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The Journal of Neuroscience, March 1, 2003, 23(5):1710

Overexpression of Copper/Zinc Superoxide Dismutase in Transgenic Mice Protects against Neuronal Cell Death after Transient Focal Ischemia by Blocking Activation of the Bad Cell Death Signaling Pathway

Atsushi Saito, Takeshi Hayashi, Shuzo Okuno, Michel Ferrand-Drake, and Pak H. Chan

Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California 94305-5487

The Bad signaling pathway contributes to the regulation of apoptosis after a variety of cell death stimuli, and Bad plays a key role in determining cell death or survival. We have reported that overexpression of copper/zinc superoxide dismutase (SOD1) reduces apoptotic cell death after transient focal cerebral ischemia (tFCI). However, both the role of the Bad pathway after tFCI and the role of oxygen free radicals in the regulation of apoptosis remain unknown. To clarify these issues, we used an in vivo tFCI model of SOD1 transgenic mice and wild-type mice. Moreover, to examine the role of protein kinase A (PKA) in the Bad pathway after tFCI, we administered the PKA inhibitor, H89, into the mouse brain after tFCI. Immunohistochemistry and Western blot analysis showed that dephosphorylation and translocation of Bad were detected early after tFCI and that they were promoted by H89 treatment but prevented by SOD1. Coimmunoprecipitation revealed that the dimerization of Bad progressed with 14-3-3 (Bad/14-3-3) and with Bcl-x_L (Bad/Bcl-x_L) after tFCI. Moreover, Bad/14-3-3 was prevented by H89 treatment but promoted by SOD1. Bad/Bcl-x_L was prevented by SOD1 but promoted by H89 treatment. A cell death assay revealed that apoptotic-related DNA fragmentation was aggravated by H89 treatment but reduced by SOD1. These results suggest that the Bad pathway mediated by PKA is involved in apoptotic cell death after tFCI and that overexpression of SOD1 may attenuate this apoptotic cell death.

Key words: cerebral ischemia; apoptosis; Bad; Bcl-x_L; 14-3-3; superoxide

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2351710-09$05.00/0

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