Induction of the protective antioxidant response element pathway by 6-hydroxydopamine in vivo and in vitro.
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.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
Rebekah J
RJ
Jakel
Jonathan T
JT
Kern
Delinda A
DA
Johnson
Jeffrey A
JA
Johnson
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D006873:Hydroquinones / Q000494:pharmacology; D051379:Mice; D051267:NF-E2-Related Factor 2; D018384:Oxidative Stress; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D020218:Response Elements / Q000187:drug effects*; D015534:Trans-Activators / Q000502:physiology
D000975:Antioxidants; D004268:DNA-Binding Proteins; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D015534:Trans-Activators; D016627:Oxidopamine; C018855:2-tert-butylhydroquinone