Zhang Hongmei, Chang Lijun, Zhang Huajun, Nie Jisheng, Zhang Zhihong, Yang Xiaorong, Vuong Ann M, Wang Zemin, Chen Aimin, Niu Qiao
Department of Environmental Health, Shanxi Medical University, Taiyuan 030001, China.
Department of Environmental Health, Shanxi Medical University, Taiyuan 030001, China.
Toxicol Lett. 2017 Aug 5;277:41-53. doi: 10.1016/j.toxlet.2017.05.027. Epub 2017 May 27.
Polybrominated diphenyl ethers (PBDEs) have been demonstrated to induce neurotoxicity in experimental rats and mice, with neuronal apoptosis as one of the major mechanisms, however, the mechanisms underlying PBDEs-induced neuronal apoptosis remain unclear. In this study, we aimed to investigate the role of calpain/p35-p25/Cdk5 pathway in BDE-153-induced neuronal apoptosis in the hippocampus and primary neurons in rats. Results showed that compared to the controls, neuronal apoptosis was significantly increased in vivo and ex vivo, as manifested by the increased hippocampus TUNEL-positive cell rates, apoptotic neurons in Hoechst and AO/EB staining, and the increased LDH activity and percentage of Annexin V-positive cells in rat hippocampus and primary neurons. Calpain activity was significantly increased in all the BDE-153-treated groups in vivo and ex vivo when compared to non-treatment controls. In addition, we showed that calpain-2 accounted for the calpain activation instead of calpain-1, as demonstrated by the up-regulated mRNA and protein expressions in calpain-2 but not calpain-1. Activated calpain truncated p35 into p25, which resulted in the p25/Cdk5 formation and activation. Calpain inhibitor PD150606 or p25/Cdk5 inhibitor Roscovitine relieved neuronal apoptosis mainly via inhibiting the p25/Cdk5 activation. Overall, the findings suggested that calpain-2/p35-p25/Cdk5 pathway was involved in BDE-153-induced neuronal apoptosis, which provides novel insight into the mechanisms of PBDE neurotoxicity.
多溴二苯醚（PBDEs）已被证明可在实验大鼠和小鼠中诱导神经毒性，神经元凋亡是主要机制之一，然而，PBDEs诱导神经元凋亡的潜在机制仍不清楚。在本研究中，我们旨在探讨钙蛋白酶/p35-p25/Cdk5通路在BDE-153诱导的大鼠海马和原代神经元凋亡中的作用。结果表明，与对照组相比，体内和体外神经元凋亡均显著增加，表现为海马TUNEL阳性细胞率增加、Hoechst和AO/EB染色中的凋亡神经元增加，以及大鼠海马和原代神经元中LDH活性增加和Annexin V阳性细胞百分比增加。与未处理对照组相比，体内和体外所有BDE-153处理组的钙蛋白酶活性均显著增加。此外，我们发现是钙蛋白酶-2而非钙蛋白酶-1导致了钙蛋白酶的激活，这表现为钙蛋白酶-2的mRNA和蛋白表达上调，而钙蛋白酶-1则没有。激活的钙蛋白酶将p35截短为p25，从而导致p25/Cdk5的形成和激活。钙蛋白酶抑制剂PD150606或p25/Cdk5抑制剂Roscovitine主要通过抑制p25/Cdk5的激活来减轻神经元凋亡。总体而言，这些发现表明钙蛋白酶-2/p35-p25/Cdk5通路参与了BDE-153诱导的神经元凋亡，这为PBDE神经毒性机制提供了新的见解。
