Exploring the therapeutic potential of Diosgenin as a Semaphorin-4D antagonist against neurodegenerative disorders.

Abstract

Neurodegenerative disorders represent a significant health challenge for the population, with their mechanisms of action being poorly understood. The development of inhibitory pharmaceuticals has encountered several obstacles, resulting in therapies that lacks the necessary efficacy. Neurodegenerative disorders are marked by a gradual deterioration of neurons, leading to a decline in various functions directed by central nervous system (CNS) including motor and non-motor symptoms. Recent focus has turned towards targeting Sema4D as a potential target for mitigating neuroinflammation and inhibiting demyelination, prevalent in various neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, etc. But despite the efforts the treatment options developed poses a major hinderance in terms of side effects. An effective answer to this is Ayurvedic phytochemicals. Phytochemicals of the Piperaceae family have been known to reverse the adversities caused by neurodegeneration. In pursuit of effective interventions, this study has conducted In-silico and In-vitro studies to evaluate the efficacy of Piper nigrum and Piper betle bioactive phytochemicals as antagonists against Sema4D. Among these, Diosgenin has emerged with notable promise, demonstrating a remarkable binding affinity of -8.84 kcal/mol with Sema4D. Molecular dynamics simulations (RMSF, RMSD, PCA, SASA, FEL, etc.) have further underscored its stability, exhibiting a consistent complex structure over 100 ns. In addition to its favourable binding properties, Diosgenin has exhibited compelling effects In-vitro. It's not only enhanced cellular viability and proliferation but also exerts protective effects against oxidative stress-induced injury in PC12 cells. These findings suggest Diosgenin's potential as a therapeutic agent against Sema4D, offering a promising avenue in the battle against neurodegenerative diseases. However, further studies are required to elucidate its precise molecular mechanisms, assess its bioavailability and toxicity in vivo, and validate its therapeutic efficacy in animal models and clinical settings.