In the modern era, the neurological disease like dementia is increasingly day by day and it is being recognized as one of the most important medical problems in the elderly with a prevalence rising from 1% at the age of 60 to at least 35% at the age of 90 years (Ferri et al., 2005). The Parkinson's disease (PD) and Alzheimer’s disease (AD) are two major dementia/ neurodegenerative related diseases, linked with deficiencies in dopamine and acetylcholine molecules, which are necessary for nerve communication (Pérez-Hernández et al., 2016; Houghton and Howes, 2005). Among them, AD is an age-related disease that results progressive, irreversible, disabling, brain disorder, cognitive function deficiency and is the leading cause of dementia, for which no cure is available to date (Barnes and Yaffe, 2011). Because of AD, there is gradual loss of memory, state of confusion, impaired orientation, language skills diminution and cognitive impairment at cortex and hippocampus of cerebrovascular regions of the brain, projects a deficit of basal forebrain cholinergic system (Whitehouse et al., 1982). The main risk factors for AD include age, genetics, metal toxicity, head injury, environmental pollution, smoking, vascular injury, smoking, psychological stress hyperlipidemia, hypertension, obesity, variation in lifestyle, and diabetes mellitus (Chin-Chan et al., 2019; Ballard et al., 2011). According to World Alzheimer’s Report 2015, 74.7 million people will be prevalent might be at risk of dementia by 2030, and in 2050 numbers will be 131.5 million (World Alzheimer Report 2015). According to recent a report in 2018, about 50 million people have been affected by AD and there is a vast increase upto 152 million by 2050 and the shocking fact that for every 3 seconds there is a report of a new case of dementia (World Alzheimer Report. 2018). Therefore these statistics tempt chemists and biologists to develop better drugs for the treatment of AD.
The mechanism of AD pathogenesis is complex enough and its cause is related to multiple factors. Several attempts at explanation, therefore, have been made to explain AD, such as the β-amyloid glutamatergic, tau hypotheses, cholinergic, inflammation, oxidative, and metal hypothesis (Bais et al 2016; Graham et al 2017; Kumar and Singh 2015; Sanabria-Castro et al 2017). Among these hypotheses, the main drugs approved for the treatment of AD are cholinesterase inhibitors which are called acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). According to the cholinergic theory, the development of AD symptoms is mainly related to structural alterations in cholinergic synapses, loss of specific subtypes of acetylcholine (ACh) receptors, the death of ACh-generating neurons, and consequently, the deterioration of cholinergic neurotransmission. These issues lead to a relative accumulation of the ACh-hydrolyzing enzyme, acetylcholinesterase (AChE) (Stanciu et al 2020; Elmorsy et al 2021). The most probable hypothesis much talked about on AD is an amyloid hypothesis. It refers to the formation of amyloid aggregates or senile plaques at extracellular space of the neuronal network leading to pathologic processes by triggering various molecular entities and destroying the cellular homeostasis final staging the neuronal death. The process of senile plaques starts from amyloid-beta (Aβ) monomers which are the products of the cleaved APP. APP is an integral membrane with glycosylated N-terminus protruding towards extracellular neuron cellular space and C-terminus towards the cytoplasmic core. APP isoforms vary from 695 to 770 amino acids and functions regulating the synaptic formation, repair, and iron transport (Kametani and Hasegawa 2018; Chen et al 2017). Despite great research efforts on the development of new AD therapies, aimed at targeting the main pathological hallmarks of the disease, including the amyloid plaque formation, to date they have not yet resulted in clinically effective treatments. Several generic drugs like Tacrine, Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne), Memantine (Namenda) can best hold symptomatic cure like first four are cholinergic drugs and latter act as NMDA receptor antagonist (World Alzheimer Report. 2018).
According to World Health Organization (2002), more than 90% of therapeutic classes derive from a natural product prototype and roughly two-thirds to three-quarters of the world’s population relies upon medicinal plants for its primary pharmaceutical care (Daniel et al., 2012). Many such examples motivate us for discovering new drugs with chemical diversity from natural resources based on ayurvedic principles and ethnopharmacology. Madhuca longifolia (M. longifolia, ML) belongs to the family Sapotaceae and is commonly known as Madhuca/Mahua/Butternut tree. It is a multipurpose forest tree of India that provides food, fodder, fuel, and medicines (Patel et al 2011). Almost all parts of M. longifolia tree have medicinal properties. The bark is used for rheumatism, chronic bronchitis, diabetes mellitus, ulcers, tonsillitis, and bleedings (Sunita and Sarojini 2013). Leaves are expectorant and also used for chronic bronchitis and Cushing’s disease (Rahman et al., 2011). The medicinal value of the leaves can be attributed because to the presence of flavonoids and other bioactive components present in them. The flowers have been traditionally used as a diuretic, cooling agent, aphrodisiac, analgesic, tonic, astringent, demulcent, and for the treatment of helminths, acute and chronic tonsillitis, pharyngitis, and bronchitis (Sunita and Sarojini 2013). These flowers are a rich source of sugars, calcium, appreciable number of vitamins and minerals (Sinha et al., 2017; ; Sutaria and Magar, 1958). The seed oil is mainly composed of oleic acid followed by palmitic, stearic, and linoleic acid, it is also used as biodiesel (Mani et al., 2020). Various new compounds were isolated from genus Madhuca viz. Madlongisides A-D, Madhunolic acid, 3’,4’- dihydroxy-5,2’-dimethoxy-6,7-methylendioxy, and Madhusic acid A (Yoshikawa et al., 2000; Siddiqui et al., 2007; Siddiqui et al., 2010; Hoang et al., 2016). Even though some research works have been done on the medicinal properties and phytochemical profile of M. longifolia, to date there is no attempt for AD reports are not found and this study includes the screening of both bark and leaves of M. longifolia for anti-Alzheimer’s effect. Sourcing the ethnomedical information may also be useful as a starting point for the discovery of new drugs for the treatment of AD and cognitive disorders. Considering the importance of natural plants and the continuation of our work towards the treatment of AD (Chethana et al., 2017; Chethana et al., 2018) herein we reporting M. longifolia leaves and bark extracts as an anti-AD agent. The present study is focused on screening plant extracts to evaluate the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, antioxidant studies, and amyloidogenic inhibition supported by thioflavin-T (Th-T) assay (with Cu and Zn), transmission electron microscopy (TEM), inhibition of glycation and aggregation of bovine serum albumin induced by ribose and cell toxicity in SH-SY5Y studies.