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. Alkaloids 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. Physostigmine and its Derivatives Studies have shown a clear link between the AD and deficiency of some neurotransmitters. Various forms of Physostigmine is an alkaloid 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 acetylcholinesterase (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 rivastigmine which is Center, King Abdulaziz University, P.O.Box 80216, Jeddah 21589, carbamate-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 galantamine 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 (phenserine), 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]. Ungeremine, 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 butyrylcholinesterase (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]. Huperzine A 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 “tacrine” 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