Open AccessContribution of Downregulation of L-type Calcium Currents to Delayed Neuronal Death in Rat Hippocampus after Global Cerebral Ischemia and Reperfusion
Author(s) -
Xiaoming Li,
JianMing Yang,
De-Hui Hu,
Fengqing Hou,
Miao Zhao,
Xinhong Zhu,
Ying Wang,
Jianguo Li,
Ping Hu,
Liang Chen,
Lu-Ning Qin,
Tianming Gao
Publication year - 2007
Publication title -
the journal of neuroscience/the journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.483
H-Index - 455
eISSN - 1529-2401
pISSN - 0270-6474
DOI - 10.1523/jneurosci.0802-07.2007
Subject(s) - t type calcium channel , hippocampal formation , forebrain , ischemia , hippocampus , voltage dependent calcium channel , downregulation and upregulation , calcium channel , endocrinology , neuroscience , calcium , medicine , p type calcium channel , neuron , l type calcium channel , chemistry , biology , central nervous system , biochemistry , gene
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.