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Benzie IFF, Wachtel-Galor S, editors. Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. Boca Raton (FL): CRC Press; 2011.

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Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition.

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Chapter 15Botanical Phenolics and Neurodegeneration

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15.1. INTRODUCTION

There is ample evidence indicating that different reactive oxygen species (ROS), for example, superoxide, hydrogen peroxide, and hydroxyl and peroxyl radicals, are produced in cells under normal and pathological conditions (Sun et al. 2008). When the rate of ROS generation exceeds the capacity of antioxidant defense, there is consequential oxidative damage to DNA, proteins, and lipids. In the central nervous system (CNS), oxidative stress is implicated in mechanisms leading to neuronal cell injury in various pathological states. Recently, the term “nitrosative stress” has been used to indicate cellular damage elicited by reactive nitrogen species (RNS), which include nitric oxide (NO) and its congeners such as peroxynitrite and nitroxyl anion. Together, oxidative and nitrosative stresses are implicated in the pathology of many neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and stroke. The brain is particularly vulnerable to oxidative damage because it utilizes a large amount of oxygen for energy and has relatively low antioxidant defense enzymes, especially during aging. In addition, membranes in brain cells contain abnormally high proportions of polyunsaturated fatty acids (PUFAs). Of the different types of cells in the brain, neurons are especially vulnerable to insults by toxic compounds, and are sensitive to damage by ischemia/stroke, seizure, and other excitotoxic injury. Oxidative damage to lipids (lipid peroxidation) is associated with a progressive loss of membrane integrity, reduction of mitochondrial membrane potential, and increase in plasma membrane permeability to Ca2+. Oxidative damage to proteins leads to the formation of carbonyl and nitrosylated derivatives. Further, ROS damage to DNA results in nuclear condensation and altered gene expression. Therefore, oxidative stress is an important risk factor for neurodegeneration. In recent years, extensive effort has been devoted to developing novel strategies to overcome different types of insults in the brain (Sun et al. 2008; Farooqui and Farooqui 2009).

Many vegetables, fruits, grains, roots, flowers, and seeds are rich in polyphenolic compounds, and they offer beneficial effects in protecting against diseases involving oxidative stress, such as cancers and cardiovascular and neurodegenerative diseases. Although the mechanisms through which these compounds exert beneficial effects are not well understood, there is a general consensus that they possess antioxidant and anti-inflammatory properties, and are capable of chelating metal ions (Rice-Evans and Miller 1997; Martin et al. 2002; Ndiaye et al. 2005; Sun et al. 2008). Recent studies further reveal that some compounds may contribute specific biochemical effects that are beyond their antioxidant and radical-scavenging properties, for example, involvement in alterations of members of the “vitagene” system, such as heme oxygenase-1 (HO-1), heat shock protein (Hsp) 70, thioredoxin, and sirtuins. These effects may have an impact on the onset and progression of neurodegenerative diseases and aging. The understanding of these metabolic and signaling effects of polyphenols has paved the way for novel nutritional interventions (Calabrese et al. 2008, 2009). In this chapter, we review recent studies on four botanical phenolic compounds: resveratrol from grapes, curcumin from turmeric, apocynin from Picrorhiza kurroa, and epigallocatechin (EGC)- gallate from green tea. We discuss their potential beneficial effects in the prevention and treatment of neurodegenerative diseases, with an emphasis on AD, PD, and stroke.

15.2. OXIDATIVE STRESS AND NEURODEGENERATIVE DISORDERS

15.2.1. Alzheimer’s Disease

Alzheimer’s disease is the most common form of dementia and is a progressive, age-dependent neurodegenerative disorder affecting specific regions of brain that control memory and cognitive functions. The pathogenesis of AD is characterized by the accumulation of amyloid plaques and the presence of neurofibrillary tangles in neurons (Terry et al. 1991; Selkoe and Podlisny 2002; McKeel et al. 2004). Many studies have demonstrated that oxidative stress is an early event in the development of AD (Akama and Van Eldik 2000; Butterfield 2002; Butterfield et al. 2002a,b; Perry et al. 2002; Mattson 2004). Although the underlying mechanisms are still unclear, there is evidence that the soluble oligomeric form of amyloid-β peptides (Abeta) may be a key cytotoxic compound that impairs synaptic plasticity; long before Aβ is incorporated to form the amyloid plaques (Small 2001; Small, Mok, and Bornstein 2001; Selkoe and Podlisny 2002; Mattson 2004; Takahashi et al. 2004). Studies with transgenic mice and with cultured cells demonstrated that cytotoxic Aβ may cause neuronal cell death through generation of ROS (Zerbinatti et al. 2004; Ashe 2005; Barghorn et al. 2005; Smith et al. 2005). There is evidence that Aβ induces oxidative stress and causes neuronal damage by targeting excitatory ionotropic glutamate receptors, especially the N-methyl-D-aspartic acid (NMDA) subtype. Studies conducted in our laboratories demonstrated the ability of oligomeric Aβ and NMDA to stimulate cortical neurons and trigger signaling pathways, leading to the activation of mitogen-activated protein kinases (MAPKs) and phospholipase A2 (PLA2; Shelat et al. 2008). Our study and those conducted by others further demonstrate that these excitatory pathways involve ROS production by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Zhu et al. 2005; Shelat et al. 2008; Zhu et al. 2009). Involvement of Aβ and NMDA in neuronal excitotoxicity is in line with recent developments on memantine, an NMDA receptor antagonist used for the treatment of AD. Memantine is prescribed to treat moderate to severe AD patients, and is the most recently approved AD medication in the United States.

Besides changes in glutamatergic neurotransmission, loss of cholinergic neurons is also an important abnormality in AD pathology. The cholinergic hypothesis assumes that aberrant cholinergic transmission in the basal forebrain, some cortical regions, and the hippocampus is associated with memory impairment in advanced stages of AD (Contestabile, Ciani, and Contestabile 2008). Measurement of choline acetyltransferase activity, the key enzyme for acetylcholine synthesis, has been used for many years as a reliable marker for damage of the cholinergic pathways. Stereologic counting of the basal forebrain cholinergic neurons has also been used to assess neurodegenerative changes in the forebrain cholinergic system. Acetylcholine esterase inhibitors to slow the hydrolysis of acetylcholine at the synaptic terminals are symptomatic drugs for the treatment of AD (Takada-Takatori et al. 2009). Drugs such as donepezil, rivastigmine, and galantamine are currently prescribed to treat mild to moderate AD patients. Donepezil was also recently approved to treat severe AD. In general, these drugs are helpful in maintaining the abilities of individuals to carry out their daily living activities and in maintaining thinking, memory, or speaking skills. However, these drugs can offer only transient help (over a few months) and cannot reverse the progression of the disease.

Another mechanism by which Aβ induces neurodegeneration may involve inflammatory processes, which are triggered by oxidative changes (Butterfield 2002; Butterfield et al. 2002a,b). Currently, there are several ongoing, large-scale AD-prevention trials aiming at using antioxidants to decrease oxidative and inflammatory damage and for prevention and treatment of AD. One such ongoing trial, “Prevention of Alzheimer Disease with Vitamin E and Selenium (PREADVISE),” is sponsored by the National Institute for Aging and the National Cancer Institute, and aims at assessing whether taking selenium and/or vitamin E supplements can help prevent memory loss and dementia in AD (Kryscio et al. 2004, 2006).

Due to the diverse functional effects offered by many natural botanical compounds, there is widespread interest in considering them as possible therapeutics for treating AD patients (Howes and Houghton 2003; Howes, Perry, and Houghton 2003; Bastianetto and Quirion 2004; Anekonda and Reddy 2005). Plant-derived compounds are generally safer to use as compared with synthetic drugs (Raskin et al. 2002). Since neuroinflammation and oxidative damage are observed in the brains of transgenic rodent models of AD, a number of studies have used these animal models to test the neuroprotective effects of botanical compounds (Ringman et al. 2005; Anekonda 2006; Anekonda and Reddy 2006; Chauhan and Sandoval 2007; Mancuso et al. 2007; Sun et al. 2008). A brief description of these studies is included in Sections 15.2.1.1 through 15.2.1.4.

15.2.1.1. Resveratrol and Grape Polyphenols

Resveratrol (3,4′,5-trihydroxystilbene) is a polyphenolic compound found in purple grapes, red wine, peanuts, and several other plants (Baur et al. 2006; Baur and Sinclair 2006). Our earlier studies indicated that a dietary supplement of polyphenols extracted from grape skin and seeds could offer protection against oxidative damage to brain synaptic membranes (Sun and Cheng 1999; Sun et al. 1999). Studies with rat pheochromocytoma (PC-12) cells further showed that resveratrol was more effective in protecting oxidative damage than vitamins E and C combined (Chanvitayapongs, Draczynska-Lusiak, and Sun 1997). In an animal model for aging, resveratrol was shown to protect against neuronal damage and excitotoxicity induced by the administration of kainic acid in rats (Wang et al. 2004; Wang et al. 2005c). A time-course study of bioavailability of resveratrol in rats indicated that this compound is readily transported to the blood, liver, and brain shortly after intra-peritonial (i.p.) injection, and that most resveratrol was converted to a glycoconjugate form (Wang et al. 2002). Over the years, many other studies in vitro and in vivo have attempted to elucidate the underlying mechanisms of the neuroprotective effects of resveratrol (Gao et al. 2006; Lu et al. 2006; Raval, Dave, and Perez-Pinzon 2006; Choi et al. 2007; Tsai et al. 2007; Sun et al. 2008).

Besides alleviating stroke damage, resveratrol can offer multiple protective effects for other neurodegenerative diseases. This compound appears to mimic the effects of dietary calorie restriction, which has been shown to trigger the activation of sirtuin proteins (Howitz et al. 2003; Lamming, Wood, and Sinclair 2004; Wood et al. 2004; Sinclair 2005). Indeed, resveratrol has been found to increase the life span of a number of lower organisms, including yeasts, nematodes, and fruit flies (Howitz et al. 2003), and this effect is attributed to the activation of sirtuins, which are evolutionarily conserved nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases that are known to participate in the pathomechanisms of numerous age-related disorders (Tissenbaum and Guarente 2001; Cohen et al. 2004; Parker et al. 2005; You and Mak 2005). Although the exact mechanism of resveratrol in activating sirtuin 1 (SIRT1) and prolonging life span in organisms remains unclear, there is evidence that activation of SIRT1 is associated with the triggering of downstream proteins, such as peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), the forkhead transcription factor (FOXO) family, Akt (protein kinase B), and nuclear factor κB (NF-κB; Pallas et al. 2009). Several studies with cell and animal models suggest that resveratrol can exert neuroprotective effects through its ability to activate SIRT1 and other vitagenes (Rasouri, Lagouge, and Auwerx 2007). In a study with cultured embryonic mouse neurons, activation of the SIRT1/PGC-1 pathway was shown to protect against axonal degeneration of neurons and to decrease accumulation of amyloid peptides.

Studies demonstrating the ability of resveratrol to activate SIRT1 and other vitagenes make resveratrol a promising candidate as a therapeutic agent for treating AD (Anekonda 2006;Mancuso et al. 2007). Two recently conducted studies show that the deleterious effects of high-fat and highcalorie diets in mice can be mitigated by dietary supplementation with resveratrol. In one study, resveratrol reversed the shortened life span resulted the high-fat diet, and in the second study, resveratrol increased SIRT1 activation, PGC-1α deacetylation, and mitochondrial biogenesis in muscle (Calabrese et al. 2009). Interestingly, a synergistic protection can be achieved when resveratrol is administered in combination with catechin (C), another plant phenolic compound (Conte, Pellegrini, and Tagliazucchi 2003). In a rat model of sporadic AD, administration of resveratrol prevented cognitive impairment and oxidative stress induced by intracerebroventricular streptozotocin (Sharma and Gupta 2002). In another animal model of AD and tauopathy, resveratrol decreased neurodegeneration in the hippocampus and prevented learning impairment (Kim et al. 2007). A study conducted by Wang et al. (2006) showed that consumption of red wine by Tg2576 mice can attenuate deterioration of spatial memory function and Aβ neuropathology.

It is worth noting that besides causing in vivo effects, resveratrol can also inhibit the formation of Aβ fibrils and destabilize fibrilized Aβ (Ono et al. 2006a; Ono, Naiki, and Yamada 2006b). Resveratrol was reported to decrease amyloid-β secretion from different cell lines (Marambaud, Zhao, and Davies 2005). In other studies, resveratrol suppressed neuroinflammation by inhibiting NADPH oxidase activity and attenuating NF-κB-induced expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2; Bi et al. 2005; Kim et al. 2006). Taken together, these studies indicate that besides its antioxidant property, resveratrol may also exert neuroprotective effects through activation of sirtuin and vitagenes.

15.2.1.2. Curcumin (Diferuloylmethane)

Curcumin is derived from turmeric, the powdered rhizome of the medicinal plant Curcuma longa Linn., which is widely used as a spice in Southeast Asian and Middle Eastern cooking (see also Chapter 13 on turmeric). Turmeric is thought to have many medicinal properties; it is used as an antiseptic for cuts, burns, and bruises and used as an antibacterial agent. In Asian countries, curcumin can also help with stomach problems and other ailments. Besides being a strong antioxidant and anti-inflammatory agent (Ono et al. 2004), curcumin was also found to bind amyloid directly and inhibit Aβ aggregation as well as fibril and oligomer formation in vivo (Yang et al. 2005). Curcumin was found to inhibit the formation and extension of Aβ fibrils and to destabilize fibrilized Aβ (Ono et al. 2006a; Ono, Naiki, and Yamada 2006b).

There is a great need for well-designed studies to assess whether dietary curcumin is efficient in treating AD. In a study conducted on Tg mice, conventional nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, and curcumin were compared for their ability to protect against Aβ-induced damage in mice (Frautschy et al. 2001). Dietary curcumin (2000 ppm), but not ibuprofen, suppressed oxidative damage and synaptophysin loss. Dietary curcumin also decreased Aβ deposits, prevented Aβ-induced spatial memory deficits in the Morris water maze test, and prevented postsynaptic density loss in Tg mice (Frautschy et al. 2001). Both low and high doses of curcumin significantly lowered oxidized proteins and interleukin 1β, a proinflammatory cytokine that was elevated in the brains of the AD mice (Lim et al. 2001). Besides its antiamyloidogenic, antioxidant, and anti-inflammatory abilities (Ringman et al. 2005), curcumin can also alter signaling molecules and pathways in cells (Begum et al. 2008). Clearly, more clinical trials are needed to assess the therapeutic use of curcumin for the treatment of AD (Ringman et al. 2005; Fiala et al. 2007).

15.2.1.3. Apocynin

Apocynin (4-hydroxy-3-methoxy-acetophenone) is isolated from the root of Picrorhiza kurroa, a creeping plant native to the mountains of India, Nepal, Tibet, and Pakistan. Apocynin may also be obtained from other sources, for example the rhizome of Canadian hemp (Apocynum cannabinum), and other Apocynum species (e.g., A. androsaemifolium). P. kurroa has long been used as an herbal medicine for the treatment of liver and heart problems, jaundice, and asthma. The anti-inflammatory property of this herb is attributed to its ability to prevent ROS and peroxide formation in the body.

Apocynin has been shown to specifically inhibit NADPH oxidase by blocking the assembling of cytosolic NADPH oxidase subunits with the membrane subunits. The NADPH oxidase is a superoxide-producing enzyme and is increasingly recognized for its dual-edged role in health and disease and in mediating cell-signaling pathways (Sun et al. 2008). The prototypic NADPH oxidase comprises of a membrane-associated cytochrome b558 complex containing a p22 phox and a gp91 phox subunit and several regulatory cytosolic subunits, for example, p47 phox, p40 phox, and p67 phox. In addition, the small G protein Rac1 or Rac2 can also associate with the gp91 phox subunit to confer full activity. The NADPH oxidase is expressed in all brain cells, and is especially high in activated microglial cells. Recent studies have identified several isoforms of gp91 phox in different cell types, although their specific roles in mediating pathological pathways have not yet been fully elucidated (Block 2008; Chen, Song, and Chan 2009; Sorce and Krause 2009).

There is accumulating evidence suggesting that aberrant neuron–glia interactions may play an important role in the progression of neurodegenerative diseases. Astrocytes are the most abundant cell type in the human brain, and they are important in supporting neurons in a number of functions, including synapse formation and plasticity, energetics, and redox metabolism. Both astrocytes and microglia are immunologically active cells in the CNS and are involved in the inflammatory responses to injury and disease. In the AD-affected brain, glia-mediated inflammatory response has been linked to the enhancement of the deposition of amyloid plaques and neuronal damage (Salmina 2009). In particular, microglial cells are activated by cytotoxic Aβ and by different forms of neuronal injury, and these cells become a chronic source of neurotoxic cytokines and ROS that leads to impairment of neuronal function. In activated microglial cells, ROS produced by NADPH oxidase may cause neurotoxicity by directly interacting with nearby neurons. Alternatively, intracellular ROS may stimulate signaling pathways in microglia and amplify the production of proinflammatory and neurotoxic cytokines (Block 2008). In a coculture model, addition of macrophage cell lines deficient in NADPH oxidase gp91phox subunit failed to kill neurons. This study demonstrated that ROS generation by NADPH oxidase in microglial cells can play a crucial role in neuronal killing (Qin et al. 2006). Along this line, apocynin, the NADPH oxidase inhibitor, is considered a therapeutic compound to combat Aβ-induced microglial proliferation and neuronal death (Jekabsone et al. 2006; Mander, Jekabsone, and Brown 2006).

15.2.1.4. Epigallocatechin-3-gallate (EGCG)

Human epidemiological and experimental data on animals suggest health benefits of tea drinking (see also Chapter 12 on tea). Tea consumption is inversely correlated with the incidence of dementia, AD, and PD (Mandel et al. 2008b). Analysis of individual compounds in tea by high-performance liquid chromatography (HPLC) revealed high levels of C, epicatechin (EC), EC-3-gallate (ECG), EGC, EGC-3-gallate (EGCG), and gallic acid. Among these compounds, EGCG has been found to be particularly effective in offering neuroprotection in studies with cellular and animal models. There is evidence that in addition to the known antioxidant and anti-inflammatory properties of this compound, EGCG may protect neurons through modulation of signal transduction pathways, cell survival/death genes, and mitochondrial function (Mandel et al. 2008b). In BV-2 microglial cells, EGCG pretreatment effectively ameliorated Aβ-induced cytotoxicity and manifestation of proapoptotic signals. Furthermore, Aβ induces iNOS and production of NO in BV-2 cells, and EGCG effectively suppressed the Aβ-mediated NO in these cells (Kim et al. 2009). The EGCG (or curcumin) could also attenuate Aβ-induced ROS production and β-sheet structure formation (Shimmyo et al. 2008). In Swedish Tg mice overexpressing mutant human amyloid precursor protein (APP), EGCG administered orally in drinking water (50 mg/kg) decreased Aβ deposition. Both i.p. and oral administration of EGCG to the APP Tg mice also suppressed phosphorylation of tau isoforms and improved cognitive function. Interestingly, animals treated intraperitoneally with EGCG appeared to show a more pronounced benefit than those fed orally (Rezai-Zadeh et al. 2008). In a study with human neuronal cell line MC65, EGCG was found to enhance APP processing by the nonamyloidogenic proteolytic enzymes and decreased Aβ levels. In this study, EGCG was also found to decrease nuclear translocation of c-Abl and to block APP-C99-dependent GSK3 β activation (Lin et al. 2009). Another study also demonstrated the neuroprotective effects of EGCG by suppressing Aβ-induced β-secretase (BACE)-1 upregulation in Tg2576 AD mice (Rezai-Zadeh et al. 2005). Taken together, these observations lend strong support to the neuroprotective effects of green-tea polyphenols in retarding the progression of neurodegenerative disorders such as those exhibited in AD and PD.

15.2.2. Parkinson’s Disease

Parkinson’s disease is a chronic and progressive degenerative disease associated with impaired motor control, speech, and other functions. The disease is named after an English physician named James Parkinson, who gave a detailed description of the disease in an 1817 work entitled An Essay on the Shaking Palsy. This disease belongs to pathological conditions of movement disorders and is characterized by muscle rigidity, resting tremor, slowing of movement (bradykinesia) and, in extreme cases, a nearly complete loss of movement (akinesia). Secondary symptoms may include cognitive dysfunction, subtle language problems, and depression. These symptoms are caused by loss of dopaminergic neurons in the substantia nigra. Parkinson’s disease affects approximately 1% of the population over the age of 50 years. Despite numerous hypotheses and continued speculations, the etiology of PD remains unclear. The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an environmental toxin that can selectively damage the substantia nigra and subsequently result in Parkinsonian syndromes in animals and humans, has accelerated the search for other neurotoxins as the possible cause of PD (Langston 1987; Tipton and Singer 1993). Although a number of studies have used the MPTP model for studying degeneration of dopamine (DA) neurons and related pathophysiology of PD (Adams and Odunze 1991; Schapira 1996), other environmental toxins such as manganese (Sun, Yang, and Kim 1993), dimethoxyphenyl-ethylamine (DMPEA; Koshimura et al. 1997), and paraquat (Miller, Sun, and Sun 2007; Miller et al. 2009) have also been found to kill DA neurons. These studies provide information indicating that oxidative damage, mitochondrial and proteasomal dysfunction, and inflammation are underlying factors for degeneration of dopaminergic neurons in PD.

Dopamine is metabolized by monoamine oxidase (MAO) or through auto-oxidation with the generation of superoxide, hydrogen peroxide, and hydroxyl radicals. These oxidative events are considered the underlying causes for damage of dopaminergic neurons. NO, which may be released by inflammation-induced microglia (Castano et al. 1998) or generated by excitotoxic insults (Gonzalez-Hernandez, Perez de la Cruz, and Mantolan-Sarmiento 1996; Abekawa, Ohmori, and Koyama 1997), may also play a role in the pathogenesis of PD. The production of ROS and RNS together is an important cause for damage of DA neurons in PD.

The most widely used form of treatment for PD is L-dopa, a compound that can be transformed to DA in the dopaminergic neurons by L-aromatic amino acid decarboxylase (often known as dopa-decarboxylase). However, only 1-5% of L-dopa can enter the dopaminergic neurons. The remaining L-dopa can be metabolized to DA elsewhere, and it causes a wide variety of side effects. Carbidopa and benserazide are dopa decarboxylase inhibitors. These compounds help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are generally given in combination with L-dopa. The DA agonists such as bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, and lisuride are only moderately effective and frequently produce side effects including somnolence, hallucinations, and/or insomnia. Dopamine agonists may act by stimulating the DA receptors. However, these compounds may cause the DA receptors to become progressively less sensitive, thereby eventually exaggerating the symptoms. The MAO-B inhibitors selegiline and rasagiline can decrease the symptoms somewhat by inhibiting MAO-B, thereby inhibiting the breakdown of DA in the dopaminergic neurons. Metabolites of selegiline include levoamphetamine and levomethamphetamine, both of which are adrenergic drugs and cause side effects (Aminoff 2007).

An increasing number of studies demonstrate that plant polyphenols, especially flavonoids, are useful in protecting against brain damage in PD. These studies, including ours, have used either single compounds such as resveratrol, curcumin, EGCG, or complex mixtures/extracts such as grape, blueberry, and green tea (Weinreb et al. 2004; Lau, Shukitt-Hale, and Joseph 2005; Mercer et al. 2005; Chen, Jin, and Li 2007; Sun et al. 2008). Their neuroprotective effects may involve, at least in part, their ROS-scavenging and iron/metal-chelating activities, as well as their anti-inflammatory properties. Resveratrol administration was found to protect mice from MPTP-induced motor coordination impairment, hydroxyl radical overloading, and neuronal loss (Lu et al. 2008). Resveratrol has also been tested to produce beneficial effects in the 6-hydroxydopamine (6-OHDA)-induced PD rat model. This model involves chronic inflammation, mitochondrial dysfunction, and oxidative stress, and loss of dopaminergic neurons in the substantia nigra. Resveratrol treatment significantly decreased the levels of COX-2, tumor necrosis factor (TNF)-α messenger ribonucleic acid (mRNA), and COX-2 protein expression in the substantia nigra (Jin et al. 2008).

Curcumin is known to exert neuroprotective effects and ameliorate PD symptoms, due mainly to its antioxidant and anti-inflammatory properties (Zbarsky et al. 2005; Chen et al. 2006; Rajeswari 2006; Lee et al. 2007; Jagatha et al. 2008). Similar to its ability to dissociate aggregated Aβ, curcumin can also inhibit aggregation of α-synuclein, the presynaptic protein associated with the formation of neuronal inclusions (Pandey et al. 2008). Since curcumin can target multiple reactions and proteins in cells, including transcription factors, growth factors, antioxidant enzymes, cell-survival kinases, and signaling molecules, there is increasing interest in considering the potential use of this compound as a therapeutic to combat neurodegenerative diseases (Ramassamy 2006; Salvioli et al. 2007; Goel, Kunnumakkara, and Aggarwal 2008).

NADPH oxidase is regarded an important source of ROS in 1-methyl-4-phenylpyridinum (MPP+)-induced apoptotic neuronal death (Zhang et al. 2008). Treatment with NADPH oxidase inhibitors, such as diphenyleneiodonium chloride (DPI), apocynin, and superoxide dismutase (SOD) mimetics, could block the MPP+-induced ROS production in these cells (Anantharam et al. 2007; Miller, Sun, and Sun 2007; Miller et al. 2009). The environmental toxin paraquat, when used together with iron, could activate microglial cells. Apocynin could attenuate the release of superoxide from activated microglial cells and suppress MPP+-induced cytotoxic cell death (Anantharam et al. 2007; Peng et al. 2009). Thus, specific inhibition of NADPH oxidase-targeting dopaminergic neurons may prove beneficial against the progression of PD.

A prominent pathological feature of PD is the abnormal accumulation of iron associated with neuromelanin in the melanin-containing DA neurons. Lewy bodies, which are the morphological hallmark of PD, are comprised of lipids, redox-active iron, and aggregated α-synuclein, and are associated with ubiquitinated, hyperphosphorylated neurofilaments. The EGCG has been found to protect against neurodegeneration induced by neurotoxins in mice and rats and prevent the accumulation of iron and α-synuclein in the substantia nigra pars compacta (SNpc; Youdim 2003). It can also inhibit ROS production, suppress the cytotoxicity of rotenone in human neuroblastoma SH-SY5Y cells (Chung, Miranda, and Maier 2007), and protect against MPTP-induced damage in mice (Choi et al. 2002; Mandel et al. 2008b). Since EGCG can exhibit antioxidant effects and chelate iron, a combination of iron chelation and antioxidant therapy may provide additional neuroprotective effects against PD and other neurodegenerative diseases (Mandel, Maor, and Youdim 2004).

15.2.3. Stroke

Stroke is the rapidly developing loss of brain functions caused by disturbance in blood supply to the brain, and is the third leading cause of death and the first leading cause of long-lasting disability in aging adults. Stroke can be attributed to ischemia (lack of blood supply) caused by thrombosis or embolism, or to hemorrhages caused by disruption of blood vessels. As a result, the affected area of the brain is unable to function, leading to the inability to move, understand, or formulate speech. Ischemic stroke is caused by a thrombus (blood clot) occluding blood flow in an artery in the brain. Definitive therapy is aimed at removing the blockage by breaking up the clot by thrombolysis, or by removing the clot mechanically through a thrombectomy. Stroke is occasionally treated with thrombolytic drugs. Oral anticoagulants such as warfarin are the mainstay of stroke prevention in high-risk subjects. Aspirin and antiplatelet drugs are effective in secondary prevention after a stroke or a transient ischemic attack. Tissue plasminogen activator (tPA) is a thrombolytic drug used to dissolve the clot and unblock the artery. However, the use of tPA is limited to 3 hours after the onset of stroke. In patients with intracerebral hemorrhage, anticoagulants and antithrombotics can sometimes worsen the bleeding. Effective medication or drug therapy for hemorrhagic stroke treatment is limited. Stroke prevention strategies include controlling hypertension and diet, performing regular exercise, and quitting smoking and alcohol use. In order to study the pathoetiology and possible prevention of stroke, many animal models have been developed in which blood flow is focally or globally, permanently or transiently, or completely or incompletely interrupted. Focal cerebral ischemia animal model is usually produced by occlusion of the middle cerebral artery (MCAO), since it reflects the predominant form of clinical stroke. Since oxidative stress is an important underlying cause of neuron cell death in ischemia/reperfusion (I/R) injury, a number of studies have been carried out to test the beneficial effects of dietary antioxidants, including plant polyphenolics (Bravo 1998; Youdim and Joseph 2001; Deschamps et al. 2001; Voko et al. 2003). These studies provide strong evidence for the protective effects of botanical antioxidants, which can act at multiple levels to influence both the early and late phases of stroke (Simonyi et al. 2005; Curin, Ritz, and Andriantsitohaina 2006).

Earlier studies from our laboratory indicated protective effects of resveratrol against delayed neuronal cell death (DND) induced by global cerebral ischemia in gerbils (Wang et al. 2002). We also demonstrated that dietary supplementation with grape powder for 2 months could protect the brain from global ischemic injury (Wang et al. 2005a). Results from our studies are in agreement with others showing that grape seed extract is neuroprotective against ischemic injury (Hwang et al. 2004; Feng et al. 2007).

There are in vitro and in vivo studies indicating the ability of curcumin to exert protective effects against ischemia-induced neuronal injury. In our previous study, administration of curcumin to gerbils was found to decrease global ischemia-induced lipid peroxidation, mitochondrial dysfunction, and apoptotic indices (Wang et al. 2005b). In addition, curcumin also ameliorated the increase in locomotor activity observed at 48 hours after ischemic insult (Wang et al. 2005b). In another study by Jiang et al. (2007), curcumin was protective even when administered after focal ischemia. The authors attributed the protective effects to preservation of blood-brain barrier integrity (Jiang et al. 2007). Consistent with other bioavailability studies, our study (Wang et al. 2005b) also showed a rapid increase in curcumin in plasma after i.p. injection, which reached the brain within 1 hour after treatment (Ringman et al. 2005; Goel, Kunnumakkara, and Aggarwal 2008).

Immunohistochemical studies conducted in our laboratory demonstrated an increase in NADPH oxidase subunit expression after transient focal cerebral ischemia, and the increase was attributed to activated microglia (data not shown). Apocynin was shown to inhibit ischemic damage in different animal models (Wang et al. 2006; Tang et al. 2007) and to ameliorate blood-brain barrier damage in experimental stroke (Kahles et al. 2007). In our study using the gerbil global cerebral ischemia model, apocynin was shown to inhibit I/R-induced increase in lipid peroxidation, oxidative DNA damage, and glial cell activation in the hippocampus (Wang et al. 2006). Pretreatment (but not post-treatment) with apocynin was found to decrease ischemia-induced superoxide levels and lower brain damage (Jackman et al. 2009). Several studies have demonstrated that EGCG administration before or after ischemia also significantly decreased neuronal damage (see Table 15.1).

TABLE 15.1. Studies on Botanical Compounds Used in AD, PD, and Stroke Models.

TABLE 15.1

Studies on Botanical Compounds Used in AD, PD, and Stroke Models.

15.3. INTEGRATED SIGNALING MECHANISMS OF BOTANICAL PHENOLICS IN NEURODEGENERATIVE DISORDERS

Many plant extracts and identified plant-derived compounds have been found useful for treatment and prevention of neurodegenerative disorders. However, their underlying molecular mechanisms and therapeutic value are still largely unknown (Howes and Houghton 2003; Howes, Perry, and Houghton 2003; Anekonda and Reddy 2005). Investigation of the health benefits of these natural compounds poses substantial challenges to modern medicine. Polyphenols are divided into different groups, depending on the number of hydroxyl groups and derivatives to the benzene rings. Flavonoids make up the largest and the most important group of polyphenols, which can be divided into subgroups such as flavanols (C, EC), flavonols (quercetin, myricetin, kaempferol), flavanons (hesperetin, naringenin), flavons (apigenin, luteolin), isoflavonoids (genistein, daidzein), and anthocyanins (cyanidin, malvidin). Depending on their molecular structure, the positions of their hydroxyl groups, and the presence of conjugated dienes, these flavonoids may have different antioxidant properties and ROS-scavenging activities.

The pathophysiological mechanisms underlying neurodegenerative disorders are complex and diverse, and range from oxidative stress to inflammatory responses and apoptosis (Figure 15.1). The complexity of cell-signaling pathways may explain the difficulties encountered in finding effective treatments. Although much progress has been made in understanding the pathogenesis of AD, current therapeutic approaches merely address symptoms. Novel therapeutic approaches using natural botanical antioxidants may be suggested to ameliorate neurotoxicity and chelate transition metals (e.g., iron and copper). Both experimental and epidemiological evidence demonstrate that flavonoid polyphenols improve age-related cognitive decline and are neuroprotective in models of PD, AD, and cerebral I/R injuries (Mandel et al. 2008a; Sun et al. 2008).

FIGURE 15.1. Oxidative pathway involved in neurodegenerative diseases: Preventive and protective mechanisms exerted by botanical phenolics.

FIGURE 15.1

Oxidative pathway involved in neurodegenerative diseases: Preventive and protective mechanisms exerted by botanical phenolics.

Many plant polyphenols have been suggested as excellent candidates for development as therapeutic agents for treatment of neurodegenerative diseases (Figure 15.1). In particular, there is increasing interest in using resveratrol for treatment of progressive neurodegenerative maladies such as AD and PD. It is recognized that some botanical compounds may selectively target a single pathway, whereas others may act globally on multiple pathways. For example, apocynin, a known inhibitor of NADPH oxidase, has been used mainly to block ROS production by NADPH oxidase, whereas resveratrol, curcumin, and EGCG can target multiple pathways. Besides its ROS-scavenging activity, resveratrol can activate SIRT1, which is related to histone acetylation and deacetylation and alteration of proteins involved in the suppression of apoptotic pathways (Rahman, Biswas, and Kirkham 2006). Resveratrol can also affect Nrf2/Keap 1 pathway, which is linked with the activation of antioxidant proteins (Rubiolo, Mithieux, and Vega 2008). Inhibition of the NF-κB pathway by resveratrol and EGCG can decrease the production of inflammatory factors, for example, iNOS, COX-2, and secretory phospholipase A2 (sPLA2), which, in turn, can suppress the vicious cycle of cell death caused by oxidative stress. The multiple effects associated with resveratrol may offer an effective therapeutic remedy to restore neuronal homeostasis (Saiko et al. 2008). Future studies should be directed to investigate whether other phytochemicals also exhibit multiple functions (Calabrese et al. 2008). Questions about bioavailability, biotransformation, synergism with other dietary factors, and their ability to cross the blood–brain barrier also need to be addressed prior to application of botanical compounds on humans. Table 15.1 summarizes recent studies in which different botanical compounds in different paradigms were used to test neuroprotective effects on AD, PD, and stroke models.

ACKNOWLEDGMENTS

This chapter is supported by P01 AG108357 from the National Institute of Health (NIH), Bethesda, Maryland. The authors further wish to thank Mr. Dennis Reith for his help in editing this chapter.

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