Nrf2 activators provide neuroprotection against 6-hydroxydopamine toxicity in rat organotypic nigrostriatal cocultures

Oxidative stress and inflammation appear to play a critical role in the progression of Parkinson's disease. As a result, there has been growing interest in antioxidant pathways and how these pathways might be exploited to slow the progressive loss of dopamine neurons. One such pathway that has garnered attention recently is mediated by the transcription factor Nrf2 and is integral in orchestrating cells' antiinflammatory defense. Nrf2 controls the inducible expression of numerous antioxidant and phase 2 detoxification genes, such as glutathione S‐transferase, heme oxygenase‐1, and NAD(P)H:quinone oxidoreductase 1 (NQO1). Once activated, these genes work synergistically to maintain intracellular redox homeostasis. In this study, we test the hypothesis that Nrf2 activation can protect dopaminergic neurons against 6‐hydroxydopamine (6‐OHDA)‐induced toxicity. Treatment of organotypic nigrostriatal cocultures with either tert‐butylhydroquinone (tBHQ) or sulforaphane, known activators of Nrf2, mitigated dopaminergic cell loss. The observed protection appeared to be mediated, at least in part, by an increase in antioxidant activity. Simultaneous treatment of cultures with tBHQ and 6‐OHDA increased NQO1 expression 17‐fold compared with controls. Overall, these results suggest that Nrf2 may play an important role in cellular protection in neurodegenerative diseases and may be a viable therapeutic target in the future. © 2009 Wiley‐Liss, Inc.