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Akt-dependent heme oxygenase-1 induction by NS-398 in C6 glial cells: A potential role for CO in prevention of oxidative damage from hypoxia
- Source :
-
Neuropharmacology . Sep2007, Vol. 53 Issue 4, p542-551. 10p. - Publication Year :
- 2007
-
Abstract
- Abstract: We investigated whether increased heme oxygenase (HO)-1 activity by NS-398 is responsible for protection against hypoxia-induced damage in C6 cells. The expression of HO-1 was analyzed by Western blot and cell viability was analyzed by lactate dehydroxygease (LDH) activity. NS-398 increased HO-1 expression in a concentration- and time-dependent manner during both normoxia and hypoxia (95% N2/5% CO2), but the latter was much more sensitive. Because induction of HO-1 occurred due to hypoxia itself, NS-398 seemed to potentiate the expression of HO-1. The reduced cell viability due to hypoxia was significantly reversed by either NS-398 or [Ru(CO)3(Cl)2]2, a CO-donor. Zinc protophorphrin (ZnPPIX), a HO-1 inhibitor, inhibited the protective effect of NS-398 against hypoxia. Treatment with glucose oxidase (GOX, 20mU/ml) increased ROS production and caused apoptotic death, as assayed by DCFH-DA and TUNEL, respectively. NS-398 significantly reduced GOX-induced cell death and ROS production; these effects were reversed by pre-treatment with oxyhemoglobin (HbO2), a CO/NO scavenger, or ZnPPIX. Finally, NS-398 increased PPAR-γ luciferase activity in transiently PPAR-γ transfected C6 cells, which was antagonized by ZnPPIX. NS-398 increased phosphorylation of Akt, and LY-294002, a specific PI3 kinase inhibitor, inhibited NS-398-induced HO-1 expression. Taken together, we conclude that therapeutic use of NS-398 in the treatment of oxidative stress-oriented neuronal disorders would be beneficial through dual actions: HO-1 induction and COX-2 inhibition. [Copyright &y& Elsevier]
- Subjects :
- *NEUROGLIA
*HYPOXEMIA
*NEUROPHARMACOLOGY
*NEUROSCIENCES
Subjects
Details
- Language :
- English
- ISSN :
- 00283908
- Volume :
- 53
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 26340937
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2007.06.022