Poliumoside inhibits apoptosis, oxidative stress and neuro-inflammation to prevent intracerebroventricular streptozotocin-induced cognitive dysfunction in Sprague-Dawley rats: an in vivo, in vitro and in silico study.

Background: Alzheimer's disease (AD) is a severe neurological illness that causes cognitive decline and death if not treated early. The current therapeutic modalities are inefficient in managing the cognitive dysfunction of AD. Therefore, in this study, we aimed to investigate the pharmacological benefit of poliumoside (PMD) in streptozotocin-induced cognitive dysfunction in Sprague-Dawley (SD) rats.

Materials and methods: Initially, cognitive dysfunction in rats was induced by the intracerebroventricular administration of streptozotocin. Then rats received PMD at 5 mg and 10 mg/kg body weight. Various behavioural analyses, such as the Morris water maze (MWM) and the object recognition test (ORT), and locomotor analysis was conducted in the PMD-treated group. Biochemical analysis was conducted to analyse the effect of PMD on hippocampus oxidative-nitrosative stress and pro-inflammatory cytokines. MTT assay and annexin V/PI staining were 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 restored dopamine, 5-HT, and NE levels and reduced their metabolic deactivation, as evidenced by increased levels of DOPAC, HVA, and 5-HIAA. Nitrite, MDA, SOD, CAT, and GSH levels were restored to 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 prevented H₂O₂-induced neuronal death in PC12 cells. In silico docking analysis showed that PMD fitted 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: This study has demonstrated that PMD has a significant impact on AD by inhibiting ACheE and restoring neurotransmitter levels, which enhances Ach levels in rats, and improves cognitive impairment in STZ rats.