Send Orders of Reprints at [email protected]

1006 CNS & Neurological Disorders - Drug Targets, 2012, 11, 1006-1011 An Overview on Potential Neuroprotective Compounds for Management of Alzheimer’s Disease

Ishfaq Ahmed Sheikh1,§, Riyasat Ali2,§, Tanveer A. Dar 3 and Mohammad Amjad Kamal*,1

1King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Kingdom of Saudi Arabia 2Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India 3Department of Clinical Biochemistry, University of Kashmir, Hazratbal, Srinagar, 190006, India

Abstract: Alzheimer’s disease (AD) is one of the major neurodegenerative diseases affecting almost 28 million people around the globe. It consistently remains one of the major health concerns of present world. Due to the clinical limitations like severe side effects of some synthesized drugs, alternative forms of treatments are gaining global acceptance in the treatment of AD. Neuroprotective compounds of natural origin and their synthetic derivatives exhibit promising results with minimal side effects and some of them are in their different phases of clinical trials. and their synthetic derivatives form one of the groups which have been used in treatment of neurodegenerative diseases like AD. We have further grouped these alkaloids into different sub groups like Indoles, piperdine and isoquinolines. Polyphenols form another important class of natural compounds used in AD management. Keywords: Alkaloids, polyphenols, Alzheimer’s disease, neuroprotective function.

INTRODUCTION been proposed as one of the alternative forms of the treatment. Large number of these molecules have been Alzheimer’s disease (AD) is the most common type of reported to play significant roles in removal of deficiency of dementia and it accounts for an estimated 60 to 80 percent of neurotransmitters either by increasing their level using reported cases of dementia [1]. AD is a progressive, agonists or inhibiting enzymes which are involved in their neurodegenerative disease that primarily affects the elderly depletion from the immediate locality of synapse. Some of population. It is characterised by loss of cognitive function these natural products and their synthetic derivatives have leading to dementia [2]. It is a major public health concern in been brought into clinical use. In present review we have developed countries. The main symptoms associated with attempted to shed some light on molecules belonging to AD involve a decline in cognitive dysfunction, primarily polyphenols and alkaloids reported to exhibit memory loss [3, 4] and in the later stages of the disease neuroprotective function and are thought to be potential language deficits, depression, agitation, mood disturbances candidates in the management of AD. and psychosis are often seen [5]. According to 2012 World Health Organization report on dementia [6], the number of people affected worldwide with dementia is estimated to be ALKALOIDS around 35.6 million and this number is expected to double Alkaloids have proven to be effective in alleviating the by 2030 and more than triple by 2050. In 2012, the number symptoms of neurodegenerative diseases like AD. So far of people of all ages living with AD in America alone is large numbers of natural alkaloids and their synthetic estimated to be 5.4 million which includes 5.2 million people derivatives have been reported to show neuroprotective of age 65 and older [1], and 200,000 individuals below 65 effects. We have further classified these alkaloids into years age [7]. One in every eight Americans of age 65 and different subgroups. older has Alzheimer’s disease [8]. The number will escalate rapidly in coming years. and its Derivatives Studies have shown a clear link between the AD and deficiency of some neurotransmitters. Various forms of Physostigmine is an obtained from Physostigma treatments have been reported to overcome AD related venenosum Balf. It has pyrroloindole skeleton with potent deficiencies and prevention of age-related neurological inhibition for (AChE) [9]. It improves diseases. Using natural compounds and their derivatives has the cognitive functions in vivo both in normal and AD patients [10]. In quest of improving the efficiency of physostigmine, various analogues have been studied. The

*Address correspondence to this author at the King Fahd Medical Research most potent and successful was which is Center, King Abdulaziz University, P.O.Box 80216, Jeddah 21589, -type reversible AChE inhibitor. In an attempt to Kingdom of Saudi Arabia; Fax: + 15016368847; gain the therapeutic advantages over rivastigmine, many E-mails: [email protected], [email protected] AChE inhibitors were synthesized using physostigmine as a

§Authors have contributed equally. template. For dual modes of action some of these efficient

1996-3181/12 $58.00+.00 © 2012 Bentham Science Publishers Natural Potential Neuroprotective Compounds CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 8 1007 and selective AChE inhibitors have been pharmacomodu- new alkaloid 11-hydroxygalantamine which is an epimer of lated to target both cognitive and depressive symptoms in habranthine shows an important in vitro AChE inhibitory AD [11, 12]. activity [29]. Some of these analogues were suggested to have Some of these derivatives (heterodimeric potential application in modulating AD symptoms and alkenyl linked bis-galantamine derivatives) showed more pathology. One of these being carbamate derivative efficient AChE inhibition than Galantamine. Memogain xanthostigmine, which inhibits AChE induced -amyloid (Gln-1062), which is a prodrug of Galantamine shows aggregation [13] and a phenylcarbamate derivative of improved results than Galantamine with respect to physostigmine (), inhibiting AChE and amyloid bioavailibility in the brain and cognitive effects in an animal precursor protein (APP) [14-16]. Methyl substitution of model of amnesia [30]. , isolated from Nerine phenserine at the C-20 position produces tolserine with bowdenii W. Watson and from species of Galanthus and enhanced selectivity for AChE in comparison to Narcissus showed stronger AChE inhibition than (BChE) [17-19]. Other analogues of galantamine [31-33]. physostigmine with cyclic alkyl carbamate of eseroline exhibited improved selectivity and more potent AChE Isoquinoline Alkaloids inhibition than phenserine [20]. In-spite of having developed numerous derivatives of physostigmine, few have reached Isoquinoline alkaloids from Colchicum speciosum Steven advanced stages of clinical development for AD. (Colchicaceae) corms are reversible inhibitors of both AChE and BChE in vitro [34] and several benzylisoquinoline alkaloids from Coptis (Ranunculaceae) and Corydalis Indole Alkaloids (Papaveraceae) species inhibit AChE [11, 35]. Alkaloids Using indole alkaloids like Rutaecarpine and like groenlandicine from Coptis chinensis Franch. Rhizomes dehydroevodiamine from Evodia rutaecarpa (Juss) Benth exhibit activities relevant in AD therapy as it shows non- (Rutaceae) as templates, new AChE inhibitors were competitive -secretase (BACE1) inhibitory activity and is synthesized. The plant extract and dehydroevodiamine an antioxidant [36]. Nigellastrines I and II and various other inhibit AChE in vitro and reverse scopolamine-induced quinolines show AChE inhibitory activity [37]. memory impairment in vivo [21]. Among some of these from Huperzia serrata (Thunb.) Trevis. (Lycopodiaceae) has synthetic analogs structural features of the AChE inhibitor, potent AChE inhibitory function and has been reported to “” was included, but few showed greater selectivity improve the cognitive functions in AD and vascular for BChE affinity [22] while as other 3-aminoalkanamido- dementia patients [4]. Huperzine B, also from H. serrata, is a substituted 7,8-dehydrorutaecarpine derivatives were more less potent AChE inhibitor than Huperzine A [38]. potent and exhibited selectivity for AChE [23]. Only 19,20- Using an in vitro AChE inhibition assay, stem-bark of the dihydrotabernamine and 19,20- dihydroervahanine A which Berberis darwinii plant was investigated for treating AD and are two of the four bisindole alkaloids isolated from the root was found to be a potent inhibitor of AChE [39]. Multiple of Tabernaemontana divaricata (L.) R.Br. ex Roem. & therapeutic functions of berberine have been reviewed by Ji Schult. (Apocynaceae), inhibited AChE more potently than et al. suggesting berberine may act as promising multipotent galantamine in vitro [24]. agent to combat AD [40]. Recently hybrid molecules have Geissospermine an indole alkaloid with AChE inhibitory been synthesized by making berberine to react with function from Geissospermum vellosii Allema benzenediol, melatonin and ferulic acid. It was found that all (Apocynaceae) stembark, reduced scopolamine-induced of these hybrid products were better antioxidants and amnesia in vivo [25]. Serpentine from the roots of inhibited A aggregation to a greater extent, than the lead Catharanthus roseus (L.) G.Don (Apocynaceae) was 10 fold compound, berberine. Among these all synthesized hybrid more potent and efficient than Physostigmine [26]. Other molecules, two molecules have been suggested to have promising candidates could be indole alkaloid derivatives potential to be excellent candidates for AD therapy. These from the fungus Cortinarius infractus Berk. (Cortinariaceae) molecules are berberine-pyrocatechol hybrid which were because they inhibit AChE with greater selectivity than much better inhibitors of AChE than unconjugated berberine galantamine, they comply with Lipinski rule and are and had the greatest ability to inhibit A aggregation [41]. predicted to cross the blood–brain barrier [27]. Anatabine, (a minor alkaloid present in plants of the Piperdine Alkaloids Solanace family) has been reported to lower A1-40 and A1- Some piperidine alkaloids derived from Cassia 42 levels in both in vitro and in vivo studies. Anatabine was spectabilis DC. (Leguminosae) shows therapeutic relevance suggested to be an interesting compound for regulating brain for cognitive disorders. They also include some semi- A accumulation [28]. synthetic derivatives as AChE inhibitors [11]. Synthetic derivative (2R,3R,6S)-2-methyl-6-(13-oxotetradecyl)- Galantamine and its Derivatives piperidin-3-yl acetate hydrochloride (LASSBio-767) inhibits rat brain AChE more selectively than BChE and reverses Galantamine, an AChE inhibitor marketed as a scopolamine-induced amnesia in vivo [42, 43]. Piperine, hydrobromide salt for the treatment of AD, is obtained from Amaryllidaceae plants, especially those belonging to the from Piper species (Piperaceae) inhibits monoamine oxidases [44]. It also improves memory impairment and genera Leucojum, Narcissus, Lycoris and Ungernia. Various neurodegeneration in vivo and AChE inhibition in the derivatives of Galantamine were synthesized and studied. A 1008 CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 8 Sheikh et al. hippocampus [45], suggesting it may also alleviate effects on intracellular signalling pathways and gene depressive symptoms in dementia. expression [59, 60]. Polyphenols, a broad group of compounds having aromatic rings and are characterized by Sinapine (an ester of sinapic acid and , that occurs the presence of one or more hydroxyl groups with different in several plants including Raphanus sativus L. (Brassicaceae)), is another alkaloid which potently inhibits structural complexities. Flavonoids include flavonols, flavones, isoflavones and anthocyanidins. The most common AChE in vitro and in brain tissues [11]. Tapsine (a dietary polyphenols in general are the flavonols (quercetin protoalkaloid from Magnolia soulangiana Soul-Bod. and catechin) as well as the compound resveratrol. (Magnoliaceae) leaves) inhibits AChE and is more potent Resveratrol (3, 5, 40-trihydroxystilbene), a nonflavoid, is a than galantamine [46]. phytoalexin present in red wine and grapes [59]. Quercetin Alkaloid 16a-hydroxy-5N-acetylardeemin from the (2-(3, 4-dihydroxyphenyl) - 3, 5, 7-trihydroxy-4H-chromen- fungus Aspergillus terreus is potent AChE inhibitor with 4-one) is a flavonol found in apples, tea, capers, and onions. almost same activity as tarcine [47]. AChE inhibition Catechins are flavanol monomers comprising chemically activity has been reported from alkaloid fraction from similar compounds such as (+/)-epicatechin, (+)- Trigonella foenum-graecum L. (Leguminosae) and the gallocatechin, ()-epicatechin gallate (EGC), and ()- component alkaloid trigonelline [48]. AChE inhibitory epigallocatechin gallate (EGCG) [61]. There are more than activity of trigonelline (also present in coffee) has been 50 different plant species and over 8000 phenolic supported by other studies reporting intake of coffee (Coffea compounds identified from different plant extracts [62]. arabica L., Rubiaceae) to be associated with a reduced risk Green tea derived polyphenols are rich in flavonoids of dementia [49]. including catechins and their derivatives of which epigallocatechin-3-gallate (EGCG) is the main constituent. -Carboline And its Derivatives EGCG followed by ()-epigallocatechin (EGC), ()- epicatechin (EC), and ()-epicatechin-3-gallate (ECG) [63]. Harmine, a -carboline alkaloid, is a high affinity These flavonoids have antioxidant potencies in the order of inhibitor of the dual specificity tyrosine phosphorylation EGCG > ECG > EGC > EC [64]. regulated kinase 1A (DYRK1A) protein. DYRK1A is involved in the phosphorylation of tau protein associated Various metals like iron, copper and zinc have been with tau pathology in the AD. Harmine and -carboline implicated in the pathophysiology of certain compounds potently reduce the expression of all three neurodegenerative diseases. Altered iron homeostasis has phosphorylated forms of tau protein, and inhibit the also been reported in AD, as indicated by changes in the DYRK1A catalyzed direct phosphorylation of tau protein on levels of iron, ferritin and transferrin receptor (TfR) in the serine 396 [50]. hippocampus and cerebral cortex [65-67]. Iron promotes both deposition of A and induction of oxidative stress (OS). Reserpine, a FDA-approved antihypertensive drug, Indeed, it has been demonstrated that amyloid deposits are increases C. elegans lifespan with a high quality of life and enriched with zinc, iron and copper [68]. Antioxidant-iron ameliorates A toxicity in C. elegans. So far its mode of chelating activity of the major green tea polyphenol EGCG action and the pathways of activation are not known, but plays a major role in the prevention of neurodegeneration in AChE was found to be the crucial player for Reserpine a variety of cellular and animal models of neurodegenerative action [51]. diseases [69, 70]. Administration of green tea extracts In addition other alkaloids like Sinomenine, present in a reduced A production/aggregation when amyloid protein Chinese medicinal plant has been reported to prevent precursors (APPs) APP/A was over-expressed in mice and oligomeric A-induced microglial activation and confers neuron cell cultures [71]. EGCG has been shown to reduce protection against neurotoxicity. These results suggest the gamma and beta-secretase activity, reduce the presence of possibility of sinomenine having a therapeutic potential for A aggregation, and in return prevent neuron cell death in Alzheimer’s treatment [52]. AD [72]. Another study, using pheochromocytoma (PC12) cells, demonstrated the protective effects of EGCG and extracts from grape skin on the neurotoxicity caused by A POLYPHENOLS [73]. More recently, EGCG was shown to exert a Polyphenols are one of the most important secondary neurorescue activity in long-term serum deprived PC12 cells metabolites exhibiting natural antioxidant property. These and to promote neurite outgrowth [74]. Also, catechins and are abundantly present in fruits, vegetables, herbs, and epicatechins reversed the aggregation of tau in AD [75]. An various drinks (tea, wine, and juices). These phenolic alternative and putative mechanism for decreased compounds have received increasing interest because of aggregation of A in neurons is the ability of certain numerous epidemiological studies. Polyphenols, both polyphenols to interact with metals such as copper. It is flavoids and non-flavoids, have proven to be effective in known that aggregates of A interact with copper and alleviating and protecting against the neurodegenerative promote increases in ROS production [76]. Ginkgolides and diseases in various cell culture and animal models. bilobalides, flavonoids obtained from Ginkgo-biloba extract Epidemiological evidence has shown that the Mediterranean (EGb), has been reported to protect the brain against hypoxic diet, which is rich in antioxidants, is effective in the damage and inhibit ROS formation in cerebellar neurons. prevention of age-related diseases such as Alzheimer’s [53- EGb protected the change of the protein conformation on the 58]. Polyphenols provide neuroprotective effects through membrane caused by free radical. The total flavonoid interaction with transition metals, inactivation of free components of EGb761 and a mixture of flavonoids and radicals, modulation in the activity of different enzymes, and terpens synergistically protected cerebellar granule cell from Natural Potential Neuroprotective Compounds CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 8 1009 oxidative damage and apoptosis induced by hydroxyl Gln-1062 = Galantamine. Memogain radicals [77, 78]. LASSBio-767 = (2R,3R,6S)-2-methyl-6-(13-oxotetra- Other well-known polyphenols include Baicalin and decyl)-piperidin-3-yl acetate hydrochloride Curcumin. Baicalin, an ancient Chinese herbal medicine, is FDA = Food And Drug Administration another well-known flavonoid that is isolated from the Scutellaria baicalensis root (Huang Qin, Scullcap or Chinese EGC = ()-epigallocatechin golden root). More than 30 flavonoid compounds have been EGCG = ()-epigallocatechin gallate identified in the root, the main are flavones: baicalein (5, 6, 7-trihydroxyflavon) and wogonin (5, 7-dihydroxy-8- EC = ()-epicatechin methoxyflavon) and their glucuronides: baicalin (baicalein- ECG = ()-epicatechin-3-gallate 7-0-glucuronide) and wogonoside (wogonin-7-0- glucuronide) oroxylin A (5, 7-dihydroxy-6-methoxyflavone), TfR = Transferrin receptor scullcupflavones I and II [79]. Baicalin inhibits the OS = Oxidative stress aggregation of A and reduce the production of H2O2 and oxidative damage in SH-SY5Y cells [80]. Curcumin PC12 = Pheochromocytoma (diferuloylmethane), a non-flavonoid polyphenol, is derived ROS = Reactive Oxygen Species from turmeric (Curcuma longa Linn). It has been H O = Hydrogen Peroxide demonstrated that besides potent anti-oxidative and anti- 2 2 inflammatory properties, curcumin also exhibits anti- EGb = Ginkgo-biloba extract amyloidogenic effects by directly binding to amyloid and BACE1 = -secretase 1 inhibits A aggregation preventing fibril and oligomer formation [81, 82]. Other studies have shown that curcumin Nrf2 = NF-E2-related Factor 2 may also be able to increase Nrf2 expression and increase DYRK1A = Dual-specificity tyrosine-(Y)-phospho- the neuroprotective effects in AD [83]. rylation regulated kinase 1A

CONCLUSION CONFLICT OF INTEREST AD which is characterised by loss of cognitive functions The authors confirm that this article content has no leading to dementia is one of the major public health conflict of interest. concerns particularly in developed countries. Using synthetic compounds in the treatment of AD has not been widely accepted due to their side effects like toxicity and triggering ACKNOWLEDGEMENTS different cancerous pathways. Therefore management of AD Declared none. using compounds of natural origin like dietary polyphenols and alkaloids is gaining more attention. Large numbers of REFERENCE these molecules have been used as neuroprotective agents. The mechanism of action for only few of these molecules [1] Hebert, L.E.; Scherr, P.A.; Bienias, J.L.; Bennett, D.A.; Evans, has been well studied and some of them are already in D.A. Alzheimer disease in the U.S. population: Prevalence estimates using the 2000 Census. Arch. Neurol., 2003, 60, 1119- different phases of clinical trial. In this regard structural 1122. biology approaches like rational based drug designing would [2] Francis, P.T.; Palmer, A.M.; Snape, M. The hypothesis be of significant importance in elucidating the mechanism of of Alzheimer’s disease: A review of progress. J. Neurol. unknown ones and taking these molecules further to different Neurosurg. Psychiatry, 1999, 66, 137-147. stages of clinical development. [3] Ranges, B.; Baron, J.C.; de la Sayette, V. The neural substrates of memory systems impairment in Alzheimer’s disease. Brain, 1998, Current AChE inhibitors alleviate AD symptoms for 121, 611-631. short term hence alternative methods are constantly being [4] Forstl, H.; Hentschel, F.; Sattel, H. Age-associated memory impairment and early Alzheimer’ disease. Drug Res., 1995, 45, studied. In this context, in addition to synthesizing derivates 394-397. using neuroprotective alkaloids and polyphenols one [5] McGuffey, E.C. Alzheimer’s disease: An overview for the important approach could be using plant extracts containing pharmacist. JAMA, 1997, NS37, 347-352. different neuroprotective compounds or combination of [6] World health organization report on dementia. Dementia: A Public Health Priority 2012. isolated natural products from different plant sources. This [7] Alzheimer’s Association. Early-Onset Dementia: A National may yield better results than using individual compounds in Challenge, A Future Crisis. Washington, D.C.: Alzheimer’s combating AD and may exhibit long term effects in Association, 2006. alleviating AD symptoms. [8] Alzheimer’s Disease Facts and Figures. Alzheimer’s Association 2012, 8. [9] Julian, P.L.; Pikl, J. J. Am. Chem. Soc., 1935, 57, 755-757. ABBREVIATIONS [10] Houghton, P.J.; Ren, Y.; Howes, M.J. Acetylcholinesterase inhibitors from plants and fungi. Nat. Prod. Rep., 2006, 23, 181- APP = Amyloid Precursor Protein 199. [11] Musia, A.; Bajda, M.; Malawska, B. Recent developments in AD = Alzheimer’s disease cholinesterases inhibitors for Alzheimer's disease treatment. Curr. AChE = Acetylcholinesterase Med. Chem., 2007, 14, 2654-2679. [12] Tumiatti, V.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Milelli, BChE = Butyrylcholinesterase A.; Matera, R.; Melchiorre, C. Expert Opin. Ther. Pat., 2008, 18, 387-401. 1010 CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 8 Sheikh et al.

[13] Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, [32] Labrana, J.; Machocho, A.K.; Kricsfalusy, V.; Brun, R.; Codina, V.; Recanatini M.; Melchiorre, C. Multi-target-directed ligands to C.; Viladomat, F.; Bastida, J. Alkaloids from Narcissus combat neurodegenerative diseases. J. Med. Chem., 2008, 51, 347- angustifolius subsp. transcarpathicus (Amaryllidaceae). 372. Phytochemistry, 2002, 60, 847-852. [14] Greig, N.H.; Utsuki, T.; Yu, Q.S.; Kamal, M.A.; Holloway, H.W.; [33] Rhee, I.K.; Appels, N.; Hofte, B.; Karabatak, B.; Erkelens, C.; Perry, T.; Tweedie, D.; Li, Y.; Giordano, T.; Alley, G.M.; Chen, Stark, L.M.; Flippin, L.A.; Verpoorte, R. Isolation of the D.M.; Rogers, J.T.; Sambamurti, K.; Lahiri, D.K. Dissociation acetylcholinesterase inhibitor ungeremine from Nerine bowdenii by between the potent b-amyloid protein pathway inhibition and preparative HPLC coupled on-line to a flow assay system. Biol. cholinergic actions of the Alzheimer drug candidates phenserine Pharm. Bull., 2004, 27, 1804-1809. and . In: Advances in Alzheimer's and Parkinson's [34] Rozengart, E.; Basova, N.; Suvorov, A. J. Evol. Biochem. Physiol., Disease: Insights, Progress, and Perspectives; Eds. Fisher, A.; 2006, 42, 408-416. Memo, M.; Stocchi, F.; Hanin, I.; Springer Science and Business [35] Jung, H.; Lee, E.; Kim, J.; Kang, S.; Lee, J.; Min, B.; Choi, J. Arch. Media, USA, 2008, pp. 445-462. Pharmacol. Res., 2009, 32, 1399-1408. [15] Al-Jafari, A.A.; Kamal, M.A.; Alhomida, A.S.; Greig, N.H. [36] Jung, H.A.; Min, B.; Yokozawa, T.; Lee, J.;. Kim, Y.S.; Choi, J.S. Kinetics of rat brain acetylcholinesterase inhibition by two Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma experimental Alzheimer's disease drugs, phenserine and tolserine. alkaloids. Biol. Pharm. Bull., 2009, 32, 1433-1438. J. Biochem. Mol. Biol. Biophys., 2000, 4, 323-335. [37] Zheng, X.; Zhang, Z.; Chou, G.; Wu, T.; Cheng, X.; Wang, C.; [16] Butler, M.S. Natural products to drugs: natural product-derived Wang, Z. Arch. Pharmacol. Res., 2009, 32, 1245-1251. compounds in clinical trials. Nat. Prod. Rep., 2008, 25, 475-516. [38] He, X.; Feng, S.; Wang, Z.; Shi, Y.; Zheng, S.; Xia, Y.; Jiang, H.; [17] Loizzo, M.R.; Tundis, R.; Menichini, F.; Menichini, F. Natural Tang, X.; Bai, D. Study on dual-site inhibitors of products and their derivatives as cholinesterase inhibitors in the acetylcholinesterase: Highly potent derivatives of bis- and treatment of neurodegenerative disorders: an update. Curr. Med. bifunctional huperzine B. Bioorg. Med. Chem., 2007, 15, 1394- Chem., 2008, 15, 1209-1228. 1408. [18] Kamal, M.A.; Greig, N.H.; Alhomida, A.S.; Al-Jafari, A.A. [39] Perry, E.K.; Howes, M.R. CNS Neurosci. Ther., 2010, DOI: Kinetics of human acetylcholinesterase inhibition by the novel 10.1111/j.1755-5949.2010.00202.x. experimental Alzheimer therapeutic agent, tolserine. Biochem. [40] Habtemariam, S. The therapeutic potential of Berberis darwinii Pharmacol., 2000, 60, 561-570. stem-bark: quantification of berberine and in vitro evidence for [19] Kamal, M.A.; Greig, N.H.; Al-Jafari, A.A. A new, simple and Alzheimer's disease therapy. Nat. Prod. Commun., 2011, 6, 1089- economical approach to analyse the inhibition kinetics of 1090. acetylcholinesterase using tolserine. Em. Med. J., 2002, 20(3), 333- [41] Ji, H.F.; Shen, L. Berberine: a potential multipotent berberine 337. natural product to combat Alzheimer's disease. Molecules, 2011 16, [20] Zhan, Z.J.; Bian, H.L.; Wang, J.W.; Shan, W.G. Synthesis of 6732-6740. physostigmine analogues and evaluation of their anticholinesterase [42] Castro, N.G.; Costa, R.S.; Pimentel, L.S.B.; Danuello, A.; activities. Bioorg. Med. Chem. Lett., 2010, 20, 1532-1534. Romeiro, N.C.; Viegas, C.; Barreiro, E.J.; Fraga, C.A.M.; Bolzani, [21] Park, C.H.; Kim, S.H.; Choi, W.; Lee, Y.J.; Kim, J.S.; Kang, S.S.; V.S.; Rocha, M.S. CNS-selective noncompetitive cholinesterase Suh, Y.H. Novel anticholinesterase and antiamnesic activities of inhibitors derived from the natural piperidine alkaloid (-)- dehydroevodiamine, a constituent of Evodia rutaecarpa. Planta spectaline. Eur. J. Pharmacol., 2008, 580, 339-349. Med., 1996, 62, 405-409. [43] Viegas, C.; Bolzani, V.S.; Pimentel, L.S. B.; Castro, N.G.; Cabral, [22] Decker, M. Novel inhibitors of acetyl- and butyrylcholinesterase R.F.; Costa, R.S.; Floyd, C.; Rocha, M.S.; Young, M.C.M.; derived from the alkaloids dehydroevodiamine and rutaecarpine. Barreiro, E.J.; Fraga, C.A.M. New selective acetylcholinesterase Eur. J. Med. Chem., 2005, 40, 305-313. inhibitors designed from natural piperidine alkaloids. Bioorg. Med. [23] Wang, B.; Mai, Y.; Li, Y.C.; Hou, J.Q.; Huang, S.L.; Ou, T.M. ; Chem., 2005, 13, 4184-4190. Tan, J.H.; An, L.K.; Li, D.; Gu, L.Q.; Huang, Z.S. Synthesis and [44] Rahman, T.; Rahmatullah, M. Proposed structural basis of evaluation of novel rutaecarpine derivatives and related alkaloids interaction of piperine and related compounds with monoamine derivatives as selective acetylcholinesterase inhibitors. Eur. J. Med. oxidases. Bioorg. Med. Chem. Lett., 2010, 20, 537-540. Chem., 2010, 45, 1415-1423. [45] Chonpathompikunlert, P.; Wattanathorn, J.; Muchimapura, S. [24] Ingkaninan, K.; Changwijit K.; Suwanborirux, K. Vobasinyl-iboga Piperine, the main alkaloid of Thai black pepper, protects against bisindole alkaloids, potent acetylcholinesterase inhibitors from neurodegeneration and cognitive impairment in animal model of Tabernaemontana divaricata root. J. Pharm. Pharmacol., 2006, 58, cognitive deficit like condition of Alzheimer's disease. Food Chem. 847-852. Toxicol., 2010, 48, 798-802. [25] Lima, J.A.; Costa, R.S.; Epifanio, R.A.; Castro, N.G.; Rocha, M.S.; [46] Rollinger, J.M.; Schuster, D.; Baier, E.; Ellmerer, E.P.; Langer, T.; Pinto, A.C.. Geissospermum vellosii stembark: anticholinesterase Stuppner, H. : bioactivity-guided isolation and molecular activity and improvement of scopolamine-induced memory ligand-target insight of a potent acetylcholinesterase inhibitor from deficits. Pharmacol. Biochem. Behav., 2009, 92, 508-513. Magnolia x soulangiana. J. Nat. Prod., 2006, 69, 1341-1346. [26] Pereira, D.M.; Ferreres, F.; Oliveira, J.M.A.; Gaspar, L.; Faria, J.; [47] Ge, H.; Peng, H.; Guo, Z.; Cui, J.; Song, Y.; Tan, R. Bioactive Valenta˜o, P.; Sottomayor, M.; Andrade, P.B. Pharmacological alkaloids from the plant endophytic fungus Aspergillus terreus. effects of Catharanthus roseus root alkaloids in acetylcholinesterase Planta Med., 2010, 76, 822-824. inhibition and cholinergic neurotransmission. Phytomedicine, 2010, [48] Satheeshkumar, N.; Mukherjee, P.K.; Bhadra, S.; Saha, B.P. 17, 646-652. Acetylcholinesterase enzyme inhibitory potential of standardized [27] Geissler, T.; Brandt, W.; Porzel, A.; Schlenzig, D.; Kehlen, A.; extract of Trigonella foenum graecum L and its constituents. Wessjohann, L.; Arnold, N. Acetylcholinesterase inhibitors from Phytomedicine, 2010, 17, 292-295. the toadstool Cortinarius infractus. Bioorg. Med. Chem., 2010, 18, [49] Jiang, H.; Wang, X. ; Huang, L.; Luo, Z.; Su, T.; Ding, K.; Li, X. 2173-2177. Benzenediol-berberine hybrids: multifunctional agents for [28] Paris, D.; Beaulieu-Abdelahad, D.; Bachmeier, C.; Reed, J.; Ait- Alzheimer's disease. Bioorg. Med. Chem., 2011, 19, 7228-7235. Ghezala, G.; Bishop, A.; Chao, J.; Mathura, V.; Crawford, F.; [50] Frost, D.; Meechoovet, B.; Wang, T.; Gately, S.; Giorgetti, M.; Mullan, M. Anatabine lowers Alzheimer's A production in vitro Shcherbakova, I.; Dunckley, T. -carboline compounds, including and in vivo. Eur. J. Pharmacol., 2011, 670, 384-391. harmine, inhibit DYRK1A and tau phosphorylation at multiple [29] de Andrade, J.P.; Berkov, S.; Viladomat, F.; Codina, C.; Zuanazzi, Alzheimer's disease-related sites. PLoS One, 2011, 6, e19264. J.A.; Bastida, J. Alkaloids from Hippeastrum papilio. Molecules, [51] Saharia, K.; Arya, U.; Kumar, R.; Sahu, R.; Das, C.K.; Gupta, K.; 2011, 16, 7097-7104. Dwivedi, H.; Subramaniam, J.R. Reserpine modulates [30] Maelicke, A.; Hoeffle-Maas, A.; Ludwig, J.; Maus, A.; neurotransmitter release to extend lifespan and alleviate age- Samochocki, M.; Jordis, U.; Koepke, A.K.E. Memogain is a dependent A proteotoxicity in Caenorhabditis elegans. Exp. galantamine pro-drug having dramatically reduced adverse effects Gerontol., 2012, 47, 188-197. and enhanced efficacy. J. Mol. Neurosci., 2010, 40, 135-137. [52] Shukla, S.M.; Sharma, S.K. Sinomenine inhibits microglial [31] Berkov, S.; Codina, C.; Viladomat, F.; Bastida, J. Alkaloids from activation by A and confers neuroprotection. J. Galanthus nivalis. Phytochemistry, 2007, 68, 1791-1798. Neuroinflammation, 2011, 8, 117. Natural Potential Neuroprotective Compounds CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 8 1011

[53] De Lorgeril, M.; Salen, P.; Martin, J.L.; Monjaud, I.; Delaye, J.; neuroprotective drugs R-apomorphine and green tea polyphenol (– Mamelle, N. Mediterranean diet, traditional risk factors, and the )-epigallocatechin-3-gallate. J. Mol. Neurosci., 2004a, 24, 401-416. rate of cardiovascular complications after myocardial infarction: [70] Mandel, S.; Youdim, M.B.H. Catechin polyphenols: final report of the Lyon Diet Heart Study. Circulation, 1999, 99, neurodegeneration and neuroprotection in neurodegenerative 779-785. diseases. Free Radical Biol. Med., 2004, 37, 304-317. [54] Tuttle, K.R. ; Shuler, L.A.; Packard, D.P.; Milton, J.E.; Daratha, [71] Rezai-Zadeh, K.; Shytle, D.; Sun, N.; Mori, T.; Hou, H.; Jeanniton, K.B.; Bibus, D.M. Comparison of low-fat versus Mediterranean D. Green tea epigallocatechin-3-gallate (EGCG) modulates style dietary intervention after first myocardial infarction (from The amyloid precursor protein cleavage and reduces cerebral Heart Institute of Spokane Diet Intervention and Evaluation Trial). amyloidosis in Alzheimer transgenicmice. J. Neurosci., 2005, 25, Am. J. Cardiol., 2008, 101, 1523-1530. 8807-8814. [55] Gu, Y.; Luchsinger, J.A.; Stern, Y.; Scarmeas, N. Mediterranean [72] Lee, W.C.; Wang, C.J.; Chen, Y.H.; Hsu, J.D.; Cheng, S.Y.; Chen, diet, inflammatory and metabolic biomarkers, and risk of H.C. Polyphenol extracts from Hibiscus sabdariffa Linnaeus Alzheimer’s disease. J. Alzheimers Dis., 2010, 22, 483-492. attenuate nephropathy in experimental type 1 diabetes. J. Agric. [56] Scarmeas, N.; Stern, Y.; Mayeux, R.; Luchsinger, J.A. Food Chem., 2009, 57, 2206-2210. Mediterranean diet, Alzheimer disease, and vascular mediation. [73] Harvey, B.K.; Richie, C.T.; Hoffer, B.J.; Airavaara, M. Transgenic Arch. Neurol., 2006, 63, 1709-1717. animal models of neurodegeneration based on human genetic [57] Sofi, F.; Macchi, C.; Abbate, R.; Gensini, G.F.; Casini, A. studies. J. Neural Transm., 2011, 118, 27-45. Effectiveness of the Mediterranean diet: can it help delay or [74] Reznichenko, L.; Amit, T.; Youdim, M.B.H.; Mandel, S. Green tea prevent Alzheimer’s disease. J. Alzheimers Dis., 2010, 20, 795- polyphenol (-)-epigallocatechin-3-gallate induces neurorescue of 801. long-term serum-deprived PC12 cells and promotes neurite [58] Sofi, F.; Abbate, R.; Gensini, G.F.; Casini, A. Accruing evidence outgrowth. J. Neurochem., 2005, 93, 1157-1167. on benefits of adherence to the Mediterranean diet on health: an [75] Ksiezak-Reding, H.; Ho, L.; Santa-Maria, I.; Diaz-Ruiz, C.; Wang, updated systematic review and meta-analysis. Am. J. Clin. Nutr., J.; Pasinetti, G.M. Ultrastructural alterations of Alzheimer’s disease 2010, 92, 1189-1196. paired helical filaments by grape seed-derived polyphenols. [59] Obrenovich, M.E.; Nair, N.G.; Beyaz, A.; Aliev, G.; Reddy, V.P. Neurobiol. Aging, 2010, (In Press). The role of polyphenolic antioxidants in health, disease, and aging. [76] Adlard, P.A.; Bush, A.I. Metals and Alzheimer’s disease. J. Rejuvenation Res., 2010, 13, 631-643. Alzheimers Dis., 2006, 10, 145-163. [60] Soobrattee, M.A.; Bahorun, T.; Aruoma, O.I. Chemopreventive [77] Chen, C.; Wei, T.T.; Gao, Z.; Zhao, B.L.; Hou, J.W.; Xu, H.B. actions of polyphenolic compounds in cancer. Biofactors, 2006, 27, Different effects of the constituents of Egb-761 on apoptosis in rat 19-35. cerebellar granule cells induced by hydroxyl radicals. Biochem. [61] Chung, S.; Yao, H.; Caito, S.; Hwang, J.W.; Arunachalam, G.; Mol. Biol. Int., 1999, 47, 397-405. Rahman, I. Regulation of SIRT1 in cellular functions: role of [78] Xin, W.J. ; Wei, T.T.; Chen, C.; Ni, Y.C.; Zhao, B.L.; Hou, J.W. polyphenols. Arch. Biochem. Biophys., 2010, 501, 79-90. Mechanisms of apoptosis in rat cerebellar granule cells induced by [62] Sun, A.Y.; Wang, Q.; Simonyi, A.; Sun, G.Y. Botanical phenolics hydroxyl radicals and effects of Egb761 and its constitutes. and brain health. Neuromolecular Med., 2008, 10, 259-274. Toxicology, 2000, 148, 103-110. [63] Moyers, S.B.; Kumar, N.B. Green tea polyphenols and cancer [79] Bochorakova, H.; Paulova, H.; Slanina, J.; Musil, P.; Taborska, E. chemoprevention: multiple mechanisms and endpoints for phase II Main flavonoids in the root of Scutellaria baicalensis cultivated in trials. Nutr. Rev., 2004, 62, 204-211. Europe and their comparative antiradical properties. Phytother. [64] Morris, M.C.; Evans, D.A.; Bienias, J.L.; Tangney, C.C.; Bennett, Res., 2003, 17, 640-644. D.A. Aggarwal N. Dietary intake of antioxidant nutrients and the [80] Yin, F.; Liu, J.; Ji, X.; Wang, Y.; Zidichouski, J.; Zhang, J. Baicalin risk of incident Alzheimer disease in a biracial community study. J. prevents the production of hydrogenperoxide and oxidative stress Am. Med. Assoc., 2002, 287, 3230-3237. induced by A aggregation in SH-SY5Ycells. Neurosci. Lett., [65] Beard, J.L.; Connor, J.R.; Jones, B.C. Iron in the brain. Nutr. Rev., 2011, 492, 76-79. 1993, 51, 157-170. [81] Hirohata, M.; Hasegawa, K.; Tsutsumi-Yasuhara, S.; Ohhashi, Y.; [66] Sipe, J.C.; Lee, P.; Beutler, E. Brain iron and Ookoshi, T.; Ono, K. The anti-amyloidogenic effect is exerted neurodegenerative disorders. Dev. Neurosci., 2002, 24, 188-196. against Alzheimer’s beta-amyloid fibrils in vitro by preferential and [67] Honda, K.; Smith, M.A.; Zhu, X.; Baus, D.; Merrick, W.C.; reversible binding of flavonoids to the amyloid fibril structure. Tartakoff, A.M.; Hattier, T.; Harris, P.L.; Siedlak, S.L.; Fujioka, Biochemistry, 2007, 46, 1888-1899. H.; Liu, Q.; Moreira, P.I.; Miller, F.P.; Nunomura, A.; Shimohama, [82] Yang, F.; Lim.G. P.; Begum, A.N.; Ubeda, O.J.; Simmons, M.R.; S.; Perry, G. Ribosomal RNA in Alzheimer disease is oxidized by Ambegaokar, S.S. Curcumin inhibits formation of amyloid beta bound redox-active iron. J. Biol. Chem., 2005, 280, 20978-20986. oligomers and fibrils, binds plaques, and reduces amyloid in vivo. [68] Atwood, C.S.; Obrenovich, M.E.; Liu, T.; Chan, H.; Perry, G.; J. Biol. Chem., 2005, 280, 5892-5901. Smith, M.A.; Martins, R.N. Amyloid-beta: a chameleon walking in [83] Yang, C.; Zhang, X.; Fan., H.; Liu, Y. Curcumin upregulates two worlds: a review of the trophic and toxic properties of transcription factor Nrf2, HO-1 expression and protects rat brains amyloid-beta. Brain Res. Brain Res. Rev., 2003, 43, 1-16. against focal ischemia. Brain Res., 2009, 1282, 133-141. [69] Mandel, S.; Maor, G.; Youdim.; M.B.H. Iron and alpha-synuclein in the substantia nigra of MPTP-treated mice: effect of

Received: July 4, 2012 Revised: August 17, 2012 Accepted: August 19, 2012

PMID: 23244435