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ToxSci Advance Access originally published online on June 23, 2005
Toxicological Sciences 2005 87(1):176-186; 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

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

Rebekah J. Jakel*,{dagger},{ddagger}, Jonathan T. Kern*, Delinda A. Johnson* and Jeffrey A. Johnson*,{ddagger},§,1

* Department of Pharmaceutical Sciences, School of Pharmacy, {dagger} Medical Scientist Training Program, Medical School, {ddagger} Neuroscience Training Program, § Center for Neuroscience, Molecular and Environmental Toxicology, and Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin 53705

Received May 21, 2005; accepted June 20, 2005

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.

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


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