Valproic acid attenuates Aβ25-35-induced neurotoxicity in PC12 cells through suppression of mitochondria-mediated apoptotic pathway

Abstract

Aggregation of amyloid-β (Aβ) peptides is a pathological hallmark of Alzheimer's disease (AD). The purpose of the present study was to identify the protective role of valproic acid (VPA) against β-amyloid protein fragment 25-35 (Aβ_25-35)-caused neurotoxicity in PC12 cells. Different doses of VPA was added to cultures of differentiated PC12 cells, 1 h before Aβ_25-35. We found that VPA effectively prevented Aβ_25-35-stimulated cytotoxicity through attenuating apoptosis and increasing the ratio of Bcl-2/Bax in PC12 cells. VPA also significantly inhibited the generation of ROS induced by Aβ_25-35 in PC12 cells in a dose-dependent manner. In addition, VPA significantly alleviated mitochondrial dysfunction through improvement of mitochondrial membrane potential, inhibition of cytochrome c release, and promotion of mitochondrial ATP synthesis. Furthermore, VPA treatment reduced the expression levels of proinflammatory cytokines and attenuated the activation of NF-κB signaling. In conclusion, our results suggested that VPA might serve as a novel protective agent against Aβ_25-35-induced cytotoxicity in AD.

Keywords: Alzheimer’s disease; Apoptosis; Aβ(25)–(35); Inflammation; Mitochondrial dysfunction; NF-κB signaling; Oxidative stress; PC12 cells; Valproic acid.