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J. Biol. Chem., Vol. 280, Issue 32, 29194-29198, August 12, 2005

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Superoxide Dismutase/Catalase Mimetics Are Neuroprotective against Selective Paraquat-mediated Dopaminergic Neuron Death in the Substantial Nigra

IMPLICATIONS FOR PARKINSON DISEASE^*

Jun Peng, Fang Feng Stevenson, Susan R. Doctrow, and Julie K. Andersen¶

From the Buck Institute for Age Research, Novato, California 94945 and Eukarion, Inc., Bedford, Massachusetts 01730

Exposure of mice to the herbicide paraquat has been demonstrated to result in the selective loss of dopaminergic neurons of the substantia nigra, pars compacta (SNpc) akin to what is observed in Parkinson disease (PD). In this study, we investigate the efficacy of two synthetic superoxide dismutase/catalase mimetics (EUK-134 and EUK-189) in protecting against paraquat-induced dopaminergic cell death in both the rat dopaminergic cell line 1RB₃AN₂₇ (N27) and primary mesencephalic cultures in vitro and in adult mice in vivo. Our data demonstrate that pretreatment with either EUK-134 or EUK-189 significantly attenuates paraquat-induced neurotoxicity in vitro in a concentration-dependent manner. Furthermore, systemic administration of EUK-189 decreases paraquat-mediated SNpc dopaminergic neuronal cell death in vivo. These findings support a role for oxidative stress in paraquat-induced neurotoxicity and suggest novel therapeutic approaches for neurodegenerative disorders associated with oxidative stress such as PD.

Received for publication, January 26, 2005 , and in revised form, May 27, 2005.

^* This work was supported by National Institutes of Health Grant U54 ES12077 (to J. K. A.). S. R. D. is Vice President, Research at Eukarion, Inc. and has been granted options to purchase stock in the company. EUK-189 is under development by Eukarion as a potential therapeutic product. 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.

^¶ To whom correspondence should be addressed: Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945. Tel.: 415-209-2070; Fax: 415-209-2231; E-mail: jandersen{at}buckinstitute.org.

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