Sphingosine-1-Phosphate Receptor Modulator – Siponimod: An Evaluation to Ameliorate Aluminium Chloride Induced Behavioural Change and Biochemical effects

Abstract

Introduction: Alzheimer's disease (AD) is a neurodegenerative condition characterised by the gradual loss of hippocampal and cortical neurons, resulting in diminished memory and cognitive function. Siponimod (SPM) a selective modulator of sphingosine 1-phosphate receptor subtype 1 and 5(S1P1,S1P5 receptors), was found to have neuroprotective effect in neurological disorders. The present study was conducted to evaluate its beneficial effects in AD. Materials and Methods: In-silico molecular docking and molecular dynamic simulation studies were carried to know its potential interactions with selected target proteins. In-vivo study was conducted inthirty rats divided randomly into five groups with six rats per group: Control group received Carboxy methyl cellulose; disease group were administered aluminium chloride (AlCl3);standard group received rivastigmine (RVST) with AlCl3; and the test groups received SPM (0.05mg/kg and 0.2mg/kg) with AlCl3. Morris water maze test and elevated plus maze was used to evaluate learning and memory. Behavioural changes and biochemical parameters estimation were performed at the end of experiment. Results: The molecular docking study using selected protein and ligands showed higher docking score and stable interactions at acetylcholinesterase (AChE) protein with SPM.Behavioural studies showed: decrease in transfer latency time in elevated plus maze; decrease in time to reach target platform and increase in time spent in target quadrant in Morris water maze test in SPM treated rats. Biochemical evaluation showed marked decrease in malondialdehyde (MDA), nitrite, myeloperoxidase (MPO)levels and increased antioxidant levels in SPM treated groups. SPM exhibited significant inhibitory activity onAChE. Conclusion: SPM was found to be effective in ameliorating AlCl3 induced AD. The observed benefits in restoring learning and memory were attributed to its inhibitory activity on AChE and its ability to suppress free radical mediated oxidative damage.