Sarsasapogenin: A steroidal saponin from Asparagus racemosus as multi target directed ligand in Alzheimer’s disease
Graphical abstract
Introduction
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease characterized by extracellular senile plaques formation and intracellular neurofibrillary tangles. The current rate of AD doubles every 20 years, thus the disease burden is estimated to reach 131.5 million cases of AD by 2050 [1]. With such high incidence, the economic burden to society is bound to increase. Current treatment mainly covers only symptomatic relief and prevention strategies only. Presently there is need to discover novel drug compounds that could have disease modifying abilities with fewer or no side effects. With this approach the current study was undertaken to evaluate therapeutic effect of natural compounds mentioned in our Ayurveda.
AD pathophysiology is based on many hypothesis, mainly amyloid cascade hypothesis [2]. Amyloid precursor protein (APP) miscleavage by BACE1 which results in sticky insoluble peptide fragments called amyloid beta fibrils (Aβ) which forms Aβ oligomers [3]. Aβ fibril formation initiates AD and increases oxidative stress in central nervous system (CNS). Aβ fibrillation also accelerates upon binding to AChE [4]. Therefore, drug compounds that could inhibit AChE would be effective for disease modifying properties. Furthermore, accumulation of reactive oxygen species (ROS) in AD plays important role in progression of disease. The high lipid content of the nervous tissue, in the form of myelin, with abundance of unsaturated fatty acids and long chain fatty acids in cell membranes, coupled with its high aerobic metabolic activity, make it particularly susceptible to oxidative damage [5]. In addition, Aβ has high affinity for redox-active metals being able to reduce them and consequently lead to the formation of hydrogen peroxide and oxidized Aβ [6]. MAO-B is also responsible for over production of ROS [7]. Thus anti-oxidant compounds might be useful therapeutic target in diseases like AD. In view of this, the present study focussed on multiple targets such as Aβ peptides, BACE-1, AChE, BuChE, ROS and MAO-B implicated in AD.
Asparagus racemosus (commonly known as Śatāvari) is the species used medicinally in India. The drugs are listed in the Ayurvedic Pharmacopoeia and Chinese Pharmacopoeia and are commercially important in the global herbal drug market due to their rich steroidal contents such as shatavarin I–VIII [8], [9]. The root tubers of A. racemosus are particularly recognized in Ayurveda for their phytoestrogenic, fertility-promoting and hormone-modulating properties in both males and females. In addition, they have neuroprotective, immune-adjuvant, anti-anxiety, cardio-protective, anti-bacterial and anti-diarrhoeal properties [10]. SRS, the steroidal sapogenin from A. racemosus has been shown to possess anti-depressant properties though it has not been evaluated for factors implicated in AD [11].
Section snippets
Materials
MAO-B inhibition kit from Biovision; BACE-1 activity assay kit from Sigma Aldrich, LC-MS grade Water, Methanol, Acetonitrile, Formic Acid, Zorbax UPLC C18 Silica Column, Agilent 6520 QTOF instrument, Acetylcholinesterase (AChE) from electric eel, Butyrylcholinesterase (BuChE) from equine serum, Amyloid beta (Aβ42) protein (Link biotech), Thioflavin T (ThT), Congo red dye, Sarsasapogenin was purchased from Sigma Aldrich, India. RPMI 1640 medium, FBS, PBS and other tissue culture grade chemicals
Phytochemical characterization of an aqueous extract of A. Racemosus
The LCMS (Fig. 1) showed presence of abundant steroids present in A. racemosus along with other secondary metabolites. Their phytosteroids found were primarily saponins. ESI positive mode gave better identification and resolution of phyto-compounds. The masses, which were unmatched from library and couldn’t be identified on the basis of daughter ions in MS/MS were assigned as unknown masses.
Upon analyzing the most abundant masses present in the extract by comparing intensities of individual
Discussion
The cognitive decline and memory deficit in AD is attributed to diverse factors such as miscleavage of APP protein, amyloid beta plaque formation, cholinergic dysfunction, oxidative stress and neurofibrillary tangles [18]. Moreover, amyloid cascade hypothesis is considered to be the primary cause of senile dementia. With the advancement of research, new insight into disease progression revealed novel targets responsible for pathophysiology and associated symptoms. Various strategies were
Conclusions
In conclusion, the novel study showed that SRS could act as multi-target directed ligands (MTDL) and can be used to develop into novel hybrid compounds that can be used against several targets Aβ42, AChE, BuChE, MAO-B, BACE1 and ROS that are implicated in AD and thus help in alleviation of symptoms and having disease modifying effect in AD.
Funding
This work was supported by Faculty Research Grant Scheme (FRGS) grant of Guru Gobind Singh Indraprastha University, New Delhi, India.
Ethics approval and consent to participate
Ethical approval was obtained from GGS Indraprastha University for all the animal tissue culture work done in proper confined facilities.
Conflict of interest
The authors declare that they have no financial or non-financial competing interest.
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