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The Journal of Neuroscience, February 13, 2008, 28(7):1721-1727; doi:10.1523/JNEUROSCI.4973-07.2008

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Neurobiology of Disease
Free Radical Production in CA1 Neurons Induces MIP-1 Expression, Microglia Recruitment, and Delayed Neuronal Death after Transient Forebrain Ischemia

Hyo Kyun Wang,^1,2 Ui Jin Park,^1,2,3 Soo Yoon Kim,^1,2 Jin Hwan Lee,^1,2,3 Seung U. Kim,^1,2,5 Byoung Joo Gwag,^1,2,3,4 and Yong Beom Lee^1,2,3

¹Neuroscience Graduate Program, ²Brain Disease Research Center, ³Division of Cell Transformation and Restoration, and ⁴Department of Pharmacology, Ajou University School of Medicine, Suwon 443-721, Korea, and ⁵Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3

Correspondence should be addressed to either of the following: Yong Beom Lee, Brain Disease Research Center, Ajou University School of Medicine, san-5 Woncheon-dong Youngtong-gu, Suwon 443-721, Korea, Email: yblee{at}ajou.ac.kr; or Byoung Joo Gwag, Department of Pharmacology, Ajou University School of Medicine, san-5 Woncheon-dong Youngtong-gu, Suwon 443-721, Korea, Email: bjgwag{at}ajou.ac.kr

Several studies report microglial accumulation and activation in the CA1 area in response to transient forebrain ischemia (TFI). Here we examine the possibility that free radicals and chemokines mediate the transient activation of microglia. Free radicals are produced primarily in CA1 pyramidal neurons within 2 h of TFI. Administration of trolox, a vitamin E analog, led to the inhibition of free radical production and recruitment of microglia in the CA1 area. In addition, intrahippocampal injection of Fe²⁺ triggered free radical production in CA1 neurons, followed by the recruitment and activation of microglial cells into this area. TFI-induced expression of macrophage inflammatory protein-1 (MIP-1) was increased in CA1 neurons before microglial recruitment, and blocked by trolox. Moreover, the MIP-1 level was upregulated in cultured hippocampal neurons exposed to Fe²⁺, suggesting an essential role of free radicals in TFI-induced expression of MIP-1. Intracerebroventricular injection of vMIP-2 (viral macrophage inflammatory protein-2), a broad-spectrum peptide antagonist of chemokine receptors, attenuated microglial recruitment and delayed CA1 neuronal degeneration after TFI. Our data suggest that free radicals produced in CA1 neurons contribute to the recruitment and activation of microglia and neurodegeneration through MIP-1 expression.

Key words: CA1; microglia; free radicals; MIP-1; vMIP-2; transient forebrain ischemia

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Received July 7, 2007; revised Dec. 17, 2007; accepted Dec. 17, 2007.

Correspondence should be addressed to either of the following: Yong Beom Lee, Brain Disease Research Center, Ajou University School of Medicine, san-5 Woncheon-dong Youngtong-gu, Suwon 443-721, Korea, Email: yblee{at}ajou.ac.kr; or Byoung Joo Gwag, Department of Pharmacology, Ajou University School of Medicine, san-5 Woncheon-dong Youngtong-gu, Suwon 443-721, Korea, Email: bjgwag{at}ajou.ac.kr

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