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ToxSci Advance Access published online on June 23, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi241
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received May 21, 2005
Accepted June 20, 2005

Neurotoxicology

Induction of the Protective Antioxidant Response Element Pathway by 6-Hydroxydopamine In Vivo and In Vitro

Rebekah J. Jakel 1, Jonathan T. Kern 2, Delinda A. Johnson 2, and Jeffrey A. Johnson 3*

1 Department of Pharmaceutical Sciences, School of Pharmacy; Medical Scientist Training Program, Medical School; Neuroscience Training Program
2 Department of Pharmaceutical Sciences, School of Pharmacy
3 Neuroscience Training Program; Center for Neuroscience, Molecular and Environmental Toxicology, and Waisman Center.University of Wisconsin-Madison USA

* To whom correspondence should be addressed.
Jeffrey A. Johnson, E-mail: jajohnson{at}pharmacy.wisc.edu


  Abstract

Parkinson's disease, a progressive neurodegenerative disorder, is characterized by loss of midbrain dopaminergic neurons. The etiology of sporadic Parkinson's disease is unknown; however, oxidative stress is thought to play a major role in disease pathogenesis. Little is known regarding the transcriptional changes that occur in Parkinson's disease. The antioxidant response element is a cis-acting enhancer sequence that is upstream of many phase II detoxification and antioxidant genes. Here we show that 6-hydroxydopamine, a mitochondrial inhibitor used to model Parkinson's disease, activates the antioxidant response element both in cultured neurons and in the striatum and brainstem of 6-OHDA-lesioned mice. Pretreatment with antioxidants or NMDA receptor antagonists reduced but did not abolish activation. Further induction of this pathway with tert-butylhydroquinone was able to significantly reduce cell death due to 6-OHDA in vitro. These observations indicate that 6-OHDA activates the antioxidant response element through components of oxidative stress, excitotoxicity, and potential structural factors. Further induction of this endogenous defense mechanism may suggest a novel therapeutic venue in Parkinson's disease.

Keywords: 6-hydroxydopamine; Parkinson's disease; oxidative stress; antioxidant response element; tert-butylhydroquinone.
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