Vitegnoside Mitigates Neuronal Injury, Mitochondrial Apoptosis, and Inflammation in an Alzheimer's Disease Cell Model via the p38 MAPK/JNK Pathway

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive impairments. Vitegnoside is a flavonoid present in the medicinal plant Vitex negundo, widely used as a folk medicine in several Asian countries including China. It possesses several biological activities, including axon outgrowth, but no evidence is available on its effect on AD. Since no effective treatment is available to cure AD, the effect of vitegnoside on this disease was investigated. The human neuroblastoma SH-SY5Y cell line carrying the Swedish mutation that induces A beta PP overexpression was used as an in vitro AD cell model. A beta PP overexpression does not induce toxicity per se unless triggered by copper. Vitegnoside promoted neuroprotection through the improvement of cell viability, maintenance of cytomembrane integrity and nuclear homogeneity in these cells, but these effects were not observed in the copper-treated SH-SY5Y cells without A beta PP overexpression used as the wild-type control, indicating that vitegnoside exerted neuroprotection under copper-triggered A beta toxic conditions. Vitegnoside failed to decrease A beta PP expression, A beta(40/42) levels, and oxidative stress due to copper-induced A beta toxicity. However, its administration protected the mitochondrial function and restored the imbalance between pro-apoptotic and anti-apoptotic proteins. Additionally, vitegnoside inactivated p38 MAPK/MK2, JNK/c-Jun, and downstream NF-kappa B inflammatory transductions. Furthermore, the inactivation of p38 MAPK/JNK signaling contributed to vitegnoside-mediated neuroprotection resulting from pharmacological inhibition of p38 MAPK/JNK and in silico interaction prediction. Our study revealed the neuroprotective effect of vitegnoside and its potential mechanisms against copper-induced A beta neurotoxicity. These findings highlighted the potential therapeutic effect of vitegnoside against AD progression.