Systemic administration of cystamine is known to protect from both chemical and genetic models of neurotoxicity. Despite positive effects in laboratory models, cystamine has not been successfully translated to clinical application for neurodegenerative disease. Furthermore, the long held assumption that cystamine protects through tissue transglutaminase inhibition has recently been challenged. The studies described here examine other potential mechanisms of cystamine-mediated protection in an attempt to reveal molecular targets for neurodegenerative therapy. Based on previously described effects of cystamine, we examined the potential for activation of NF-E2 related factor 2 (Nrf2) mediated signaling through the antioxidant response element (ARE). We found that cystamine activates Nrf2/ARE both in cell culture and in brain tissue and then probed the mechanism of activation in cell culture. In live animals, we show that neuroprotection from 3-nitropropionic acid (3NP) toxicity is Nrf2-dependent. Therefore, these findings provide strong evidence that Nrf2 signaling may be an effective target for prevention of neurodegeneration.
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