Nrf2-mediated protection against 6-hydroxydopamine

Abstract

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by cell loss in the substantia nigra resulting in striatal dopamine depletion. Although the cause of sporadic PD is unknown, oxidative stress is thought to contribute to disease pathogenesis. One mechanism by which cells defend themselves against oxidative stress is through the transcriptional upregulation of cytoprotective genes. Under oxidative stress conditions, the transcription factor NF-E2-related factor (Nrf2) binds to the antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes. Here we show that loss of Nrf2-mediated transcription exacerbates vulnerability to the neurotoxin 6-hydroxydopamine (6-OHDA) both in vitro and in vivo. We further demonstrate that activation of the Nrf2-ARE pathway by the known chemical inducer tert-butylhydroquinone can protect against 6-OHDA in vitro. Induction of this pathway by transplantation of astrocytes overexpressing Nrf2 can protect against 6-OHDA-induced damage in the living mouse. This suggests that the Nrf2-ARE pathway is a promising target for therapeutics aimed at reducing or preventing cell death in PD.

The role of neuroinflammation on the pathogenesis of Parkinson's disease

“…Two asterisks mark P＜0. Nrf-2 activators protects DA neurons from the neurotoxicity of 6-OHDA in vivo (63) and in rat organotypic nigrostriatal cocultures (64). These results collectively suggest that astrocytes are involved in antioxidant signaling both in vivo and in vitro.…”

Activation of Nuclear Factor Erythroid 2-Related Factor 2 Cytoprotective Signaling by Curcumin Protect Primary Spinal Cord Astrocytes against Oxidative Toxicity

“…8 significant protection to neurons in vivo. [28][29][30][31] Chemical/ drugs that activate this pathway may have efficacy in blocking neuronal cell death. A focused effort to find those that cross the blood-brain barrier efficiently, activate the pathway in astrocytes, and have efficacy against neurotoxicity is underway.…”

Sulforaphane protects against 6-hydroxydopamine-induced cytotoxicity by increasing expression of heme oxygenase-1 in a PI3K/Akt-dependent manner

“…6-OHDA stimulates the production of superoxide radicals and induces cell death (8). Numerous experiments have revealed that antioxidants exert beneficial effects in the prevention of 6-OHDA-induced cytotoxicity (9,10).…”