OXIDATIVE STRESS NEGATIVELY INFLUENCES THE EFFECTS OF ANDROGENS ON DOPAMINE NEURONAL VIABILITY

Purpose: Parkinson's disease (PD) is a neurodegenerative disease characterized by oxidative stress and loss of dopaminergic neurons in the nigrostriatal pathway, in which men have a higher risk than women. The mechanisms involved in this gender bias remains elusive, one possibility may be that oxidative stress converts the neuronal response to androgens, which is toxic. Specifically, we hypothesize that in an oxidative stress environment, androgens such as testosterone compromises the viability of dopamine neurons. Methods: To test our hypothesis, we exposed a dopaminergic cell line (N27 cells) to a sublethal concentration of the pro-oxidant, tert-butyl-hydrogen peroxide (H202) for 24 hours and assessed cell viability in the presence or absence of testosterone. Results: Physiologically relevant concentrations of the androgen, testosterone (0, 1, 10, 100 nM) failed to compromise cell viability in non-oxidatively stressed cells. In contrast, testosterone and testosterone conjugated to BSA (T-BSA) did promote cell death in the H202 pre-treated cells. Interestingly, androgen pre-treatment protected dopamine cells from H202-induced cell death. Supporting the role of oxidative stress as a switch in this effect, the antioxidant, N-acetyl cysteine, prevented the damage promoting effects of testosterone in H202 pretreated cells. Neither the androgen receptor nor the estrogen receptor antagonists, flutamide (10 uM) and ICI 182, 780(1 uM), respectively, altered the death promoting effect of testosterone. Conclusions: Coupled with the observation that the membrane-impermeable T-BSA mimicked the effects of testosterone, we suggest that the cell death promoting effects may be mediated by a putative membrane-associated androgen receptor. Overall, these results indicate that oxidative stress acts as a molecular switch in dopamine neurons that can reverse the neuroprotective effects of androgens to that, which is neurotoxic. Thus, the interplay between oxidative stress and androgens on dopamine neuronal viability may underlie the male gender bias found in PD.