| Title | Cilnidipine Mediates a Neuroprotective Effect by Scavenging Free Radicals and Activating the Phosphatidylinositol 3-Kinase Pathway. | | Author(s) | Lee YJ, Park KH, Park HH, Kim YJ, Lee KY, Kim SH, Koh SH | | Institution | Department of Neurology, Hanyang University College of Medicine, Seoul, Korea. | | Source | J Neurochem 2009 Jul 23. | | Abstract | We investigated the neuroprotective effect and mechanisms of action of cilnidipine, a long-acting, second-generation 1,4-dihydropyridine inhibitor of L- and N-type calcium channels, in PC12 cells that were neuronally differentiated by treatment with nerve growth factor (nPC12 cells). To evaluate the effect of cilnidipine on viability, nPC12 cells were treated with several concentrations of this drug before performing viability assays. Free radical levels and intracellular signaling proteins were measured with the fluorescent probe, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and Western blotting, respectively. Cell viability was not affected by low concentrations of cilnidipine up to 150 muM, but it was slightly decreased at 200 muM cilnidipine. Following hydrogen peroxide (H(2)O(2)) exposure, the viability of nPC12 cells decreased significantly; however, treatment with cilnidipine increased the viability of H(2)O(2)-injured nPC12 cells in a concentration-dependent manner. Treatment with H(2)O(2) resulted in a concentration-dependent increase in free radical levels in nPC12 cells, and cilnidipine treatment reduced free radical levels in H(2)O(2)-injured nPC12 cells in a dose-dependent manner. Cilnidipine treatment increased the expression of p85aPI3K, phosphorylated Akt, phosphorylated GSK-3beta, and HSTF-1, which are proteins related to neuronal cell survival, and decreased levels of cytosolic cytochrome c, activated caspase-3, and cleaved PARP, which are associated with neuronal cell death, in H(2)O(2)-injured nPC12 cells. These results indicate that cilnidipine mediates its neuroprotective effects by reducing oxidative stress, enhancing survival signals (e.g., PI3K, phosphorylated Akt, phosphorylated GSK-3beta, and HSTF-1), and inhibiting death signals from cytochrome c release, caspase-3 activation, and PARP cleavage. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19650875 |
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