PI3K/Akt signaling pathway and Hsp70 activate in hippocampus of rats with chronic manganese sulfate exposure

Abstract

Manganese (Mn) has come to the forefront of environmental concerns due to its neurotoxicity. However, the toxic effect of Mn is not fully understood. The purpose of this study is to investigate the impacts of chronic manganese sulfate (MnSO₄) exposure in regulating the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling pathway in rats. In this study, rats were treated with 0, 5.0, 10.0, and 20.0 mg/kg MnSO₄•H₂O five days a week for 24 weeks via intraperitoneal injection. At the end of the exposure period, the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), malondialdehyde (MDA), and heat shock protein (Hsp70) in rats' plasma were quantified; the mRNA expression levels of caspase-3, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), serine-threonine protein kinase (Akt-1), and forkhead box O3a (FoxO3a) were measured through real-time quantitative PCR (RT-PCR); and the levels of protein Hsp70 and Akt were assessed by western blot. With an increasing dose of MnSO₄, the organ coefficients of all tested organs were significantly increased, except the testis. Compared with the control group, the activities of plasma SOD, GSH-Px, and CAT in MnSO₄-exposed groups were significantly decreased, while the concentrations of plasma MDA and Hsp70 were significantly increased. Moreover, the hippocampal mRNA levels of Bcl-2, caspase-3, Akt-1, and FoxO3a in MnSO₄-exposed groups were downregulated, but the level of Bax was upregulated. Meanwhile, the level of phosphorylation of Akt (p-Akt) and Hsp70 proteins tends to be upregulated by increasing MnSO₄ exposure (P < 0.05). The plasma Hsp70 level was negatively associated with SOD, CAT, and GSH-Px activities (P < 0.05), and positively associated with blood MDA concentration and hippocampal Hsp70 levels (P < 0.05). Chronic MnSO₄ exposure can result in apoptosis of central nerve cells, activate the PI3K/Akt signaling pathway in rats' hippocampus, and upregulate Hsp70 transcription and translation.

Keywords: Apoptosis; Hippocampus; Hsp70; Manganese; PI3K/Akt.