CerebralIschemiaandReperfusion创新.PDFVIP

The Journal of Neuroscience, May 9, 2007 • 27(19):5249–5259 • 5249 Neurobiology of Disease Contribution of Downregulation of L-type Calcium Currents to Delayed Neuronal Death in Rat Hippocampus after Global Cerebral Ischemia and Reperfusion Xiao-Ming Li, Jian-Ming Yang, De-Hui Hu, Feng-Qing Hou, Miao Zhao, Xin-Hong Zhu, Ying Wang, Jian-Guo Li, Ping Hu, Liang Chen, Lu-Ning Qin, and Tian-Ming Gao Department of Anatomy and Neurobiology, Southern Medical University, Guangzhou 510515, People’s Republic of China Transient forebrain ischemia induces delayed, selective neuronal death in the CA1 region of the hippocampus. The underlying molecular mechanisms are as yet unclear, but it is known that activation of L-type Ca 2 channels specifically increases the expression of a group of genes required for neuronal survival. Accordingly, we examined temporal changes in L-type calcium-channel activity in CA1 and CA3 pyramidal neurons of rat hippocampus after transient forebrain ischemia by patch-clamp techniques. In vulnerable CA1 neurons, L-type Ca2 -channel activity was persistently downregulated after ischemic insult, whereas in invulnerable CA3 neurons, no change occurred. Downregulation of L-type calcium channels was partially caused by oxidation modulation in postischemic channels. Furthermore, L-type but neither N-type nor P/Q-type Ca 2 -channel antagonists alone significantly inhibited the survival of cultured hippocampal neurons. In contrast, specific L-type calcium-channel agonist remarkably reduced neuronal cell death and restored the inhibited channels induced by nitric oxide donor. More importantly, L-type calcium-channel agonist applied after reoxygenation or reperfusion significantly decreased neuronal injury in in vitro oxygen-glucose deprivation ischemic model and in animals subjected to forebrain ischemia–reperfusion. Together, the prese