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The Journal of Neuroscience, May 27, 2009, 29(21):7003-7014; doi:10.1523/JNEUROSCI.1110-09.2009

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Neurobiology of Disease
Regulation of Mn-Superoxide Dismutase Activity and Neuroprotection by STAT3 in Mice after Cerebral Ischemia

Joo Eun Jung,^1,2,3 * Gab Seok Kim,^1,2,3 * Purnima Narasimhan,^1,2,3 Yun Seon Song,^1,2,3 and Pak H. Chan^1,2,3

¹Departments of Neurosurgery and ²Neurology and Neurological Sciences, and ³Program in Neurosciences, Stanford University School of Medicine, Stanford, California 94305

Correspondence should be addressed to Pak H. Chan, Neurosurgical Laboratories, Stanford University, 1201 Welch Road, MSLS #P314, Stanford, CA 94305-5487. Email: phchan{at}stanford.edu

Cerebral ischemia and reperfusion increase superoxide anions (O₂^·–) in brain mitochondria. Manganese superoxide dismutase (Mn-SOD; SOD2), a primary mitochondrial antioxidant enzyme, scavenges superoxide radicals and its overexpression provides neuroprotection. However, the regulatory mechanism of Mn-SOD expression during cerebral ischemia and reperfusion is still unclear. In this study, we identified the signal transducer and activator of transcription 3 (STAT3) as a transcription factor of the mouse Mn-SOD gene, and elucidated the mechanism of O₂^·– overproduction after transient focal cerebral ischemia (tFCI). We found that Mn-SOD expression is significantly reduced by reperfusion in the cerebral ischemic brain. We also found that activated STAT3 is usually recruited into the mouse Mn-SOD promoter and upregulates transcription of the mouse Mn-SOD gene in the normal brain. However, at early postreperfusion periods after tFCI, STAT3 was rapidly downregulated, and its recruitment into the Mn-SOD promoter was completely blocked. In addition, transcriptional activity of the mouse Mn-SOD gene was significantly reduced by STAT3 inhibition in primary cortical neurons. Moreover, we found that STAT3 deactivated by reperfusion induces accumulation of O₂^·– in mitochondria. The loss of STAT3 activity induced neuronal cell death by reducing Mn-SOD expression. Using SOD2–/+ heterozygous knock-out mice, we found that Mn-SOD is a direct target of STAT3 in reperfusion-induced neuronal cell death. Our study demonstrates that STAT3 is a novel transcription factor of the mouse Mn-SOD gene and plays a crucial role as a neuroprotectant in regulating levels of reactive oxygen species in the mouse brain.

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Received March 6, 2009; revised April 10, 2009; accepted April 29, 2009.

Correspondence should be addressed to Pak H. Chan, Neurosurgical Laboratories, Stanford University, 1201 Welch Road, MSLS #P314, Stanford, CA 94305-5487. Email: phchan{at}stanford.edu

This article has been cited by other articles:

				G. S. Kim, J. E. Jung, K. Niizuma, and P. H. Chan CK2 Is a Novel Negative Regulator of NADPH Oxidase and a Neuroprotectant in Mice after Cerebral Ischemia J. Neurosci., November 25, 2009; 29(47): 14779 - 14789. [Abstract] [Full Text] [PDF]

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