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The Journal of Neuroscience, October 22, 2008, 28(43):10919-10927; doi:10.1523/JNEUROSCI.3421-08.2008

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Neurobiology of Disease
Essential Role for Zinc-Triggered p75^NTR Activation in Preconditioning Neuroprotection

Jin-Yeon Lee,^1 * Yu-Jin Kim,^1 * Tae-Youn Kim,² Jae-Young Koh,^2,3 and Yang-Hee Kim¹

¹Department of Molecular Biology, Sejong University, Seoul 143-747, South Korea, and ²National Research Laboratory Neural Injury Research Center and ³Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, South Korea

Correspondence should be addressed to either Yang-Hee Kim, 98 Gunja-Dong Gwangjin-Gu, Seoul 143-747, South Korea, Email: yhkim{at}sejong.ac.kr; or Jae-Young Koh, 388-1 Poongnap-Dong Songpa-Gu, Seoul 138-736, South Korea, Email: jkko{at}amc.seoul.kr

Ischemic preconditioning (PC) of the brain is a phenomenon by which mild ischemic insults render neurons resistant to subsequent strong insults. Key steps in ischemic PC of the brain include caspase-3 activation and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, but upstream events have not been clearly elucidated. We have tested whether endogenous zinc is required for ischemic PC of the brain in rats. Mild, transient zinc accumulation was observed in certain neurons after ischemic PC. Moreover, intraventricular administration of CaEDTA during ischemic PC abrogated both zinc accumulation and the protective effect against subsequent full ischemia. To elucidate the mechanism of the zinc-triggered PC (Zn PC) effect, cortical cultures were exposed to sublethal levels of zinc, and 18 h later to lethal levels of zinc or NMDA. Zn PC exhibited the characteristic features of ischemic PC, including caspase-3 activation, PARP-1 cleavage, and HSP70 induction, all of which are crucial for subsequent neuroprotection against NMDA or zinc toxicity. HSP70 induction was necessary for protection, as it halted caspase-3 activation before apoptosis. Interestingly, in both Zn PC in vitro and ischemic PC in vivo, p75^NTR was necessary for neuroprotection. These results suggest that caspase-3 activation during ischemic PC, a necessary event for subsequent neuroprotection, may result from mild zinc accumulation and the consequent p75^NTR activation in neurons.

Key words: poly(ADP-ribose) polymerase; caspase-3; heat shock protein 70; ischemia; zinc toxicity; excitotoxicity

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Received July 21, 2008; revised Aug. 12, 2008; accepted Sept. 12, 2008.

Correspondence should be addressed to either Yang-Hee Kim, 98 Gunja-Dong Gwangjin-Gu, Seoul 143-747, South Korea, Email: yhkim{at}sejong.ac.kr; or Jae-Young Koh, 388-1 Poongnap-Dong Songpa-Gu, Seoul 138-736, South Korea, Email: jkko{at}amc.seoul.kr

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