Males have a higher risk for developing Parkinson's disease and parkinsonism after ischemic stroke than females. Although estrogens have been shown to play a neuroprotective role in Parkinson's disease, there is little information on androgens' actions on dopamine neurons. In this study, we examined the effects of androgens under conditions of oxidative stress to determine whether androgens play a neuroprotective or neurotoxic role in dopamine neuronal function. Mitochondrial function, cell viability, intracellular calcium levels, and mitochondrial calcium influx were examined in response to androgens under both nonoxidative and oxidative stress conditions. Briefly, N27 dopaminergic cells were exposed to the oxidative stressor, hydrogen peroxide, and physiologically relevant levels of testosterone or dihydrotestosterone, applied either before or after oxidative stress exposure. Androgens, alone, increased mitochondrial function via a calcium-dependent mechanism. Androgen pretreatment protected cells from oxidative stress-induced cell death. However, treatment with androgens after the oxidative insult increased cell death, and these effects were, in part, mediated by calcium influx into the mitochondria. Interestingly, the negative effects of androgens were not blocked by either androgen or estrogen receptor antagonists. Instead, a putative membrane-associated androgen receptor was implicated. Overall, our results indicate that androgens are neuroprotective when oxidative stress levels are minimal, but when oxidative stress levels are elevated, androgens exacerbate oxidative stress damage.
Parkinson's disease, a progressive neurodegenerative disorder, is associated with oxidative stress and neuroinflammation. These pathological markers can contribute to the loss of dopamine neurons in the midbrain. Interestingly, men have a 2-fold increased incidence for Parkinson's disease than women. Although the mechanisms underlying this sex difference remain elusive, we propose that the primary male sex hormone, testosterone, is involved. Our previous studies show that testosterone, through a putative membrane androgen receptor, can increase oxidative stress-induced neurotoxicity in dopamine neurons. Based on these results, this study examines the role of nuclear factor κ B (NF-κB), cyclooxygenase-2 (COX2), and apoptosis in the deleterious effects of androgens in an oxidative stress environment. We hypothesize, under oxidative stress environment, testosterone via a putative membrane androgen receptor will exacerbate oxidative stress-induced NF-κB/COX2 signaling in N27 dopaminergic neurons, leading to apoptosis. Our data show that testosterone increased the expression of COX2 and apoptosis in dopamine neurons. Inhibiting the NF-κB and COX2 pathway with CAPE and ibuprofen, respectively, blocked testosterone's negative effects on cell viability, indicating that NF-κB/COX2 cascade plays a role in the negative interaction between testosterone and oxidative stress on neuroinflammation. These data further support the role of testosterone mediating the loss of dopamine neurons under oxidative stress conditions, which may be a key mechanism contributing to the increased incidence of Parkinson's disease in men compared with women.
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