Poliumoside inhibits apoptosis, oxidative stress and neuro-inflammation to prevent intracerebroventricular Streptozotocin-induced cognitive dysfunction in Sprague-Dawley Rats: in in-vivo, in-vitro and in-silico study
Abstract
Background: Alzheimer’s disease (AD) is a severe neurological illness causes cognitive decline and mortality if not treated early. However, the current therapeutic modalities are inefficient to manage the cognitive dysfunction of AD. Therefore, in the present manuscript, we have enumerated the pharmacological benefit of Poliumoside in the Streptozotocin-induced cognitive dysfunction in Sprague-Dawley (SD) rats.
Materials and methods: Initially, the cognitive dysfunction in rats was induced by the intracerebroventricular administration of Streptozotocin, then rats received PMD (5 mg and 10 mg/kg body weight) was given. Various behavioural analysis, such as Morris water maze (MWM), and object recognition tests (ORT), and locomotor analysis was conducted in PMD treated group. Various biochemical analysis was conducted to analyze the effect of PMD on hippocampus oxidative-nitrosative stress and pro-inflammatory cytokines. MTT assay and annexin V/PI staining was performed to analyse the effect of PMD on the cell viability and neuronal toxicity of PC12 cells, respectively. Molecular docking analysis was also conducted with crystal structure of human AChE.
Results: PMD treatment improved cognitive capacity in rats in MWM and ORT. Compared to STZ rats, PMD-treated rats had significantly higher locomotor activity and lower AChE activity. PMD also restores dopamine, 5-HT, and NE levels and reduces metabolic their deactivation as evidenced by increased levels of DOPAC, HVA, 5-HIAA. Nitrite, MDA, SOD, CAT, and GSH levels were restored near normal in PMD-treated rats, reducing hippocampus oxidative-nitrosative stress. Pro-inflammatory cytokines were similarly lowered in PMD-treated rats. In in-vitro studies, PMD did not affect PC12 cell survival at the maximal dose of 10 µM. In addition, PMD concentration-dependently prevents H2O2-induced neuronal death in PC12 cells. The in-silico docking analysis showed that the PMD fit snugly into the active site of human AChE by engaging with the anionic domain and the catalytic triad of Trp86, Tyr337, Phe338, and Gly121 residues.
Conclusions: In conclusion, our study demonstrated that PMD have significant impact on AD by inhibiting ACheE and restoring neurotransmitter levels, which enhances Ach levels in rats and improves cognitive impairment in STZ rats.
Keywords: behavioural activitylocomotor activityneurotransmitterapoptosisdocking
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