Browsing by Subject "testosterone"

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Androgen Modulation of CNS During Chronic Intermittent Hypoxia
(2018-05) Snyder, Brina D.; Cunningham, Rebecca L.; Barber, Robert C.; Cunningham, J. Thomas; Schreihofer, Derek A.; Planz, John V.
The underlying causes of age-related neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, are unknown. It is likely conditions which contribute to an abundance of oxidative stress throughout life renders an individual more susceptible to late-life neurodegenerative processes. Sex differences are observed in the onset and prevalence of these diseases, suggesting estrogens and androgens influence these processes. This study investigates the early role of androgens under a known oxidative stressor, sleep apnea, which frequently goes untreated in the clinical population but is but is associated with an increased risk of late-life neurodegeneration. The hypoxic events of sleep apnea can be modeled in rats by the use of chronic intermittent hypoxia (CIH). Male rats are more susceptible to hypertensive effects of CIH, a key characteristic of sleep apnea. After one week of CIH treatment, they also exhibit oxidative stress and inflammation in circulation and in brain nuclei associated with early stages of Parkinson's disease or Alzheimer's disease. This led to the hypothesis that oxidative stress and inflammation would be associated with behavior deficits and these effects are mediated by androgens. Results show that oxidative stress and inflammatory dysregulation can be prevented by testosterone, but are highly exacerbated by testosterone's non-aromatizable metabolite, dihydrotestosterone (DHT). Administration of DHT also resulted in significant memory impairments under CIH. In the central nervous system, DHT significantly altered oxidative stress and pro-inflammatory signals, which may underlie its detrimental actions in an oxidative stress environment. There was also evidence of hypothalamic-pituitary-adrenal axis dysregulation, which can influence testosterone and circadian rhythms. These findings have broad implications for clinical populations with conditions which chronically increase oxidative stress and inflammation, while at the same time alter endocrine function. Conditions, such as untreated sleep apnea, may pose a latent risk for neurodegeneration and should be addressed early to prevent later detrimental effects.
Effects of Testosterone on Obesity-Related Cardiac Hypertrophy and Fibrosis
(2009-08-01) Wilson, Ana Kaye; Carroll, Joan F.; Caffrey, James L.; Mallet, Robert T.
Wilson, Ana Kaye. Effects of testosterone on obesity-related cardiac hypertrophy and fibrosis. Master of Science (Integrative Physiology), August 2009, 71 pp, 3 tables, 6 figures. Both testosterone and obesity are known to increase renin-angiotensin system activity, leading to cardiovascular dysfunction. This study determined the interactive effects of obesity and testosterone on left ventricular hypertrophy and cardiac fibrotic factors. Male New Zealand White rabbits were fed a lean or 10% added fat diet. After 12 weeks, fat-fed rabbits exhibited increased left ventricular weight (6.05±0.16 vs. 4.75±0.10 g, respectively, p≤0.05) and cardiomyocyte cross-sectional area compared to lean rabbits (372.3±19.0 vs. 305.0±13.4μm2, respectively; p≤0.01). These effects were attenuated by both castration and treatment with the angiotensin type 1 receptor blocker, losartan. Obese rabbits did not exhibit increased myocardial collagen as expected. However, castration and losartan treatment increased matrix metalloproteinase-2 (MMP-2) activity in obese rabbits. Despite the effects of castration hypertrophy and MMP-2 activity, castration did not attenuate plasma renin activity of aldosterone. These data suggest that testosterone contributes to obesity-related left ventricular hypertrophy and decreases collagen degradation, independent of renin activity.
Novel androgen receptor splice variant in the substantia nigra
(2017-08-01) Contreras, Jo Garza; Cunningham, Rebecca L.; Basha, Riyaz; Salvatore, Michael
Testosterone can increase calcium influx and cell death in dopamine neurons via a putative membrane androgen receptor (mAR). The mAR induced calcium increase may be due to activation of G-proteins involved in calcium mobilization. Previous studies using an N-terminal targeted androgen receptor (AR) antibody yielded low AR expression in dopamine neurons. Studies in our lab show high AR expression using a C-terminal targeted AR antibody. This difference in expression may be due to an AR variant. We hypothesize an AR variant is present in the membrane of dopaminergic neurons and associated with G proteins. To identify the presence of AR in dopaminergic neurons. We performed immunoblot, sucrose gradient, and immunohistochemistry studies. To determine the protein-protein interaction between mAR and G-proteins we performed co-immunoprecipitation studies. Our results show AR45 localizes in the membrane lipid rafts of dopaminergic neurons. Furthermore, AR45 interacts with Gαq and Gαo G-proteins, which can impact calcium signaling.
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.
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, Derek
Parkinson’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.
The Role of Lipid Rafts and Membrane Androgen Receptors in Androgen's Neurotoxic Effects
(Oxford University Press, 2022-02-21) Fadeyibi, Oluwadarasimi; Rybalchenko, Nataliya; Mabry, Steve; Nguyen, Dianna H.; Cunningham, Rebecca L.
Sex differences have been observed in multiple oxidative stress-associated neurodegenerative diseases. Androgens, such as testosterone, can exacerbate oxidative stress through a membrane androgen receptor (mAR), AR45, localized to lipid rafts in the plasma membrane. The goal of this study is to determine if interfering with mAR localization to cholesterol-rich lipid rafts decreases androgen induced neurotoxicity under oxidative stress environments. We hypothesize that cholesterol-rich caveolar lipid rafts are necessary for androgens to induce oxidative stress generation in neurons via the mAR localized within the plasma membrane. Nystatin was used to sequester cholesterol and thus decrease cholesterol-rich caveolar lipid rafts in a neuronal cell line (N27 cells). Nystatin was applied prior to testosterone exposure in oxidatively stressed N27 cells. Cell viability, endocytosis, and protein analysis of oxidative stress, apoptosis, and mAR localization were conducted. Our results show that the loss of lipid rafts via cholesterol sequestering blocked androgen-induced oxidative stress in cells by decreasing the localization of mAR to caveolar lipid rafts.