Deciphering the mechanistic action of phytoformulation against scopolamine‐induced Alzheimers in rodents

Abstract

AbstractBackground Brahmi Nei (BN), an Indian traditional phytoformulation composed of eleven plant constituents has been traditionally used for treating various psychiatric disorders, hypertension and cerebral palsy. Some of the key phytoconstituents in this formulation have been explored for their potential role in plaque disruption, crossing the blood‐brain barrier, reversing the cognitive deficit and promoting tau dephosphorylation independently as a mono‐drug. Since Alzheimer’s disease (AD) is a multifactorial disorder affecting various signaling pathways, we hypothesize that BN formulation may be an effective option to treat AD.MethodThe major constituents in BN were identified using LC‐MS/MS technique. The Alzheimer’s model was created using scopolamine hydrobromide in animals through intra‐hippocampal injection at a concentration of 10 µg/µL. After seven days of post‐operative care, treatment was started with three different doses BN1 (0.5 of therapeutic dose, n=5), BN2 (Therapeutic dose, n=5), BN3 (twice the therapeutic dose, n=5) for a period of 28 days. The cognition and spatial learning were assessed using Morris water maze, radial arm maze and elevated plus maze. RT‐PCR, Western blots, biochemical assays analysis were performed to evaluate the therapeutic efficacy of BN against various signaling pathways deregulated in AD. Neuritic plaque deposits were detected using Bielchowsky silver staining while dendritic morphology and spine types were studied using Golgi‐Cox staining.ResultOur results reveal that BN treatment influences the working memory and hippocampal‐dependent learning pattern in AD‐induced rodents. BN reduced acetylcholine esterase and malondialdehyde concentration in hippocampal tissues. It significantly regulates dephosphorylation of tau, inflammatory pathway and also inhibits the BBB disruption by activating YAP/TAZ. At the cellular level, synaptic degeneration and hippocampal neuronal loss were reversed by BN treatment which also regenerated neurons and increased spine density that is reflected in the superior cognitive improvement displayed by the BN2 and BN3 treated animals in the behavioral studies.ConclusionThe BN formulation is an efficient therapeutic option in treating the multiple pathways involved in AD when compared to conventional mono‐drug treatment.