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J. Biol. Chem., Vol. 281, Issue 14, 9460-9470, April 7, 2006

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Intracellular Zinc Release and ERK Phosphorylation Are Required Upstream of 12-Lipoxygenase Activation in Peroxynitrite Toxicity to Mature Rat Oligodendrocytes^*

Yumin Zhang, Hong Wang, Jianrong Li, Ling Dong, Ping Xu, Weizhi Chen, Rachael L. Neve, Joseph J. Volpe, and Paul A. Rosenberg¹

From the Department of Neurology and Program in Neuroscience, Children's Hospital and Harvard Medical School, the Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115 and McLean Hospital, Belmont, Massachusetts 02478

Peroxynitrite toxicity has been implicated in the pathogenesis of white matter injury. The mechanisms of peroxynitrite toxicity to oligodendrocytes (OLs), the major cell type of the white matter, are unknown. Using primary cultures of mature OLs that express myelin basic protein, we found that 3-morpholinosydnonimine, a peroxynitrite generator, caused toxicity to OLs. N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine, a zinc chelator, completely blocked peroxynitrite-induced toxicity. Use of FluoZin-3, a specific fluorescence zinc indicator, demonstrated the liberation of zinc from intracellular stores by peroxynitrite. Peroxynitrite caused the sequential activation of extracellular signal-regulated kinase 42/44 (ERK42/44), 12-lipoxygenase, and generation of reactive oxygen species, which were all dependent upon the intracellular release of zinc. The same cell death pathway was also activated when exogenous zinc was used. These results suggest that in addition to preventing the formation of peroxynitrite, useful strategies in preventing disease progression in pathologies in which peroxynitrite toxicity plays a critical role might include maintaining intracellular zinc homeostasis, blocking phosphorylation of ERK42/44, inhibiting activation of 12-lipoxygenase, and eliminating the accumulation of reactive oxygen species.

Received for publication, September 29, 2005 , and in revised form, December 22, 2005.

^* This work was supported by grants from the Muscular Dystrophy Association, the United Cerebral Palsy Research Foundation, the Ron Shapiro Charitable Foundation, and National Institutes of Health Grants HD 18655 and NS 38475. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 300 Longwood Ave, Boston, MA 02115. Tel.: 617-355-6962; Fax: 617-730-0243; E-mail: paul.rosenberg{at}childrens.harvard.edu.

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