title: Contribution of downregulation of L-type calcium currents to delayed neuronal death in rat hippocampus after global cerebral ischemia and reperfusion.
abstract: 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.
authors.affiliation: Department of Anatomy and Neurobiology, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Li
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Yang
authors.forename: De-Hui
authors.initials: DH
authors.lastname: Hu
authors.forename: Feng-Qing
authors.initials: FQ
authors.lastname: Hou
authors.forename: Miao
authors.initials: M
authors.lastname: Zhao
authors.forename: Xin-Hong
authors.initials: XH
authors.lastname: Zhu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Lu-Ning
authors.initials: LN
authors.lastname: Qin
authors.forename: Tian-Ming
authors.initials: TM
authors.lastname: Gao
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type