate pa-thology by influencing neuronal function [15]. Although adetailed characterization of how these insoluble intracellularand extracellular deposits develop is still unclear, multiple fac-tors such as pH, metal ions, protein concentration, and oxida-tive stress have been reported to play a role in theirformation.
It has been estimated that AD and PD are the twoneurodegenerative diseases with the greatest incidence in theUSA and that AD accounts for 60–80% of all dementiadiagnosed [20]. The costs associated with treating thesediseases and paying caregivers, as well as the loss of produc-tivity of those afflicted, in 2010 has been estimated to be �800billion Euros [21]. These statistics strongly suggest that devel-oping therapies aimed to reduce or delay neurodegenerativedisease should be a priority for the biomedical community.
PD is named after James Parkinson who described ‘‘shak-ing palsy’’ in 1817. This disease is characterized by severalsymptoms such as bradykinesia, tremors, rigidity, dementia,and depression. At the molecular level, this motor dysfunctionhas been associated with pathological spherical inclusions inneurons of the substantia nigra, known as Lewy bodies, andwith a loss of nigrostriatal dopamine (DA) neurons. Despitegreat effort, the etiology of this disease is still undetermined.However, it does seem clear that a cumulative loss of dopami-nergic neurons during aging could contribute to the onset/pro-gression of the disease. This pathology can be accelerated byexposure to environmental toxins, excitotoxicity, oxidativestress, or mutations in the a-synuclein gene, which encodes aprotein found in Lewy bodies in idiopathic PD lesions. Becauseof the loss of dopaminergic neurons in the substantia nigra,striatal cholinergic neurons are disinhibited, leading to animbalance of dopaminergic/cholinergic neurotransmission [22].As DA does not cross the blood–brain barrier, pharmacologicalapproaches to treat PD have focused on developing drugs ableto increase DA or reduce acetylcholine (ACh) activity in thebrain. The primary approaches include the use of levodopa, aDA precursor and indirect agonist of G protein-coupled D2receptors, which increase DA production; direct stimulation ofD2 receptors with selective agonists such as bromocriptine,ropinirole, pramipexole, or rotigotine; or preventing DA enzy-matic catabolism by enzymes such as monoamine oxidase typeB (e.g., selegiline and rasagiline) or catechol-O-methyltransfer-ase (e.g., entacapone and tocalpone). These compounds are of-ten administered with antimuscarinics, such as benztropine ortrihexyphenidyl, to decrease striatal cholinergic excitability[23].
AD is a neurodegenerative illness characterized by earlyonset of short-term memory loss and cognitive decline thateventually leads to dementia. This disease is associated with aparticular brain pathology that includes neurofibrillar tanglesand senile plaques (b-amyloid, Ab). Aggregated Ab in senileplaques have a b sheet secondary structure and are arranged
in fibrils [24]. A significant amount of neuronal loss has beenreported during AD progression (e.g., basal forebrain, hippo-campus, and associative cerebral cortex). At molecular level,this neuronal loss seems to be associated with a reduction ofcholine acetyltransferase activity and, as a consequence, witha marked diminution in ACh levels. No drugs are currentlyavailable to prevent this neuronal degeneration. To date, thepotential antiamyloid therapeutic approaches to treat AD focuson the amyloid cascade theory, such as the Ab vaccine ortreatment with metal-complexing agents [25,26]. However,several drugs that prevent ACh degradation have also beenused to improve cognition during AD (e.g., tacrine ordonepezil).
HD is a neurodegenerative disorder caused by the autoso-mal dominant mutation of the huntingtin gene. Altered proteinaggregates affect muscle coordination and lead to abnormalinvoluntary movements, known as chorea, as well as cognitiveand psychiatric problems. Tetrabenazine, an inhibitor of thevesicular monoamine transporter 2 (VMT2) that promotes do-pamine degradation, is used to treat Huntington’s chorea, butnot to treat HD itself [27].
Unfortunately, current treatments in PD, AD, and HD,beyond symptomatic improvement, do not have neuroprotec-tive properties or the potential to modify the course of the dis-ease, and even symptomatic relief is temporary. Additionally,all these compounds are highly toxic and can cause severeside effects (nauseas, stomach cramps, dizziness, drowsiness,insomnia, headache, diarrhea, dry mouth, mydriasis and evendelirium, depression, or hallucinations).
2. An Important Role for Curcumin
With all this in mind, it is easy to understand the excitementgenerated by a compound like curcumin. If curcumin could beshown to have strong efficacy, it has the potential to become acandidate for nutraceutical intervention in neurodegenerativedisease. It is interesting to note that, because of its strong af-finity for fibrillar amyloid proteins, curcumin is already usedto stain in vitro tissue sections from affected individuals [28].The search for curcumin derivatives with higher specificitiesfor Ab fibrils and adequate lipophilic properties for crossingthe blood–brain barrier is a subject of current research[29,30]. Further fueling these efforts is research showing thatcurcumin is able to prevent aggregation of Ab in vitro and incell cultures [31,32], suggesting that curcumin could alter theeffects of protein aggregation in animal models and potentiallyin humans.
However, as alluded earlier, one of the principal limita-tions for the use of curcumin in nutraceutical interventions isits limited bioavailability, which is mainly because of its poorabsorption and fast metabolism. Although curcumin is verystable in acidic media, at physiological pH it is easily degradedto ferulic acid and feruloylmethane [33]. Whether these metab-olites could have similar properties to those reported for
Monroy et al. 123
curcumin is still an active field of research. In parallel, effortsto increase its bioavailability in mammals, particularly inhumans [34–37], by conjugating it to a stable carrier or bycoadministering it with inhibitors of curcumin metabolismhave rendered some interesting results. Research in this areais comprehensively covered in Dr. Helson’s review in this spe-cial issue.
Despite what are apparent pharmacokinetic limitations,curcumin has been reported to have multiple pharmacologicalactivities and to be effective against a wide variety of diseasesbecause of its anticarcinogenic [2,3,7,37–40], hepatoprotective[8,41–44], thrombosuppressive [45,46], cardioprotective [47–49], antiarthritic [9–11], and anti-infectious properties [50–54].
Everything considered, the demographic shift toward anolder population makes compounds with this broad spectrumof potential clinical applications particularly interesting. Theremainder of this review will summarize the effects of curcu-min in diverse experimental models of neurodegenerative dis-eases and speculate on the directions the field is headed inthe immediate future. We particularly emphasize studies ofcurcumin in invertebrate models, mice and clinical trials inhumans.
3. Effect of Curcumin in Cell Cultures
In addition to the reported benefits of curcumin in traditionalChinese and Indian medicine, the beneficial effects of curcu-min have been demonstrated in a wide variety of cells, includ-ing neurons [55], astrocytes [56], and microglia [57]. Effectshave also been tested in primary cell cultures from differentregions of the central nervous system, including cerebral cor-tex [58], mesencephalon [59], hippocampus [55], and spinalcord [60]. Curcumin is known to possess neuroprotective prop-erties [61], and its anti-inflammatory [62], antioxidant [63],and insulin-sensitizing effects [64] have been described usingneuronal/glial primary and immortalized cells though its inter-action with different molecular targets including metals, proin-flammatory cytokines, protein kinases, and other enzymes[65].
Ab aggregation is a feature of AD and curcumin has beenshown to be able to inhibit the formation of the Ab fibrils invitro [66]. In fact, in a classic experiment where 214 antioxi-dant compounds were tested, curcumin proved the strongestinhibitor effect on the formation of Ab fibrils [67]. Further-more, curcumin demonstrates a dose-dependent effect on theinhibition of Ab1–40/1–42 fibrils and even destabilizes preformedfibrils in vitro [66]. Several studies have also demonstrated theability of some curcuminoid compounds, including turmericextract, to suppress Ab aggregation and oligomerization [68–70]. Yang et al. documented the ability of curcumin to inhibitAb aggregation and protect against Ab-induced cell death [31].In addition, Zhang et al. showed that curcumin decreased bothAb levels and amyloid precursor protein (APP) maturation in
mouse primary cortical neurons [71]. Curcumin-mediated cellsurvival in Ab as well as APP-challenged cell systems is due toattenuation of apoptosis and oxidative injury. Curcumin treat-ment of human neuroblastoma SK-M-NC cells prevents celldeath elicited by the Ab peptide through the inhibition of NFjBactivation [72]. Similarly, PC12 rat pheochromocytoma cellsare protected from Ab insult through an antioxidant pathway[73]. Interestingly, curcumin is also able to prevent the fibrilla-tion pattern of a-synuclein, the main protein involved in PD,in vitro [74].
Neuroinflammation plays a key role in the onset and pro-gression of neurodegenerative diseases. In line with this idea,curcumin reduces the expression of IL-1a, IL-6, and TNF-a inLPS-stimulated BV2 microglia in a dose-dependent manner[75]. It is known that amyloid aggregates can be cleared viaphagocytosis by brain macrophages and that patients with ADshow signs of defective phagocytosis that results in an ineffec-tive clearance of Ab plaques. Interestingly, curcumin can stim-ulate microglial phagocytosis and clearance of Ab in vitro aswell as increase the induction of heat-shock proteins inresponse to the addition of soluble Ab aggregates to neuronalcultures [76].
A link between iron metabolism and AD pathogenesis issuggested by the presence of an iron-responsive element in the50 UTR of the APP mRNA [77]. Additionally, high amounts ofiron and copper in amyloid plaques could be responsible forstimulating free radical generation and thus increasing proteinand DNA oxidation, lipid peroxidation, advanced glycation endproducts, carbonyls, malondialdehyde, peroxynitrite, and hemeoxygenase-1 (OH-1) while decreasing levels of cytochrome c oxi-dase [78]. In this context, the antioxidant properties of curcu-min might also be linked to its capacity to complex with redox-active metals because curcumin can bind iron or copper ions inin vitro experiments [79] and because copper–curcumin com-plexes show radical scavenger and superoxide dismutase-likeproperties [80].
PD has been modeled in vitro through the specificneurotoxic effect of the 6-hydroxydopamine (6-OHDA) and1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [81] ondopaminergic neurons. Neurotoxicity triggered by 6-OHDA isattenuated by curcumin treatment in both SH-SY5Y andMES23.5 cells through the inhibition of reactive oxygenspecies (ROS), mitochondrial protection, and antiapoptoticmechanisms [82,83]. Curcumin also confers protection againstMPTP- (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) andMPPþ (1-methyl-4-phenylpyridinium)-induced apoptosis inPC12 cells through the Bcl-2-mitochondria-ROS-iNOS pathway[84] and by the inhibition of the JNK pathway, which contrib-utes to preventing dopaminergic neuronal death in SH-SY5Ycells [85].
Taken together, these results suggest that curcumin couldalso have beneficial effects in whole organisms. In the nextsection, we will analyze the current state of research involvingcurcumin and invertebrate models of aging and neurodegener-ative disease.
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124 Neuroprotective Effects of Curcumin
4. Effect of Curcumin in InvertebratesModels of Aging and Neurodegeneration
Caenorhabditis elegans has been used to identify moleculeswith a broad range of activities such as antihelminthics, anti-fungals, and compounds with neuronal activity [86–91]. Addi-tionally, a number of pharmacological interventions on theaging process have been demonstrated in this system [92–105]. Many of the C. elegans small-molecule studies to datehave focused on the effects of natural products such asextracts from Ginkgo biloba [106], blueberry phenols [107], orresveratrol [108]. Interestingly, curcumin is also able toincrease lifespan through a mechanism that involves theregulation of protein homeostasis [104]. However, curcuminseems to have no effect on mouse lifespan [109], although it ispossible that this compound could affect other aspects of agingincluding neurodegenerative diseases or that it could extendlifespan when administered differently.
In addition to the multiple benefits and resources for ex-ploitation of the worm system as a platform for drug discovery,worms have also been genetically engineered to expresshuman disease-associated proteins. For example, a robustmodel of protein aggregation in which human Ab peptide3–42 isexpressed under the control of the unc-54 myosin promoter inmuscle tissue has been developed in C. elegans [110]. Modelsexpressing tau protein in neurons [111,112], a-synuclein in dif-ferent tissues [113–116], and mouse prion protein [117] havealso been generated in this model system. There are alsotransgenic worms expressing chains of polyQ of differentlengths, characteristic of the huntingtin protein, tagged to YFPdriven by the unc-54 promoter. As observed in humans, theydemonstrate an aggregation rate that is dependent on thepolyQ repeat length, which culminates in a paralysis pheno-type [118,119]. Several compounds that increase lifespan havebeen reported to prevent protein aggregation in these models[120]. Recently, we exploited some of these worm models ofneurodegenerative diseases to test several compounds that weidentified as having prolongevity properties [104]. We foundthat these compounds significantly decreased the paralysisphenotype associated with Ab peptide3–42, PolyQ, myosin, andperlecans aggregation through a mechanism that requirescomponents of the protein homeostasis network. In particular,we found that 100 lM curcumin supplementation increasesworm lifespan by a mechanism that depends on both the heatshock factor 1 (HSF-1), a transcription factor that has longbeen associated with the control of stress resistance, as wellas a dietary restriction (DR)-like mechanism [121]. Theseresults were later confirmed by another laboratory that foundthat curcumin’s antioxidant properties are also required forthe lifespan increase induced by this compound [13].
Curcumin also increases lifespan, enhances stressresistance, and improves spontaneous locomotion in two dif-ferent strains of Drosophila melanogaster [12]. Similar to thecase in worms, Drosophila has been genetically engineered toproduce models of neurodegenerative disease including AD,
PD, tauopathies, several polyglutamine disorders, amyotrophiclateral sclerosis, and Prion disease [122]. Unfortunately, just afew interventions in neurodegenerative diseases are found inthe literature. Recently, Caesar et al. showed that curcumin(1–100 lg/g yeast paste) is able to increase lifespan andimprove locomotion in five different genetic models of AD inDrosophila [123]. After curcumin treatment, they found nochanges in number or size of Ab deposits but instead observeda tendency to favor amyloid fibril formation over the solubleoligomeric Ab species.
These studies demonstrate that a process long associatedwith age-related neurodegenerative disease is also a generalfeature of aging, suggesting that the loss of protein homeosta-sis could be a common mechanism of aging and disease. It fol-lows that pharmacologically targeting the age-related declineof protein homeostasis could reduce and/or postpone neurode-generative disease and extend lifespan.
There are, of course, many limitations to using these sim-ple animal models and we should not underestimate the com-plexity of human disease by comparing to the events modeledin worms and flies. Indeed, most of the enzymatic machinerythat processes neurotoxic proteins is not present in theseinvertebrates, and in most cases they lack critical modulatorsof disease progress such as complex inflammatory responses.
Nevertheless, these results suggest that edible compoundslike curcumin could be used to suppress age-related diseasepathologies and underline some important concepts for a novelapproach to the discovery of new drugs with the potential toimprove the conditions of neurodegenerative diseases. It isalso important to consider that compounds that affect the dy-namics and patterns of protein aggregation could also gener-ate some soluble oligomeric species potentially toxic to thecell. Additionally, at the concentration required to affect pro-tein aggregation, some compounds could have off-targeteffects that act in parallel to produce deleterious effects on cellphysiology. Therefore, caution ought to be taken when consid-ering compounds identified through this experimentalapproach for use as potential therapeutic drugs.
5. Effect of Curcumin in Mammals
A small number of compounds have been tested for their abil-ity to increase lifespan and improve healthspan in mammals.Among others, nordihydroguaiaretic acid and aspirin (2-ace-toxybenzoic acid) increase the lifespan of male, but notfemale mice [124], probably because of sex-specific pharma-cokinetics of these drugs. Interestingly, the immunosuppres-sant rapamycin that inhibits mTOR signaling is able toincrease lifespan in both male and female mice when admin-istered late in life [125,126]. Therefore, it is reasonable toassume that compounds that positively affect lifespan couldalso produce beneficial effects on degenerative diseases andhence, the effect of these compounds on healthspan is anactive field of research.
Monroy et al. 125
Despite there being no evidence that curcumin affects life-span in either male or female mice when administered begin-ning at 4 months of age [109], several interesting studies inrodents have examined the ability of curcumin to provide neu-roprotection from neurodegenerative disorders, especially ADand PD. For a review of the effect of curcumin in aging, pleasesee Dr. Lai’s chapter in this issue. In a pioneering study,Frautschy et al. [127] showed that a curcumin nutraceuticalintervention attenuated oxidative injury, microgliosis, synapto-physin loss, spatial memory deficits, postsynaptic loss, and Abdeposits produced by intracerebroventricular infusion of Abamyloid in rats.
The Ab-overexpressing Tg2576 APPSw transgenic mouse,a popular mouse model for AD, has also been used as a pre-clinical tool to evaluate the neuroprotective potential of curcu-minoids on this disease. Lim et al. [128] evaluated the effecton Tg2576 mice fed for 6 months with high doses (5,000 ppm)or low doses (160 ppm) of curcumin and found that both dosessignificantly decrease two biochemical conditions which nor-mally are found elevated in the brains of these mice, proteinoxidation and the levels of the proinflammatory cytokine inter-leukin-1b. In their experiment, low doses of curcumin attenu-ated Ab overexpression, decreased oxidative damage, and alsoreduced levels of glial fibrillary acidic protein, which isinvolved in brain injury and inflammation. In a subsequentstudy in Tg2576 mice, dietary administration of curcuminreduced amyloid plaque formation, attenuated both ROS andreactive nitrogen species (NOS) formation, as well asdecreased cell death [129]. Interestingly, in a study where cur-cumin was intravenously administered in Ab-overexpressingmice (PS1dE9), beneficial effects including plaque disruptionand attenuation of distorted neuritis were also observed [28].Besides its antiamyloid, antioxidant, anti-inflammatory, andcholesterol-lowing properties, curcumin can also attenuatememory deficits in AlCl3 and D-galactose-challenged Kunmingmice [130].
Taken together, these studies illustrate the potential ofcurcumin to reverse neurodegeneration and improve thecognitive impairments associated with AD. There are also datasuggesting that curcumin could have a protective effect againstneurodegeneration in PD. As found for Ab, curcumin can alsoinhibit the aggregation of a-synuclein [131], and several stud-ies performed in rodents have examined the neuroprotectivepotential of curcuminoids against both MPTP- and 6-OHDA-induced dopaminergic degeneration. In these studies, orallyand intravenously administered curcumin modulates dopami-nergic damage in 6-OHDA-treated rodents by suppressing apo-ptosis and inducing microglial activation with a consequentimprovement in locomotion [132,133]. Dietary, intravenous,and intraperitoneal curcumin administration reversed the do-paminergic neurotoxicity in MPTP-treated rodents. In theseexperiments, curcumin was able to decrease the oxidativestress, inhibit the activity of monoamine oxidase B, suppressapoptosis, inhibit protein nitration, increase levels of glutathi-one, and decrease the activity of mitochondrial complex I
induced by MPTP treatment [134–137]. Unfortunately, thereare limited data on the potential beneficial role of curcumin inother neurodegenerative diseases. This could be the result ofthe low incidence of these diseases. Recently, it has beenshown that dietary curcumin in a dose of 555 ppm causes adecrease in huntingtin protein aggregation, improved rearingdeficits, but impairing climbing behavior in the CAG140 mice,an animal model of HD [138]. These in vivo preclinical studiesexhibit the potential of curcumin as a neuroprotector and sug-gest a role for this compound in the prevention and reversal ofdegenerative diseases such as AD or PD (Table 1).
6. Curcumin in Clinical Trials
As described above, therapeutic options for the treatment ofneurodegenerative diseases offer limited benefits and multipleside effects, indicating the need to develop safe and effectivepharmacological agents for the prevention and treatment ofthese kinds of diseases. Because of its antioxidant and anti-inflammatory effects, as well as its ability to inhibit proteinaggregation, curcumin represents one of the most promisingcompounds with therapeutic potential. Epidemiologic evidenceof curcumin action is illustrated in a recent large population-based study of 1,010 elderly nondemented Asians. Subjects inthis study that consumed curry occasionally often or very oftenscored significantly better on the Mini-Mental State Examina-tion, an established measure of cognitive function, than didthose who never or rarely consumed curry [139]. The thera-peutic use of curcumin has been tested in two independentclinical trials. The first one was a 6-month randomized, pla-cebo-controlled, double-blind, clinical pilot study of curcuminconducted in patients with AD in Hong Kong, China. In thisstudy, 34 subjects started the trial and 27 completed; 8 sub-jects on 0 g, 9 on 1 g, and 11 on 4 g curcumin per day. No dif-ference was observed between the 1 and 4 g groups. On thisstudy, curcumin serum levels reached a maximum of 250 nMat 1.5 h when given with food and 270 nM at 4 h when givenwith water. The inability to detect any relative protective effectof curcumin could be due to the lack of cognitive decline in theplacebo group. However, when compared with the placebocontrol group, curcumin showed increased plasma levels ofvitamin E and increased serum Ab40, suggesting that curcumincould disaggregate Ab deposits in the brain and release Ab forcirculation and disposal [140]. The second clinical trial was aphase II double-blind study on mild to moderate AD, per-formed in CA, USA, with patients that receive 2–10 mg of cur-cumin for 6 months. Unfortunately, no significant improvementin cognitive function or changes in the levels of Ab, total tau,and phosphorylated tau in plasma and CSF were found [141](Table 1). To date, two other studies are still active. One is aphase II study in India using 2 g/day of curcumin. The second isan early intervention conducted in the USA with a combinationof 5.4 g of curcumin and bioperine, another natural productderived from black pepper that has been claimed to increase
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126 Neuroprotective Effects of Curcumin
the bioavailability of several nutritional compounds. These stud-ies are directed to evaluate the efficacy, safety, and tolerabilityof curcumin in moderate AD.
Despite the somewhat disappointing results of the clinicaltrials available to date, it is premature to conclude a total lack ofeffect of curcumin on AD or PD. Additional studies with largernumbers of patients and longer period of treatment could berequired to improve the clinical conditions, delay the onset, orameliorate the progression of these diseases.
7. Conclusions and Future Directions
Although identifying compounds that improve the healthspanof mammals is undoubtedly more relevant for human drug de-velopment, the prohibitive cost of mouse studies makes itextremely unlikely that large-scale chemical screens will becarried out in mice. Basic research in more cost-effectivemodel systems is therefore a critical starting point for identify-ing such compounds and elucidating their mechanism(s) ofaction. Cell culture and invertebrate model organisms provideopportunities to assay promising compounds, like curcumin, inan efficient manner. Moreover, once candidate compounds areidentified, model systems allow for rapid elucidation of thegenetic pathways being targeted by these compounds. Further-
more, some pathological features of certain diseases are nowbeing seen as a more general feature of aging. Perhaps, theclearest example of this is the failure of protein homeostasisassociated with age-related neurological disease, which leadsto the formation of intracellular or extracellular protein aggre-gates. This is consistent with a mechanistic relationshipbetween aging and disease.
The disappointing outcomes of dozens of phase III clinicaltrials in AD, PD, and others suggest that preclinical studies inanimal models are less relevant than we would hope. As agingis a major risk factor for many human diseases, compoundsthat slow aging are highly sought- after because of their poten-tial for treating age-related diseases. Here, we argue that therecent growth of a new subfield, the chemical biology of aging,will lead to the identification of candidate compounds andmechanistic insights that will ultimately propel forward treat-ments of age-related diseases. Curcumin is a great example ofthis general idea because of the multiple beneficial effectsreported for curcumin in vitro. Curcumin has been reported toincrease lifespan in C. elegans and Drosophila but does notseem to increase lifespan in mice. Nevertheless, there isenough evidence to suggest that curcumin could be of help inthe treatment of several neurodegenerative diseases and otherage-associated diseases to significantly improve healthspan.This could be due to its well-known antioxidant and anti-
Preclinical and clinical studies described in this paper
Animal model Dose Disease Effects Reference
Sprague-Dawley rats Diet, 500 and 2,000 ppm,
2 months
AD (Ab ICV infusion) ;Spatial memory deficits, oxidative
damage, microgliosis, synaptophysin
127
Tg2576 APPSw mice Diet, 160 and 5,000 ppm,
6 months
AD (Ab overexpression) ;IL-1b, oxidative damage, GFAP, Ab 128
Tg2576 APPSw mice Diet, 500 ppm, 4 months AD (Ab overexpression) ;Cell death, iNOS, IL-1b 129
PS1dE9 mice IV, 7.5 mg/kg/day, 7 days AD (Ab overexpression) :Restoration of distorted neuritis,
plaque disruption
28
Kunming mice PO, 200 mg/kg, 45 days AD(AlCl3, D-galactose) ;Spatial memory deficits 130
Sprague-Dawley rats PO, 50 mg/kg, 4 days PD (6-OHDA) THþ cells protection 132
ICR mice IP, 50 mg/kg, 3 times PD (MPTP) ;Oxidative damage, :dopaminergic
neurons
134
Swiss albino mice IP, 80 mg/kg, 7 days PD (MPTP) ;MAO-B 136
CAG140 Diet, 555 ppm HD ;Protein aggregation, :rearing, ;climbing 138
Humans Curry consumption AD Improve in cognitive function 139
Humans 1–4 g AD No changes in cognitive function 140
Humans 2–10 mg AD No changes in cognitive function or
Ab serum levels
141
TABLE 1
Monroy et al. 127
inflammatory properties, but could be also the result of a mod-ulation of protein aggregation through the regulation of pro-tein homeostasis or a dietary restriction-like mechanism asrecent studies in worms suggest (Fig. 1). As most of the drugtherapies for neurodegenerative diseases (like AD and PD) cur-rently available have shown little efficacy and produce multipleside effects, a nutraceutical intervention with an innocuous andcheap compound like curcumin could represent a major avenuefor the treatment of these diseases. One of the main limitationsfor a nutraceutical intervention with curcumin on neurodege-nerative diseases is its limited bioavailability. This could beaddressed by chemical modifications of curcumin, through itsconjugation with lipophilic compounds or by coadministration ofcurcumin with compounds that facilitate its absorption. Despitethat, clinical trials available to date do not provide conclusiveevidence of the efficacy of curcumin for preventing or treatingneurodegenerative diseases. There are, however, some encour-aging results suggesting that curcumin could be of therapeuticrelevance in these kinds of diseases. Of course, more studies areneeded to explore the effects of this compound in long-termnutraceutical interventions and the fact that curcumin seems tobe innocuous in humans could prompt additional studies on the
effect of curcumin in the onset and progression of several neuro-degenerative diseases.
AcknowledgementsThe authors thank Aric N. Rogers for helpful discussion. G.J.L.is supported by the NIH AG21069, AG22868, AG029631-01A1,ES016655, the Larry L. Hillblom Foundation, and UL1RR024917. S.A. was supported by the U19AGO231222 fromthe Longevity Consortium.
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through the AMPK pathway (Black arrows ¼ induction, red symbol ¼ inhibition).
FIG 1
BioFactors
128 Neuroprotective Effects of Curcumin
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BioFactors
132 Neuroprotective Effects of Curcumin