Li, Zhao-cong, Wang, Lei-lei, Zhao, Yue-song, Peng, Dong-jie, Chen, Jing, Jiang, Si-yang, Zhao, Lin, Aschner, Michael, Li, Shao-jun, and Jiang, Yue-ming
Lead (Pb) is a naturally occurring heavy metal, which can damage the brain and affect learning and memory. Sodium para-aminosalicylic acid (PAS-Na), a non-steroidal anti-inflammatory drug, can readily cross the blood-brain barrier. Our previous studies have found that PAS-Na alleviated Pb-induced hippocampal ultrastructural damage and neurodegeneration, but the mechanism has yet to be defined. Here, we investigated the molecular mechanisms that mediate Pb-induced apoptosis in hippocampal neurons, and the efficacy of PAS-Na in alleviating its effects. This work showed that juvenile developmental Pb exposure impaired rats cognitive ability by inducing apoptotic cell death in hippocampal neurons. Pb-induced neuronal apoptosis was accompanied by increased inositol 1,4,5-trisphosphate receptor (IP 3 R) expression and enhanced intracellular calcium [Ca2+] i levels, which resulted in increased phosphorylation of neuronal apoptosis signal-regulating kinase 1 (ASK1) and p38. Activation of ASK1 and p38 was blocked by IP 3 R inhibitor and a Ca2+ chelator. Importantly, PAS-Na treatment improved the Pb-induced effects on cognitive deficits in rats, concomitant with rescued neuronal apoptosis. In addition, PAS-Na reduced the expression of IP 3 R and the ensuing increase in intracellular Ca2+ and decreased the phosphorylation of ASK1 and p38 in Pb-exposed neurons. Taken together, this study demonstrates that the IP 3 R-Ca2+-ASK1-p38 signaling pathway mediates Pb-induced apoptosis in hippocampal neurons, and that PAS-Na, at a specific dose-range, ameliorates these changes. Collectively, this study sheds novel light on the cellular mechanisms that mediate PAS-Na efficacy, laying the groundwork for future research to examine the treatment potential of PAS-Na upon Pb poisoning. • Juvenile developmental Pb exposure impaired rat cognitive ability and induced apoptotic cell death in hippocampal neurons. • Pb-induced apoptosis in hippocampal neurons was secondary to IP 3 R-Ca2+-ASK1-p38 signaling pathway activation. • PAS-Na attenuated the Pb-induced effects on cognitive deficits in rats, concomitant with rescued neuronal apoptosis. • PAS-Na ameliorates the Pb-induced hippocampal neuronal apoptosis by suppressing IP 3 R-Ca2+-ASK1-p38 pathway activation. [ABSTRACT FROM AUTHOR]