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Mini-Reviews in Medicinal Chemistry, 2007, 7, 171-180
Prevention and Treatment of Alzheimer Disease and Aging: Antioxidants
Quan Liu1,3,*, Fang Xie2, Raj Rolston1, Paula I. Moreira1,4, Akihiko Nunomura5, Xiongwei Zhu1,Mark A. Smith1 and George Perry1,6,* 1Departments of Pathology and 2Pharmacology, Case Western Reserve University, Cleveland Ohio 44106 USA; 3Department of Ophthalmology, University of California, San Diego, San Diego, California 92093 USA; 4Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-517 Coimbra, Portugal; 5Department of Psy-chiatry and Neurology, Asahikawa Medical College, Asahikawa 078-8510, Japan; 6College of Sciences, University of Texas at San Antonio, San Antonio, Texas 78249 USA Abstract: There is considerable evidence showing that oxidative damage is one of the earliest neuronal and pathological
changes of Alzheimer disease and many, if not all, of the etiological and pathological causes of the disease are related, di-
rectly or indirectly, to free radical production and oxidative damage. Here we summarize the current body of knowledge
suggestive that oxidative damage is, if not the key factor, certainly a major factor in Alzheimer disease. As such, therapeu-
tic modalities encompassing antioxidants may be an effective approach to the treatment of neurodegenerative diseases and
delay the aging process.
Key Words: Antioxidant, calorie restriction, estrogen, free radical, glutathione, oxidation, oxidative stress, sirtuin, therapy,
vitamin C, vitamin E.
GENERAL INFORMATION ABOUT ALZHEIMER
exponentially with age, such that up to 47% of individuals over age of 80 develop AD [15]. On average, AD patients Alzheimer disease (AD) was first reported by Dr. Alois live about 8 years after initial diagnosis, although the disease Alzheimer, a German doctor, in 1907 at a neurology confer- can last for as long as 20 years. The areas of the brain that ence, where he described a 51-year-old woman with rapid control memory and thinking skills are affected first but, as memory degeneration who died with severe dementia several the disease progresses, neurons in other regions of the brain years later [1,2]. Although the disease was once considered are also affected. Eventually, the patient with AD will need rare, it is now established as the leading cause of dementia. complete care. The physical and emotional burden of the According to the American Health Assistance Foundation disease is borne by the patient and family members until the and the Alzheimer’s Association, there are an estimated 4 million diseased individuals in the United States and 18 mil- PATHOLOGY OF ALZHEIMER DISEASE
lion worldwide, with as many as 350,000 individuals being diagnosed with the disease each year. In the US alone, an- Two distinctive hallmark lesions found in the brains of nual expenses exceed US $70-$100 billion [3]. The disease patients with AD are senile plaques and neurofibrillary tan- is still not curable, with current clinical therapy of cholin- gles (NFTs) (reviewed in [2]) which were identified by the esterase inhibitors/NMDA receptor antagonists such as use of silver-staining techniques [16]. In addition, other neu- Reminyl (galantamine), Aricept (donepezil hydrochloride), ropathological changes associated with the disease include Exelon (rivastigmine) and Namenda (memantine), which neuronal and dendritic loss, neuropil threads, dystrophic neu- offer little more than short-term palliative effects. rites, granulovacuolar degeneration, Hirano bodies, cere-brovascular amyloid, and atrophy of the brain [2]. AD involves the parts of the brain that control thought, memory, and language. After two decades of intensive study, Senile plaques are spherical extracellular lesions, 10-200 during which much more information has been obtained, the Lm in diameter, with a central core made of bundles of 6-10 cause of AD is still a mystery. Currently, there are several nm A
[2]. In the peripheral region of the senile plaques, A
major theories of AD, such as amyloid-
(A
) toxicity [4], and amyloid-
protein precursor (A
PP), tau, and neurofila- tauopathy [5], inflammation [6,7], oxidative stress [8-13], all of which have been vigorously argued in the literature. NFTs, the major intracellular protein aggregation found CLINICAL FACTS OF ALZHEIMER DISEASE
in AD brains, are located primarily in the cerebral cortex, The risk of AD varies from 12% to 19% for women over especially in the large pyramidal neurons in the hippocampal the age of 65 years and 6% to 10% for men [14] and rises and frontotemporal regions [18]. NFTs are composed of bundles of paired helical filaments (PHF), the major compo-nent of which is the microtubule-associated protein tau [19, *Address correspondence to these authors at the Department of Ophthal-mology, University of California, San Diego, 9500 Gilman Drive # 0946, La 20]. Moreover, neurofilament proteins are also reported in Jolla, California 92093-0946 USA; Tel: 858-534-8824; Fax: 858-534-1625; NFTs [17,21]. In PHF, tau is abnormally hyperphosphory- lated [5,22,23], ubiquitinated [24-26], oxidized [8,27-29], College of Sciences, University of Texas at San Antonio, 6900 North Loop truncated [30] and aggregated into filaments [5,31,32]. The 1604 West, San Antonio, Texas 78249 USA; Tel: 210-458-4450; Fax: 210- hyperphosphorylation of tau is thought to render it unable to 1389-5575/07 $50.00+.00
2007 Bentham Science Publishers Ltd.
Mini-Reviews in Medicinal Chemistry, 2007, Vol. 7, No. 2
Liu et al.
bind to microtubules and therefore unable to promote or for a small percentage (~5%) of total AD cases, many have maintain microtubule assembly [33], although in vivo, while argued that mutations in A
PP and presenilin 1 and 2 are microtubules are disrupted, this has no relation to NFT [34]. critical genetic factors in the AD pathogenesis and in A
The resistance to proteolytic degredation of hyperphosphory- lated tau may play a key role in neurofibrillary degeneration Apolipoprotein E Gene Polymorphism: Polymorphisms of the ApoE gene are found to correlate with onset and risk While the pathological hallmarks are the basis for current of developing AD. ApoE is an abundant 34-kDa glycoprotein diagnostic standards, whether they represent the initial causes that is synthesized and secreted mainly by astrocytes and or the consequences of disease is hotly contested [37-39]. microglia in the central nervous system (CNS). It is well ETIOLOGY OF ALZHEIMER DISEASE
established that ApoE, and especially the E4 allele of ApoE,is a major genetic risk factor for the more common, late- Only about 5% of all AD cases have an early onset and onset form of AD [48,49]. The influence of ApoE genotype are related to genetic mutations of presenilin 1, presenilin 2 on AD seems to operate via multiple mechanisms. For ex- or the A
PP genes [40]. Indeed, the majority, approximately ample, polymorphisms are a determinant of brain A
burden 95%, of all AD patients are sporadic, late-onset cases where in individuals affected with AD [50,51]. Additionally, apol- the major risk factors are aging and apolipoprotein E4 ipoproteins have been suggested to act as antioxidants, with (ApoE4) polymorphisms [41,42]. In both familial and spo- the ApoE4 allele being less effective in this role [52] so that radic cases of disease, there is accumulating evidence indi- increased oxidative damage is found in specific brain regions cating a major role for free radicals and oxidative stress in of AD patients with the ApoE E4 genotype [53]. disease pathogenesis and pathophysiology [11,12]. Amyloid-
Protein Precursor
A
protein is the major component of senile plaque cores Age is the single greatest risk factor for AD and the dis- and is derived from the precursor protein, A
PP. A
PP is ease rarely occurs in people under 60 years. Thereafter, AD encoded on chromosome 21 (21q11-22) [54,55]. The normal affects 10-15% of individuals over 65 years old and up to function of A
PP is unknown, but it is involved in several 47% of individuals over the age of 80 [15]. This predomi- broad physiological functions in neurons. Mutations in A
PP nance of age as a major cause in AD etiology indicates that appear to change A
PP processing and while initially this age-related events are closely involved in the development of was thought to lead to increases in A
, thus increasing the the disease. While the processes of aging that are involved in extracellular protein aggregation [56,57], more recent reports AD pathogenesis are not fully understood, two likely candi- actually show decreases in A
[58]. Transgenic mice that dates are altered cholinergic function and oxidative stress. overexpress mutant A
PP show overproduction of A
pro- The former, decreases of cholinergic neurons with age and tein, senile plaque formation and synaptic deficits without disease [43] is the basis for therapy with three currently used NFTs pathology, indicating a key pathological role for mu- drugs that stabilize acetylcholine levels in neurons. The lat- tant A
PP protein [59,60]. The current data finds that A
PP ter, oxidative stress is discussed in detail below. mutation only accounts for a very small percentage of AD cases, 0.1-0.15% of total AD cases. Oxidative Stress
Presenilins 1 and 2
As one of the leading proposed causes of aging [44], free radical damage and oxidative stress are also thought to play a The majority (~70%) of early-onset familial AD cases are major role in the pathogenesis of AD. Oxidative stress is a associated with mutations in two genes, presenilin 1 and pre- potential source of damage to DNA, lipids, sugars and pro- senilin 2, located on chromosomes 14 and 1, respectively teins within cells. Any imbalance between the intracellular [61]. Over 50 different pathogenic mutations in presenilin 1 production of free radicals/reactive oxygen species (ROS) gene and 3 mutations in presenilin 2 gene have been de- and antioxidant defense mechanisms results in oxidative scribed [62]. There is considerable homology between the stress [8,11,12]. Since neurons have an age-related decrease gene products of presenilin 1 and presenilin 2, which are in the capacity to compensate for redox imbalance, even mi- transmembrane proteins of 463 and 448 amino acids respec- nor cellular stresses have the ability to lead to irreversible tively, with six and nine hydrophobic membrane-spanning injury and, as such, contribute to the pathogenesis of neu- domains [61]. The physiological functions of these two pro- rodegenerative diseases. ROS, including free radicals, are the teins are unknown but may be involved in the Notch receptor primary mediators of oxidative injury and cause damage to pathway [63]. Other possible roles include ion channel, pro- lipids, sugars, DNA/RNA and amino acid side-chains [13, tein processing, or cellular trafficking functions [64]. In AD, 45]. Markers for oxidative damage (carbonyls, HNE, MDA it is thought mutations in these proteins are associated with and more) may increase in neurodegenerative diseases and AD by affecting the processing of A
PP [65]. aging, but whether they can be used as quantifiable markers Tauopathy
Hyperphosphorylation of tau makes it more resistant to Genetics
proteolytic degradation, which may play a key role in neu- The greatest correlated genetic factor for the develop- rofibrillary degeneration in AD patients [35,36]. Tau aggre- ment of AD are polymorphisms of the ApoE gene, such that gation was, until quite recently, viewed as being deleterious. 50% of patients with AD patients have at least one ApoE4 However, more recent evidence indicates it is a consequence allele [41,42]. Further, although familial AD only accounts of neurodegeneration. In fact, tau aggregation may be an Prevention and Treatment of Alzheimer Disease and Aging: Antioxidants
Mini-Reviews in Medicinal Chemistry, 2007, Vol. 7, No. 2 173
adaptive change for the neurons to absorb oxidative stress 1) Oxidative damage is an earlier change compared to other [29,38,66,67]. Consistent with this notion, tau phosphoryla- pathological manifestations of the disease [94,95]. tion and aggregation and NFT epitopes have been shown 2) Increased levels of oxidative damage are found in post- experimentally to be both consequences of oxidative stress mortem tissue of AD, including oxidative modifications and post-translational oxidation of tau [29,31,68-71]. of lipid, protein, DNA and sugar [27,96-99]. Other Factors
3) Increased response to oxidative stress or compensatory factors: Hyperlipidemia, hypertension, defense exaggeration can be seen in the affected brain diabetes, and related factors of heart disease or stroke have been identified as putative antecedents to AD [72]. 4) High amounts of metal ions can be seen in AD brain Down Syndrome
Adults with Down syndrome develop the neuropa- 5) Altered mitochondria functions are commonly observed thological changes of AD by age 40, but not all patients be- come demented. The risk of AD in families with a history of 6) Formation of a specific age-associated oxidative Alcohol
Free Radical Theory of Aging and Free Radical Produc-
Individuals who drink red wine in moderate amounts daily are less likely to develop AD than either heavier drink- Aging is the inevitable decline in physiologic functions ers or abstainers [73]. The risk reduction associated with that occurs over time and, for all living organisms, ends in alcohol is possibly related to its anti-inflammatory and anti- death. At least four major theories of aging have been pro- oxidant properties or its effects on lipid metabolism by com- posed to explain most or all of the physiological and patho- Education and Early Life Experience
Several studies show that the risk of AD among poorly educated individuals or individuals in poor living condition is significantly higher than that among well-educated per- Smoking
Professor Denham Harman, the founder of the free radi- Smokers have a 2-4 fold increase in risk of AD, particu- cal theory of aging, has defined aging as the increased prob- larly those individuals without an ApoE4 allele [77,78]. ability of death as the age of an organism increases, and di-verse adverse physiologic changes accumulate [44]. Free Head Injury
radicals, the highly reactive small oxygen-containing mole- There is an increase of the risk of AD related with trau- cules, undeniably play major roles in not only the free radi- cal theory of aging but also in the mitochondrial theory, membrane theory and cross-link theory as well or is a com- Anti-Inflammatory Drugs
AD was found to be less frequent among individuals who A molecule carrying an unpaired electron, which makes it extremely reactive and ready to acquire an electron in any way possible, is termed a free radical. In the process of ac- Hormone Replacement
quiring an electron, the free radical will attach itself to an- The use of estrogen by postmenopausal women has been other molecule, thereby modifying it biochemically [109]. associated with a decreased risk of AD [81,82]. Women us- However, as free radicals acquire an electron from the other ing hormone replacement had about a 50% reduction in dis- molecules, they either convert these molecules into other free ease risk with benefit only to those taking estrogen in the radicals, or break down or alter their chemical structure. peri-menopausal period. While the exact mechanism for this Thus, free radicals are capable of damaging virtually any is unclear, recent evidence points to the feedback effect of biomolecule, including proteins, sugars, fatty acids and nu- estrogen on luteinizing hormone [83-92]. cleic acids [110]. Free radical damage to long-lived bio-molecules such as collagen, elastin, DNA, polysaccharides, OXIDATIVE STRESS IS THE KEY FACTOR IN
lipids that make up the membranes of cells and organelles, ALZHEIMER DISEASE
blood vessel walls and lipofuscins is thought of as a major contributor to cell death [111]. Evidence Supporting Oxidative Damage in Alzheimer
Disease
The most common free radicals include superoxide, hy- droxyl, hydroperoxyl, alkoxyl, peroxyl and nitric oxide radi- The histopathological and the experimental evidence, cal. Other non-free radical molecules, such as singlet oxy- which support the impact of oxidative damage in the patho- genesis of AD, are outlined below [8,10,12,93]. Mini-Reviews in Medicinal Chemistry, 2007, Vol. 7, No. 2
Liu et al.
(HOCl), are similar but not real free radicals. Together, the Many cellular molecules are active antioxidants in the free radicals and free radical mimics are called ROS. body. For example, GSH, ascorbate (vitamin C),
-tocopherol (vitamin E), -carotene, NADPH, uric acid, bilirubin, sele- Free radicals have extremely short half-lives ranging nium, mannitol, benzoate, the iron-binding protein transfer- from nanosecond to seconds. The shortest is only one nano- rin, dihydrolipoic acid, melatonin, plasma protein thiol, and second (10-9 sec) for hydroxyl radical and the longest half- reduced CoQ10 are all involved in protecting the body from life is 1-10 seconds for nitric oxide radical [112]. The half- ROS and their byproducts produced during normal cellular life dictates the intrinsic properties of the damaging effects metabolism. Of these, GSH is the most significant compo- of the free radicals, whether they can travel far enough to nent that directly quenches ROS such as lipid peroxides (like reach other cellular compartments or just attack the most hydroxynonenal) and plays major role in xenobiotic metabo- nearby molecules. The further they can travel, the broader lism. Exposure to high levels of xenobiotics causes GSH to the range of molecules and organelles they can damage. be exhausted in the process of xenobiotic neutralization and A wide range of major diseases closely related to free it is therefore less available to serve as an antioxidant. GSH radical damage, such as cancer, heart/artery disease, essential is also important in maintaining ascorbate (vitamin C) and
- hypertension, AD, cataracts, diabetes, Parkinson’s disease, tocopherol (vitamin E) in their reduced form so they may arthritis and inflammatory disease, as well as aging itself, are function as antioxidants to quench free radicals [120-122]. now believed to be caused in part or entirely by free radical Exogenous Antioxidants from the Diet
The most widely studied dietary antioxidants are vitamin Sources of Free Radicals
C, vitamin E, and -carotene. Vitamin C is considered the There are more than six primary sources of free radicals most important water-soluble antioxidant in extracellular formed endogenously within living organisms. fluids, as it is capable of neutralizing ROS in the aqueous phase before lipid peroxidation is initiated. Vitamin E is a The major source of free radicals and oxidants is through major lipid-soluble antioxidant, and is the most effective the respiratory generation of ATP using oxygen. [113-115]; chain-breaking antioxidant within the cell membrane, where the second source of free radical production is the peroxiso- it protects membrane fatty acids from lipid peroxidation. - mal oxidation of fatty acids, which generates H2O2 as a by- carotene and other carotenoids also provide antioxidant pro- product [114,115]; the third source is cytochrome P450 en- tection to lipid rich tissues. Fruits and vegetables are major zymes [115]; the fourth, and preventable, source of free radi- sources of vitamin C and carotenoids. Whole grains, cereals, cal production is from chronic inflammatory cells which use and high quality vegetable oils, are major sources of vitamin a mixture of oxidants to overcome infection by phagocytosis [110,114,115]; the fifth source is from other enzymes capa-ble of generating oxidants under normal or pathological con- The Vulnerability of The Nervous System
ditions [116]; the sixth source is various biomolecules in- The nervous system – including the brain, spinal cord, cluding thiols, hydroquinones, flavins, catecholamines, pter- and peripheral nerves – is rich in both unsaturated fatty acids ins and hemoglobin, may spontaneously auto-oxidize and and iron. The double bonds in unsaturated fatty acids make produce superoxide radicals [110]. Recent research indicates them a vulnerable target for free radicals, and this, coupled that A could induce peptide fragmentation and free radical with the high aerobic metabolic activity in neurons, makes the nervous system particularly susceptible to oxidative damage. The high level of iron, while it may be essential, Many exogenous sources, such as environmental radia- particularly during brain development, facilitates oxidative tion (sunlight), polluted urban air, cigarette smoke, iron and stress via iron-catalyzed formation of ROS [126,127]. In copper salts, some phenolic compounds found in many plant addition, those brain regions that are rich in the catechola- foods, and various drugs [110,114] could contribute to free mines, adrenaline, noradrenaline and dopamine, are excep- tionally vulnerable to free radical generation. Catechola- Antioxidant Systems
mines can induce free radicals through either spontaneous breakdown (auto-oxidization) or by being metabolized by Endogenous Antioxidants
endogenous enzymes such as monoamine oxidase. One such To protect against free radical-induced cellular damage, region of the brain is the substantia nigra, where a connec- cells have endogenous defense mechanisms to quench free tion has been established between antioxidant depletion (in- radicals that include enzymatic antioxidant systems and cel- cluding GSH) and tissue degeneration [11]. There is an increase in markers of oxidative stress in ma- SOD, catalase, and glutathione peroxidase are three pri- jor neurodegenerative diseases [8,27,28,96-98,101,128,129] mary enzymes involved in direct elimination of active oxy- and substantial evidence that oxidative stress is a cause, or at least the initial change, in the pathogenesis of AD [94]. tathione reductase, glucose-6-phosphate dehydrogenase, and ANTIOXIDANT CLINICAL TRIALS AND STUDIES
cytosolic GST are secondary enzymes. The latter function to FOR THE TREATMENT OF ALZHEIMER DISEASE
decrease peroxide levels or to maintain a steady supply of Current Clinical Drugs in Use
metabolic intermediates like glutathione (GSH) and NADPH for optimum functioning of primary antioxidant enzymes Therapy with acetylcholinesterase inhibitors, including drugs such as Reminyl, Aricept and Exelon, which aim to Prevention and Treatment of Alzheimer Disease and Aging: Antioxidants
Mini-Reviews in Medicinal Chemistry, 2007, Vol. 7, No. 2 175
stabilize acetylcholine levels in the synaptic cleft to maintain model systems [136] and prolong lifespan in C. elegans neurotransmission, is based on the hypothesis that choliner- [137]. It is reported that SOD, peroxidase and catalase activ- gic dysfunction in the process of aging contributes to the ity is reduced with age and in some pathological conditions development of AD. The newly-developed drug, Memantine, [138]. Therapy aimed at compensating for loss of activity of an NMDA receptor antagonist, blocks glutamate-mediated these enzymes is a promising approach to AD therapy. excitotoxicity. All drugs currently in clinical usage are re- Iron Chelators
A
PP transgenic mice treated with a Cu/Zn chelator Antioxidant Therapy Development
showed improvement in general health parameters and a The stages of free radical production may be arbitrarily reduction of brain A
deposition [139]. Because copper and divided into 1) conditions prior to their formation, 2) free zinc play a major role in A
toxicity and nerve cell death via radical formation and 3) adduction. The different types of ROS generation, chelator therapy is, in effect, antioxidant antioxidant therapy are based on their intervention at differ- [140-142]. In one study, 48 presumed AD patients treated ent points in the stages of free radical formation. Summa- with desferrioxamine, a transition metal chelator, (250 mg rized below are current strategies for developing antioxidant per day), showed this class of compounds to be effective in preventing AD progression [143]. Recently, desferrioxamine and others, as FDA-preapproved drugs, were shown to limit Compounds or Methods That Prevent/Reduce Formation
A
protein secretion in cell culture [144]. More iron chela- of Free Radicals
tors are under investigation and show beneficial effect in AD Modulation of SOD, Peroxidase and Catalase or Using
Their Mimics
Caloric Restriction
Overexpression of human Cu-Zn SOD in transgenic mice Studies of caloric restriction in rodents show an attenua- showed reduced oxidative damage in brain [133] and im- tion of age-related deficits in learning and memory [146] and proved cognitive functions in aged rodents [134]. Overex- dramatically extends the life-span and reduces the incidence pression of glutathione peroxidase in transgenic mice also of age-related disease in rodents and monkeys [147,148]. showed antioxidative function and rescued homocysteine- The mechanism of the beneficial effect of caloric restriction induced endothelial dysfunction [135]. Moreover, the mim- is not clearly understood but is most likely via overall reduc- ics of SOD and catalase have cytoprotective effects in AD Classification of Antioxidant Therapy to Different Stages of Free Radical Production
Classifications Importance
References
Compounds or Methods That Prevent/Reduce Formation of Free Radicals Modulation of SOD, peroxidase and catalase or using their mimics Compounds That Directly Scavenge Free Radicals Tocopherols (vitamin E), ascorbate (vitamin C) Serotonin (5-hydroxytryptamine), quercetin, idebenone Carotene, flavonoids and other polyphenols, retinol and other polyenes Compounds That Can Limit the Extent of Damage to Detoxify or Prevent the Formation of ROS Adducts Reparative enzymes (methione sulfoxide reductase) * - frequency or relative numbers of studies. Mini-Reviews in Medicinal Chemistry, 2007, Vol. 7, No. 2
Liu et al.
tion in levels of oxidative stress, including in the brain [149]. Estrogen
In humans, a low daily calorie intake is associated with a The general neuroprotective effects of estrogen (17 - reduced risk for AD [150]. In addition, the incidence of AD estradiol) have been the subject of much research. Generally, is lower in countries with low per capita food consumption estrogen through interaction with its receptors ER
and ER, compared to countries with high per capita food consump- acts as a trophic factor in the nervous system by altering tion [151,152]. Reducing caloric intake as a preventive gene transcription [165]. At the same time, in a manner more measure in populations at high risk for AD could be com- closely related to direct antioxidants, estrogen can have anti- bined with other AD treatment. The development of chemi- oxidant activity independent of estrogen receptors. The cal mimics for caloric restriction, such as resveratrol and structure of estrogen is much like -tocopherol in that both sirtuins [153,154], may make caloric restriction for normal molecules contain a phenolic radical scavenging moiety and people more easily attainable in the future. a lipophilic carbohydrate moiety. In general, phenolic A ring Compounds That Directly Scavenge Free Radicals
estrogens have been shown to be powerful inhibitors of lipid Various compounds have the ability to quench free radi- peroxidation in various cell-free test-tube experiments [166- cals by reacting with them directly. These compounds in- 168]. By changing the phenolic character of estrogen 17 - clude tocopherols (vitamin E) and other monophenols, ascor- estradiol, its antioxidant activities are lost, supporting the bate (vitamin C), carotene, flavonoids and other polyphenols, theory that estrogens are direct antioxidants because of their GSH ratio (GSH/GSSH), retinol and other polyenes, ary- phenolic ring structure [169,170]. Furthermore, this antioxi- lamines and indoles, ebselen and other selenium-containing dant activity of estrogens and other phenols is strictly related compounds, mimics of catalase/SOD, etc. The major anti- to the structural prerequisites and not dependent on the inter- oxidants in the group of direct antioxidants are the chain- action of these compounds with cellular estrogen receptors breaking antioxidants, such as phenols and carotenes. [167]. Meanwhile it has been shown that estrogens are strong antioxidants in different oxidative stress-induced cell degen- Vitamin E and Vitamin C
Vitamin E has been found in rats, to prevent neuronal cell One thing to be considered is the optimum concentration death induced by hypoxia followed by oxygen reperfusion of estrogen needed to achieve the antioxidant effect. Nor- and to prevent neuronal damage from reactive nitrogen spe- mally, estrogen is present in nanomolar concentrations in cies [155]. Both vitamin E and -carotene, by reducing oxi- vivo and, in most in vitro studies, estrogen’s antioxidant ef- dative stress, protect rat neurons from exposure to ethanol fect is achieved at a significantly higher concentration range [156]. In an experimental model of diabetes-caused neuro- of 1-10 Bmoles. Therefore, it remains to be determined how vascular dysfunction -carotene, followed by vitamins E and the antioxidant effect of estrogen can be achieved therapeuti- C, was found to protect cells effectively [157]. Vitamin E can rescue the neuronal cytotoxicity induced by aluminum in APP transgenic mice and reduce A deposition in the brain It was recently shown that HRT, in the form of estrogen plus progestin, administered as a therapeutic agent in a WHI clinical trial was shown to increase the risk for probable de- A significant amount of research with dietary vitamins E mentia in postmenopausal women aged 65 years or older and C has been done in humans. In a multicenter, double [173]. The investigators responsible for this study hypothe- blind, placebo-controlled study on 341 patients with moder- size that the negative effect of estrogen and progestin may be ately severe AD, a daily dose of approximately 1350 mg linked to the increased risk of stroke that was also reported (2000 IU) vitamin E led to a slight delay of AD progression, in the estrogen/progestin treatment group, as the relationship providing the first evidence for vitamin E as prophylaxis and between microinfarcts in the brain and susceptibility to AD treatment for AD [158]. In keeping with these results, other is likely related, yet currently not well characterized. While studies with vitamins C and E in AD patients have shown this may indeed partially explain the results of the WHI that antioxidants might have a protective effect against AD clinical trial, it is only when the role of the other hormones of the hypothalamic-pituitary-gonadal axis during the cli- In one later study, 815 non-demented individuals were macteric years and beyond is taken into account that the re- evaluated based on their intake of the antioxidants vitamins sults of the WHI clinical trial can be fully and accurately C and E and -carotene. Results showed that there is a sig- explained. For instance, it is crucial when interpreting the nificant difference in the incidence of AD between those results of this study to recognize that the hormones of the taking vitamin E and those who are not [161]. In another hypothalamic-pituitary-gonadal axis have been in disequilib- large-scale study involving 5396 non-demented individuals, rium for decades in all of the women who participated in the it was reported that a high intake of vitamins C and E sig- WHI clinical trial, so if a lack of estrogen does indeed play a nificantly reduces the risk of AD [162]. Similarly, in a 5-year role in AD pathogenesis, these women have been exposed to follow-up with 1367 non-demented individuals over 65 years this disease-promoting hormonal environment for years if of age in France, Commenges and colleagues [163] found not decades by the time the estrogen/progestin treatment was that an intake of flavonoids significantly reduced the risk of administered. This is evidenced by the fact that reports of probable dementia appeared within the first year of the study in both the treatment and placebo groups. Therefore, it is While promising, many studies have also reported nega- likely predictable that the administration of estrogen/progestin tive results to disagree with the effectiveness of vitamin E in these aged women was not only unable to restore the and vitamin C intake as detailed in other reviews [164]. proper functioning of the hypothalamic-pituitary-gonadal Prevention and Treatment of Alzheimer Disease and Aging: Antioxidants
Mini-Reviews in Medicinal Chemistry, 2007, Vol. 7, No. 2 177
axis, but that the influx of exogenous hormones actually half-maximal effective concentrations ranging from 20-75 served to exacerbate the disease process. nM, these compounds were experimentally proven to be more effective than common standard phenolic antioxidants. Glutathione
These results provide a structural basis and rationale for the GSH, the most abundant intracellular non-protein thiol, is development of new antioxidant drugs [189,190].
the main factor which directly quenches free radicals in vivo.
Compounds That Can Limit the Extent of Damage to,
It has been shown that the level of GSH is decreased in cor- Detoxify or Prevent the Formation of ROS Adducts
tical areas and in the hippocampus of patients with AD as compared with controls [174-176]. The level of GSH in red There are yet another group of compounds that can de- blood cells decreases with aging and in patients with AD toxify the formed ROS adducts and repair the damage they [177]. In the healthy cell, oxidized glutathione (GSSG) produce. These include NAC, GSH, 2-oxo-thiazolidine-4- rarely exceeds 10% of total cellular GSH. Therefore, the carboxylate, carnitine, creatine, lipoic acid (thioctic acid), ratio of GSH/GSSG can be used as a useful indicator for oxidative status in vivo [178]. GSH depletion may be the The compound tenilsetam, a cognition-enhancing drug, is ultimate factor determining vulnerability to oxidant attack. sometimes used to treat AD patients. Its mechanism of action N-acetyl-cysteine (NAC), a precursor of GSH which has is unclear but, based on in vitro and in vivo evidence, it is already been approved by the U.S. Food and Drug Admini- believed to inhibit protein glycation [191,192]. Since genera- stration for treatment of acetaminophen toxicity, may be an tion of advanced glycation endproducts is a major manifesta- effective strategy to increase GSH and spare brain degenera- tion of oxidative stress in AD [8,98,129] glycation inhibition tion in AD patients, although this remains to be tested. Other Direct Antioxidants
Many amino acid residues of proteins are susceptible to Compounds such as serotonin (5-hydroxytryptamine), oxidation by various forms of ROS. Oxidatively-modified flavanoids, quercetin, and simple alkylphenols have been proteins accumulate during aging and in a number of age- shown to prevent membrane lipid peroxidation and protect related diseases. There is an increase in oxidation of the S- neuronal cells against oxidative cell death in vitro [179,180]. containing amino acids methionine and cysteine in AD pa-tients [193]. However, unlike oxidation of other amino acid 2,4,6-trimethylphenol (TMP) is also a potent antioxidant residues, the oxidation of these two amino acids can be re- [167]. Additionally, being a small compound, TMP would paired by corresponding enzymes, methionine sulfoxide re- readily cross the blood-brain barrier, thus meeting the most ductases (MSR), thioredoxin reductase (TrxR), thioredoxin critical requirement for drugs used in the treatment of neu- (Trx), and NADPH. The level of MSR is decreased with rodegenerative diseases. The protective potential of this aging and in AD and other neurodegenerative diseases [193]. compound is currently being tested experimentally in various Also, mutation in the MSR gene in yeast, bacteria, and mice animal models of acute neurodegeneration. as well as its overexpression in yeast, neuronal PC-12 cells, In two large clinical studies, administration of idebenone, human T cells and Drosophila has been correlated with in- a compound structurally similar to ubiquinone, has been re- creased antioxidant capacity and the prolonged life span of ported to significantly reduce disease progression in a dose- dependent fashion [181,182]. Some in vivo studies in ani- CONCLUSIONS AND FUTURE PERSPECTIVES
mals as well as in vitro studies have demonstrated a protec-tive effect of idebenone in neuronal death [183]. More recent It has been well established that oxidative damage of studies argued the effectiveness of idebenone in AD treat- cellular molecules plays an important role in neurodegenera- ment [184,185], but another study showed that idebenone is tive disorders. Furthermore, it is clear that oxidative damage better than tacrine in benefit-risk ratio in AD treatment is not simply a byproduct or end product of neuronal degen- [186]. Whether idebenone acts by modulating mitochondrial erative processes but, more likely, the direct initiation factor metabolic function or directly as a radical scavenger is still Currently, even with the huge amount of data produced Uric acid, an endogenous antioxidant, was also found to and increase in knowledge, there is much skepticism regard- prevent ischemia-induced oxidative neuronal damage in rats ing the likelihood of success with antioxidant therapy in AD. [155]. In addition, cannabidiol is more effective than either The only promising results so far are from the trial of vita- vitamin C or E in protecting against glutamate neurotoxicity min E therapy in moderately severe AD [158,199]. It would [187]. It has been demonstrated that the antioxidant activity be difficult for most of the presently known compounds with of cannabinoid compounds is, similar to estrogens, exclu- antioxidant activity to pass through the blood brain barrier. sively dependent on the presence of a phenolic group and is There is much scope for research to identify smaller antioxi- independent of the cannabinoid receptor [188]. dant molecules that would more readily pass through the blood brain barrier and/or non-toxic or inert compounds that Different aromatic amino and imino compounds (e.g., would carry antioxidant drugs from the bloodstream into the phenothiazine, phenoxazine, iminostilbene) are another group brain. Additionally, it is imperative that future trials use of direct antioxidants. Aromatic amines and imines are effec- combinations, rather than single antioxidants to facilitate tive against oxidative glutamate toxicity, GSH depletion, and redox cycling as well as maximize bioavailability to different H2O2 toxicity in different cell culture systems [189]. With Mini-Reviews in Medicinal Chemistry, 2007, Vol. 7, No. 2
Liu et al.
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Received: 08 September, 2006
Revised: 21 September, 2006
Accepted: 09 October, 2006

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