Kashyap_2019_Steroids__108529

Alzheimer's Disease (AD) is multi-factorial disorder characterized by impaired memory and cognition deficit. AD is characterized by impaired cholinergic transmission, extracellular amyloid beta deposits , neurofibillary tangles and oxidative stress. A multi-target directed ligand (MTDL) approach is required to devise a therapeutic strategy against AD. In the present study, Asparagus racemosus aqueous extract was chosen, as it possess abundant medicinal properties including nootropic effect mentioned in ancient Ayurvedic texts. Moreover, its secondary metabolite sarsasapogenin (SRS) was also selected for this multi-target study for the very first time. The current study demonstrated that sarsasapogenin significantly inhibits key enzymes involved in pathogenesis of AD which are acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE1 and MAO-B in a concentration dependent manner. SRS also exhibited anti-amyloidogenic, anti-oxidant and neuroprotective effects by in vitro studies. The IC50 values of SRS is 7.7muM and 23.4muM for AChE and BuChE respectively. SRS also significantly inhibited Abeta42 fibrilisation up to 68% at 40muM concentration as compared to control. TEM visualization showed Abeta aggregates as short and scattered fibril clearly indicating SRS significantly inhibited peptide nucleation and fibril formation. Furthermore, the SRS was found to exert neuroprotective effect on PC12 cells against Abeta42 and H2O2-mediated cytotoxicity. The cell survival was 62% and 69% against Abeta42 and H2O2-mediated cytotoxicity, respectively. SRS also inhibited monoaminoxidase-B (MAO-B) and BACE1 enzymes in concentration dependent manner. Molecular docking studies indicated that SRS binds to the catalytic sites of multiple targets (AChE, BuChE, Abeta42, BACE1, and MAO-B) in a significant manner that might having disease-modifying effects. Thus SRS is acting as suitable lead and can be utilised as MTDL compound for factors implicated in AD.