Phytochemicals , Antioxidants , and Cholinesterase Inhibitory Profiles of Elatostema Papillosum Leaves : An Alternative Approach for Management of Alzheimer ’ s Disease

Page 19 of 22 Phytochemicals, Antioxidants, and Cholinesterase Inhibitory Profiles of Elatostema Papillosum Leaves: An Alternative Approach for Management of Alzheimer’s Disease A. S. M. Ali Reza1, Mst. Samima Nasrin1, A. H. M. Khurshid Alam2* 1Department of Pharmacy, Faculty of Science and Engineering, International Islamic University, Chittagong, Bangladesh 2Department of Pharmacy, University of Rajshahi, Bangladesh

Phytochemicals, Antioxidants, and Cholinesterase Inhibitory Profiles of Elatostema Papillosum Leaves: An Alternative Approach for Management of Alzheimer's Disease

Introduction
Alzheimer's disease (AD) is a neurodegenerative disorder of the brain characterized by memory dysfunction, impairment in language and judgment capacity.AD is the most common cause of presenile and senile dementia worldwide 1 .In 2006, 26.6 million AD patients were diagnosed; this is expected to rise to 106.8 million by 2050 2 .The prevalence rate of AD doubles every five to ten years and this incidence increases exponentially with age, rising from 3 % among those 65-74, to almost 50 % among those 85 or older 3 .Thus, dementia and AD have become primary areas of research due to their enormous social, economic, and health care impacts.Indeed, after cancer and coronary heart disease, AD is the third most expensive disorder in the United States; moreover, total worldwide societal costs were estimated to be $ 315 million in 2005, with about 70 % of costs occurring in developed countries 4 .
The etiology of AD is not yet completely understood.However, both genetic and environmental factors are responsible for late-onset and sporadic AD 5 , with aging being the greatest risk factor for AD 6 .The apolipoprotein E (ApoE) genotype is the second greatest risk factor for AD after age.ApoE has three isoforms ApoE2, ApoE3, and ApoE4.Among the isoforms, ApoE4 is the most common and least protective variant of AD 7,8 .Two other important factors linked to AD are the overproduction of Aβ protein and abnormal tau protein.Kuszczyk et al., (2009) and Scheff et al., (2007) reported that the highly-phosphorylated tau protein and overproduction of Aβ protein initiate the loss of neurons, neuropil, and synaptic elements 9,10 , which leads to cognitive function deficiencies and dementia.It is believed that accumulation of extracellular Aβ protein plays a central role in the pathogenesis of AD.The mechanism of number of published and ongoing clinical trials with the use of curcumin and resveratrol for AD therapy 21 .Moreover, Morris et al., (2002) and Engelhart et al., (2002) reported that eating foods rich in antioxidants such as beta carotene and vitamins C and E are associated with lower risk of AD and dementia 22,23 .Furthermore, under normal conditions, OS and cellular damage are combated by endogenous antioxidant compounds and enzymes.However, the brain is highly vulnerable to oxidative damage due to high levels of ROS and poor antioxidant systems.
In addition, ROS-mediated mitochondrial damage plays a key role in AD pathogenesis.Therefore, agents that target mitochondrial dysfunctions and reverse oxidative stress may serve as novel AD therapeutics.One such therapeutic might be MitoVitE, also known as mitotocopherol, which protects mitochondria from oxidative stress via inhibition of lipid peroxidation 8 .Pocernich et al., (2011) reported that in both AD and mild cognitive deficit brains with significantly decreased levels of antioxidant enzymes, the brains became vulnerable to deposition of Aβ protein 24 .Consequently, it was suggested that one way of enhancing brain defense was by improving the antioxidant defense system, particularly endogenous glutathione (GSH), glutathione-related enzymes, catalase, and superoxide dismutase.

Elatostema papillosum and Alzheimer's Disease Treatment
Agents which elevate acetylcholine (ACh) levels are essential targets for AD treatment.ACh is an organic neurotransmitter found in the synapses of the cerebral cortex.Decreased levels of ACh and insufficient cholinergic function have been correlated with cognitive deficits seen in AD patients 25 .Therefore, several strategies have been established to increase ACh levels, such as using the ACh precursor (choline) 26 , muscarinic and nicotinic agonists 27 , ACh releasers 28 , and acetylcholinesterase (AChE) inhibitors 29 .Among these, the acceptable option for AD treatment is restoration of ACh levels through inhibition of two major forms of cholinesterase enzymes, AChE and butrylcholinesterase (BChE) 29 .To date, only three cholinesterase inhibitors, donepezil, galantamine and rivastigmine have been approved by the US Food and Drug administration to treat AD 30 .However, these compounds have been reported to have therapeutic activity along with adverse side effects, such as hepatotoxicity, short duration of biological action, low bioavailability, and gastrointestinal disturbances 31 .Therefore, natural sources, especially plants have been gaining attention for putative use as novel cholinesterase inhibitors and/or antioxidants.
Elatostema papillosum (E.papillosum), a member of Urticaceae family, is a suberect herb (commonly known as Elya) available in Australia and Oceania, China, Bhutan, India, and Bangladesh.From existing ethnobotanical Aβ formation is complex, but several studies suggest that enhanced oxidative stress provoked by Aβ is associated with AD 11 .

Oxidative stress and Alzheimer's disease
Antioxidants are molecules involved in scavenging reactive species, which can be caused by oxidative stress (OS).Antioxidants have a wide range of effects in various disease conditions and can help to prevent onset and progression of certain diseases.OS is emerging as a key mechanism underlying the pathogenesis of AD in both human brains and animal models, alongside excess deposition of Aβ protein, neurofibrillary tangle (NFT) formation, and metabolic dysfunction [12][13][14] .The relationship between systemic OS and AD has received increased recognition in the last decade 8 .In addition, accumulation of intracellular free radicals dysfunctions the activities or expressions of antioxidant enzymes superoxide dismutase (SOD) and catalase, have also been described in the brain of a patient diagnosed with AD 15 .Moreover, oxidative damage can occur in peripheral cells as well as neuronal cells when oxidative homeostasis is disturbed; the resultant excessive production of reactive oxygen damages the cellular antioxidant defense mechanisms and triggers the occurrence of AD 8 .
There are a number of sources of OS in AD patients, including increased levels of iron-redox-active state in NFT as well as in Aβ protein 16 , activated microglia surrounded by the most senile plaques, which produce NO and O 2 - . Amyloid-β protein precursor (AβPP) responsible for formation of reactive oxygen 18 , abnormalities in the mitochondrial genome 8 , and deficiencies in key metabolic enzymes 19 .Reactive oxygen species (ROS) are those that include reactive oxygen ions and peroxides and cause detrimental effects at high concentration to all biomolecules (DNA, RNA, proteins and lipids), leading to pathological conditions in humans 18 .The imbalance between cellular production of ROS and the inability of cells to defend against ROS causes OS, which contributes to age-related neurodegeneration and cognitive decline 8 .

Antioxidants as a Therapeutic Target in Alzheimer's Disease
Antioxidants play a functional role in the pathogenesis of the different diseases, including AD.Therefore, diverse antioxidants N-acetylcysteine, curcumin, resveratrol, vitamin E, vitamin C, ferulic acid, coenzyme Q (CoQ), selenium, and melatonin, have been tested for their protective role in cognitive performance in both healthy individuals, as well as those with mild cognitive impairment and AD 20 .However, despite promising effects of these compounds on cellular oxidative status in vitro and in vivo, the realistic evidence of their therapeutic potential in humans is limited.Recently, Mazzanti et al., reviewed a literature, it is clear that E. papillosum has marked folkloric reputation as useful in combatting different afflictions, such as hysteria and abdominal pain 32 .Interestingly, some characteristics of hysteria overlap with symptoms of AD 33 .Recently, many research groups have reported that antioxidant-enriched plants and plant metabolites possess remarkable cholinesterase inhibition capacity 12,13,34 .Our group also reported that E. papillosum showed marked cholinesterase inhibition and free radical (DPPH and hydroxyl radical) scavenging activities.Furthermore, the plant possessed potent phenolic and flavonoid content along with a positive correlation between antioxidant and cholinesterase inhibition potential 14 .Recent evidence suggests that the secondary metabolites, flavonoids, have positive effects against dementia and AD [35][36][37] .Our results were consistent with those of the data published previously 12,13,34 and suggest that E. papillosum may be a valuable method for treating AD by targeting both the OS and impaired cholinergic signaling characteristic of AD.

Conclusions
Medicinal plants having potential antioxidant and free radical scavenging capacity can be applied to reduce dementia and to treat AD.Polyphenolic compounds are the most abundant antioxidants in the plant kingdom harboring neuroprotective effects.As, E. papillosum is a significant source of phenolics and flavonoids, which act as natural cholinesterase inhibitors and free radical scavengers, this plant may be a powerful future medicine for treating and managing AD.