Browsing by Subject "dopamine neurons"
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Item OXIDATIVE STRESS NEGATIVELY INFLUENCES THE EFFECTS OF ANDROGENS ON DOPAMINE NEURONAL VIABILITY(2013-04-12) Holmes, Shaletha S.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.Item The Effects of Oxidative Stress and Testosterone on Dopamine Neuron Viability: Implications for Parkinson’s Disease(2015-12-01) Holmes, Shaletha S.; Cunningham, Rebecca L.; Singh, Meharvan; Schreihofer, DerekParkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress, mitochondrial dysfunction, inflammation and apoptosis are mechanisms implicated in Parkinson’s pathology. Interestingly, males have a higher incidence of PD than females. Therefore, the major male sex hormone, testosterone may play a role in oxidative stress-induced dopamine neurodegeneration and thus underlie the sex bias observed in PD. Oxidative stress, the imbalance of antioxidant mechanisms and reactive oxygen species, mediates downstream signaling of mitochondria dysfunction, inflammation and apoptosis. Oxidative stress can induce mitochondria dysfunction via calcium neurotoxicity, and oxidative stress can stimulate the pro-inflammatory mediators of NFkB and COX2. This activation of mitochondrial dysfunction and inflammation can trigger apoptosis in dopaminergic neurons. Therefore, it is hypothesized that under oxidative stress conditions, testosterone will induce dopaminergic neurodegeneration by increasing mitochondrial dysfunction and inflammation, leading to apoptosis in dopamine neurons. To test this hypothesis, a N27 dopaminergic cell line was treated with tert-butyl hydrogen peroxide followed by exposure to physiologically relevant concentrations of testosterone to assess cell viability, mitochondria function, calcium influx, inflammation, oxidative stress and apoptosis. These results show that testosterone, alone, increase calcium influx and acts as an oxidative stressor without affecting cell viability. However, under conditions of oxidative stress, testosterone decreases cell viability and exacerbates inflammation, resulting in increased apoptosis. These results indicate that testosterone, only in an oxidative stress environment, can increase pathological features associated with dopamine neurodegeneration in PD. In conclusion, these results suggest that a testosterone mediated mechanism may underlie the increased risk of PD for men compared to women.