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The Journal of Neuroscience, May 9, 2007, 27(19):5249-5259; doi:10.1523/JNEUROSCI.0802-07.2007

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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

Correspondence should be addressed to Dr. Tian-Ming Gao, Department of Anatomy and Neurobiology, Southern Medical University, Guangzhou 510515, People's Republic of China. Email: tgao{at}fimmu.com

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 Ca²⁺ 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 Ca²⁺-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 present results suggest that ischemia-induced inhibition of L-type calcium currents may give rise to delayed death of neurons in the CA1 region, possibly via oxidation mechanisms. Our findings may lead to a new perspective on neuronal death after ischemic insult and suggest that a novel therapeutic approach, activation of L-type calcium channels, could be tested at late stages of reperfusion for stroke treatment.

Key words: calcium channels; ischemia; neuronal death; oxidation; hippocampus; rat

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Received Oct. 7, 2006; revised April 9, 2007; accepted April 11, 2007.

Correspondence should be addressed to Dr. Tian-Ming Gao, Department of Anatomy and Neurobiology, Southern Medical University, Guangzhou 510515, People's Republic of China. Email: tgao{at}fimmu.com

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