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J. Biol. Chem., Vol. 276, Issue 51, 48093-48099, December 21, 2001

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Anti-apoptotic Effect of cGMP in Cultured Astrocytes
INHIBITION BY cGMP-DEPENDENT PROTEIN KINASE OF MITOCHONDRIAL PERMEABLE TRANSITION PORE^*

Kazuhiro Takuma, Patamawan Phuagphong^§, Eibai Lee^¶, Koichi Mori, Akemichi Baba^§, and Toshio Matsuda^**

From the Departments of  Analytical Chemistry and ^¶ Pharmacology, Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University, Kobe 651-2180 Japan and the Laboratories of ^§ Molecular Neuropharmacology and  Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan

Reperfusion of cultured astrocytes with normal medium after exposure to H₂O₂-containing medium causes apoptosis. We have recently shown that ibudilast, which has been used for bronchial asthma and cerebrovascular disorders, attenuated the H₂O₂-induced apoptosis of astrocytes via the cGMP signaling pathway. This study examines the mechanism underlying the protective effect of cGMP. The membrane-permeable cGMP analog dibutyryl-cGMP attenuated the H₂O₂-induced decrease in cell viability, DNA ladder formation, nuclear condensation, reduction of the mitochondrial membrane potential, cytochrome c release from mitochondria, and caspase-3 activation in cultured astrocytes. These effects of dibutyryl-cGMP were almost completely inhibited by the cGMP-dependent protein kinase (PKG) inhibitor KT5823. In isolated rat brain mitochondria, cGMP in the presence of cytosolic extract from astrocytes inhibited the mitochondrial permeability transition pore (PTP) as determined by monitoring Ca²⁺-induced mitochondrial swelling. This ability of the cytosolic extract was inactivated by heat treatment and was mimicked by exogenous PKG. The effect of cGMP on the mitochondrial swelling was blocked by KT5823. The PTP inhibitors cyclosporin A and bongkrekic acid prevented the H₂O₂-induced decrease in cell viability and caspase-3 activation. These findings demonstrate that cGMP inhibits the mitochondrial PTP via the activation of PKG, and the prevention of mitochondrial dysfunction contributes to its anti-apoptotic effect.

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