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The Journal of Neuroscience, October 15, 1998, 18(20):8292-8299

Overexpression of SOD1 in Transgenic Rats Protects Vulnerable Neurons Against Ischemic Damage After Global Cerebral Ischemia and Reperfusion

Pak H. Chan^{1, 3}, Makoto Kawase^{1, 3}, Kensuke Murakami¹, Sylvia F. Chen^{1, 3}, Yibing Li¹, Bernard Calagui^{1, 3}, Liza Reola^{1, 3}, Elaine Carlson², and Charles J. Epstein²

CNS Injury and Edema Research Center, Departments of ¹ Neurological Surgery and Neurology and ² Department of Pediatrics, University of California, School of Medicine, San Francisco, California 94143, and ³ Departments of Neurosurgery, Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, California 94304

Transient global cerebral ischemia resulting from cardiac arrest is known to cause selective death in vulnerable neurons, including hippocampal CA₁ pyramidal neurons. It is postulated that oxygen radicals, superoxide in particular, are involved in cell death processes. To test this hypothesis, we first used in situ imaging of superoxide radical distribution by hydroethidine oxidation in vulnerable neurons. We then generated SOD1 transgenic (Tg) rats with a five-fold increase in copper zinc superoxide dismutase activity. The Tg rats and their non-Tg wild-type littermates were subjected to 10 min of global ischemia followed by 1 and 3 d of reperfusion. Neuronal damage, as assessed by cresyl violet staining and DNA fragmentation analysis, was significantly reduced in the hippocampal CA₁ region, cortex, striatum, and thalamus in SOD1 Tg rats at 3 d, as compared with the non-Tg littermates. There were no changes in the hippocampal CA₃ subregion and dentate gyrus, resistant areas in both SOD1 Tg and non-Tg rats. Quantitative analysis of the damaged CA₁ subregion showed marked neuroprotection against transient global cerebral ischemia in SOD1 Tg rats. These results suggest that superoxide radicals play a role in the delayed ischemic death of hippocampal CA₁ neurons. Our data also indicate that SOD1 Tg rats are useful tools for studying the role of oxygen radicals in the pathogenesis of neuronal death after transient global cerebral ischemia.

Key words: superoxide dismutase; transgenic rat; superoxide radicals; transient global cerebral ischemia; delayed neuronal degeneration; DNA fragmentation

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18208292-08$05.00/0

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