| Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra. Although the cause of idiopathic PD is unknown, oxidative stress is a factor in disease pathogenesis. One mechanism that cells employ to defend against oxidative stress is the coordinate upregulation of a multitude of cytoprotective enzymes via the Antioxidant Response Element (ARE). The ARE is a cis-acting enhancer sequence found in the promoter of many antioxidant and phase II detoxification genes. Changes in redox status, xenobiotics, and inducers promote the binding of the transcription factor Nrf2 to the ARE, positively regulating the transcription of the genes containing an ARE.; In a 6-hydroxydopamine (6-OHDA) model of PD, the involvement of the ARE in dopaminergic toxicity was explored. 6-OHDA was shown to activate the ARE in vitro and in a transgenic ARE reporter mouse due to factors including oxidative stress and excitotoxicity. Nrf2-mediated transcription was shown to be important in controlling the extent of cell death due to 6-OHDA both in vitro and in vivo. Further induction of the ARE by chemical or genetic means was shown to protect against 6-OHDA toxicity in culture and in vivo.; We also explored whether methamphetamine (MA), a popular drug of abuse, which causes massive striatal dopamine depletion and oxidative stress would behave similarly to 6-OHDA. Interestingly, MA exposure failed to demonstrate significant ARE activation in a cell culture model and in vivo. Nrf2 knockout mice exposed to MA demonstrated prolonged dopamine depletion one week following exposure when wildtype mice are starting to show recovery of DA levels. This implies that basal Nrf2 transcription is important in limiting MA-induced cell death. Moreover, the lack of ARE activation may explain the long-term changes observed in the brains of MA-users.; In conclusion, the Nrf2-ARE pathway is important in limiting dopaminergic neurotoxicity. However, the ARE is not universally induced by dopaminergic toxins. For this reason, further induction of the ARE is an important therapeutic venue in conditions of dopaminergic cell death such as PD. |
