Role of the phosphatidylinositol 3-kinase and extracellular signal-regulated kinase pathways in the neuroprotective effects of cilnidipine against hypoxia in a primary culture of cortical neurons

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• 作者：Sangjae Kim^a ; ¹ ; Kyu-Yong Lee^b ; ¹ ; Seong-Ho Koh^b ; ^c ; ^{ksh213@hanyang.ac.kr} ; Hyun-Hee Park^b ; Hyun-Jeung Yu^d ; Young Joo Lee^b
• 关键词：CCBs ; calcium channel blockers ; COX ; cyclooxygenase ; DAPI ; DNA-specific fluorochrome 4&prime ; 6-diamidino-2-phenylindole dihydrochloride ; DCF ; 2&prime ; 7&prime ; -dichlorofluorescein ; DCFH-DA ; dichlorodihydrofluorescein diacetate ; DCFH2 ; 2&prime ; 7&prime ; -di
• 刊名：Neurochemistry International
• 出版年：2012
• 出版时间：December, 2012
• 年：2012
• 卷：61
• 期：7
• 页码：1172-1182
• 全文大小：761 K

文摘

Cilnidipine, a calcium channel blocker, has been reported to have neuroprotective effects. We investigated whether cilnidipine could protect neurons from hypoxia and explored the role of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-related kinase (ERK) pathways in the neuroprotective effect of cilnidipine. The viability of a primary culture of cortical neurons injured by hypoxia, measured by trypan blue staining and lactate dehydrogenase (LDH) assay, was dramatically restored by cilnidipine treatment. TUNEL and DAPI staining showed that cilnidipine significantly reduced apoptotic cell death induced by hypoxia. Free radical stress and calcium influx induced by hypoxia were markedly decreased by treatment with cilnidipine. Survival signaling proteins associated with the PI3K and ERK pathways were significantly increased while death signaling proteins were markedly decreased in the primary culture of cortical neurons simultaneously exposed to cilnidipine and hypoxia when compared with the neurons exposed only to hypoxia. These neuroprotective effects of cilnidipine were blocked by treatment with a PI3K inhibitor or an ERK inhibitor. These results show that cilnidipine protects primary cultured cortical neurons from hypoxia by reducing free radical stress, calcium influx, and death-related signaling proteins and by increasing survival-related proteins associated with the PI3K and ERK pathways, and that activation of those pathways plays an important role in the neuroprotective effects of cilnidipine against hypoxia. These findings suggest that cilnidipine has neuroprotective effects against hypoxia through various mechanisms, as well as a blood pressure-lowering effect, which might help to prevent ischemic stroke and reduce neuronal injury caused by ischemic stroke.