Nrf2-Mediated Heme Oxygenase-1 Induction Confers Adaptive Survival Response to Tetrahydropapaveroline-Induced Oxidative PC12 Cell Death

Tetrahydropapaveroline (THP), a dopaminergic isoquinoline neurotoxin, has been reported to contribute to neurodegeneration in parkinsonism. As THP bears two catechol moieties, it undergoes autooxidation or enzymatic oxidation to produce reactive oxygen species (ROS), which may contribute to the THP-induced cell death. Although ROS are cytotoxic, the initial accumulation of ROS may provoke a survival response. In this study, treatment of PC12 cells with THP increased expression of heme oxygenase-1 (HO-1) as an adaptive survival response. Furthermore, THP-induced cytotoxicity was attenuated by the HO-1 inducer (SnCl₂) and exacerbated by the HO-1 inhibitor (ZnPP). To elucidate the molecular mechanisms underlying THP-mediated HO-1 expression, we examined the possible involvement of NF-E2–related factor 2 (Nrf2), which plays an important role in the transcriptional regulation of detoxifying/antioxidant genes. THP treatment elevated nuclear translocation of Nrf2 and subsequent binding to antioxidant response element (ARE). PC12 cells transfected with dominant-negative Nrf2 exhibited increased cytotoxicity and decreased HO-1 expression after THP treatment. Moreover, U0126 and LY294002, which are pharmacologic inhibitors of extracellular signal-regulated kinase1/2 and phosphoinositide 3-kinase, respectively, attenuated HO-1 expression as well as Nrf2-ARE binding activity. Taken together, these findings suggest that HO-1 induction via Nrf2 activation may confer a cellular adaptive response against THP-mediated cell death.