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The Journal of Neuroscience, March 15, 1998, 18(6):2040-2055

Manganese Superoxide Dismutase Protects nNOS Neurons from NMDA and Nitric Oxide-Mediated Neurotoxicity

Mirella Gonzalez-Zulueta¹, Lisa M. Ensz¹, Galina Mukhina¹, Russell M. Lebovitz⁴, Ralf M. Zwacka⁵, John F. Engelhardt⁵, Larry W. Oberley⁶, Valina L. Dawson^{1, 2, 3}, and Ted M. Dawson^{1, 2}

Departments of ¹ Neurology, ² Neuroscience and ³ Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, ⁴ Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, ⁵ Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52232, and ⁶ Radiation Research Laboratory, Department of Radiology, University of Iowa College of Medicine, Iowa City, Iowa 52242

Neuronal nitric oxide synthase (nNOS) neurons kill adjacent neurons through the action of NMDA-glutamate receptor activation, although they remain relatively resistant to the toxic effects of NMDA and NO. The molecular basis of the resistance of nNOS neurons to toxic insults is unknown. To begin to understand the molecular mechanisms of the resistance of nNOS neurons, we developed a pheochromacytoma-derived cell line (PC12) that is resistant to the toxic effects of NO. We found through serial analysis of gene expression (SAGE) that manganese superoxide dismutase (MnSOD) is enriched in the NO-resistant PC12 cell-derived line (PC12-R). Antisense MnSOD renders PC12-R cells sensitive to NO toxicity and increases the sensitivity to NO in the parental, NO-sensitive PC12 line (PC12-S). Adenoviral transfer of MnSOD protects PC12-S cells against NO toxicity. We extended these studies to cortical cultures and showed that MnSOD is enriched in nNOS neurons and that antisense MnSOD renders nNOS neurons susceptible to NMDA neurotoxicity, although it has little effect on the overall susceptibility of cortical neurons to NMDA toxicity. Overexpression of MnSOD provides dramatic protection against NMDA and NO toxicity in cortical cultures, but not against kainate or AMPA neurotoxicity. Furthermore, nNOS neurons from MnSOD ^/ mice are markedly sensitive to NMDA toxicity. Adenoviral transfer of MnSOD to MnSOD^/ cultures restores resistance of nNOS neurons to NMDA toxicity. Thus, MnSOD is a major protective protein that appears to be essential for the resistance of nNOS neurons in cortical cultures to NMDA mediated neurotoxicity.

Key words: nitric oxide; nNOS neuron; MnSOD; NMDA toxicity; resistance to nitric oxide; neurodegenerative diseases

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1862040-16$05.00/0

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