Oxidative Stress Defines the Neuroprotective or Neurotoxic Properties of Androgens in Immortalized Female Rat Dopaminergic Neuronal Cells

Holmes, Shaletha; Abbassi, Babak; Su, Chang; Singh, Meharvan; Cunningham, Rebecca L.

doi:10.1210/en.2013-1242

Cited by 65 publications

(82 citation statements)

References 93 publications

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“…Whether this effect is due to a reduced inflammation and/or a DHT-mediated antioxidant action in the tissue remains obscure. However, a recent report suggested that androgens might prevent, at least in an in vitro model, oxidative stress damage through a preconditioning mechanism [78] , opening the possibility for a DHT involvement. We demonstrate here that administration of this steroid was also able to significantly increase mtDNA content and augment the content of all the functional subunits of the mitochondrial respiratory chain complexes, even if statistical significance was reached only in the case of the Uqcrc2 protein from complex III.…”

Section: Discussionmentioning

confidence: 99%

Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis

et al. 2015

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Multiple sclerosis is a chronic inflammatory disease affecting the central nervous system. As reported by clinical observations, variation in hormonal levels might alter disease susceptibility and progression. Specifically, decreased levels of testosterone in males are reported to be permissive for disease onset. Accordingly, testosterone seems to exert protective effects in experimental autoimmune encephalomyelitis (EAE). In this context, it is important to highlight that testosterone is further metabolized into 17ß-estradiol or dihydrotestosterone (DHT). In this study, we aimed to explore the protective effects of DHT treatment in EAE Dark Agouti rats (i.e. an experimental model showing a protracted relapsing EAE). Data obtained 45 days after EAE induction showed that DHT exerts a beneficial effect on clinical scores, coupled with decreased gliosis (i.e. glial fibrillary acidic protein and major histocompatibility complex of class II staining) and inflammation (i.e. translocator protein 18 kDa, interleukin-1ß, Toll-like receptor 4 and nuclear factor-κB expression) in the spinal cord. Moreover, parameters linked to oxidative stress and tissue damage, like thiobarbituric acid-reactive substance levels and Bcl-2-associated X protein expression, and to mitochondrial activity (i.e. content of mitochondrial DNA and proteins), were improved after DHT administration. This neuroactive steroid may be further metabolized into 3a- or 3ß-diol. However, assessment of the levels of these metabolites after DHT treatment seems to suggest that the protective effects observed here are due to DHT itself. Altogether, the present results indicate that DHT was effective in reducing the severity of chronic EAE and, consequently, may represent an interesting perspective for multiple sclerosis treatment.

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Section: Discussionmentioning

confidence: 99%

Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis

et al. 2015

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“…Interestingly, pretreatment of neuronal dopaminergic cell lines with testosterone has also been shown to protect them against oxidative damage induced by hydrogen peroxide [95]. The neuroprotective effect was correlated with a slight increase in the calcium-induced mitochondrial ROS production.…”

Section: Redox Imbalancementioning

confidence: 99%

“…Gpx catalyzes the oxidation of two monomeric glutathione molecules by hydrogen peroxide into H 2 O and glutathione disulfide, thus reducing the concentration of hydrogen peroxide. Thus, down-regulation of Gpx activity by AS increases hydrogen peroxide bioavailability, which is correlated to increased lipoperoxidation and reduced thiol residues induced by AS exposure in the brain [79,95].…”

Section: Redox Imbalancementioning

confidence: 99%

“…The neuroprotective effect was correlated with a slight increase in the calcium-induced mitochondrial ROS production. In contrast, in conditions of sustained redox imbalance, post-exposure of dopaminergic neurons to testosterone can further increase the oxidative damage and decrease cell viability by mitochondrial calcium overload, an effect mediated by membrane-attached receptor [95]. Furthermore, activation of membrane-attached receptors has also been shown to be involved, as co-exposure with flutamide did prevent neither mitochondrial calcium overload nor decreased cell viability [95].…”

Section: Redox Imbalancementioning

confidence: 99%

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Neurophysiological Repercussions of Anabolic Steroid Abuse: A Road into Neurodegenerative Disorders

Seara¹,

Fortunato²,

Carvalho³

et al. 2018

Sex Hormones in Neurodegenerative Processes and Diseases

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Since its discovery, several chemical modifications in the testosterone molecule have been done by pharmaceutical industry in order to improve its pharmacological effects, resulting in the creation of anabolic steroids (AS). Despite the therapeutic benefits, AS abuse has spread among elite and recreational athletes in the search for improvements on physical appearance and physical performance. Illicit use of anabolic AS has been correlated with several adverse effects, such as cardiovascular, endocrine, reproductive, and neurobehavioral dysfunctions. Recently, declines on cognitive and mnemonic performance have been demonstrated clinically and experimentally. Experimental studies have demonstrated that these neurological dysfunctions are correlated to spread neuronal apoptosis throughout important areas of the central nervous system (CNS), such as hippocampus and cortex. Several pathophysiological mechanisms have been linked to the AS-induced neurotoxicity, including redox imbalance and recruitment of pro-apoptotic downstream pathways. Furthermore, exposure to AS has arisen as a potential risk factor to the development of Alzheimer's disease. Altogether, these evidences imply that AS abuse per se induces neurodegeneration and can aggravate the prognosis of neurodegenerative diseases.

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“…In addition to those mentioned above, and as shown in Table 1, testosterone-induced ROS generation has been reported in renal cells (37,65,144), in human prostate cancer cells (112,148,151,181), and leukocytes, among others. However, in myocardial (50,103,206) and neuronal cells (2,55,85), testosterone also has antioxidant effects. It reinforces the notion that the effects of testosterone on ROS generation are controversial, mainly because androgens have prooxidant, as well as antioxidant effects, depending on the tissue/cell being studied (and sometimes even when the same cell type is being studied).…”

Section: Other Mechanisms: Testosterone and Ros Generation/oxidative mentioning

confidence: 99%

Reactive oxygen species: players in the cardiovascular effects of testosterone

Tostes

Carneiro

Carvalho

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Tostes RC, Carneiro FS, Carvalho MH, Reckelhoff JF. Reactive oxygen species: players in the cardiovascular effects of testosterone. Am J Physiol Regul Integr Comp Physiol 310: R1-R14, 2016. First published November 4, 2015 doi:10.1152/ajpregu.00392.2014.-Androgens are essential for the development and maintenance of male reproductive tissues and sexual function and for overall health and well being. Testosterone, the predominant and most important androgen, not only affects the male reproductive system, but also influences the activity of many other organs. In the cardiovascular system, the actions of testosterone are still controversial, its effects ranging from protective to deleterious. While early studies showed that testosterone replacement therapy exerted beneficial effects on cardiovascular disease, some recent safety studies point to a positive association between endogenous and supraphysiological levels of androgens/testosterone and cardiovascular disease risk. Among the possible mechanisms involved in the actions of testosterone on the cardiovascular system, indirect actions (changes in the lipid profile, insulin sensitivity, and hemostatic mechanisms, modulation of the sympathetic nervous system and renin-angiotensin-aldosterone system), as well as direct actions (modulatory effects on proinflammatory enzymes, on the generation of reactive oxygen species, nitric oxide bioavailability, and on vasoconstrictor signaling pathways) have been reported. This mini-review focuses on evidence indicating that testosterone has prooxidative actions that may contribute to its deleterious actions in the cardiovascular system. The controversial effects of testosterone on ROS generation and oxidant status, both prooxidant and antioxidant, in the cardiovascular system and in cells and tissues of other systems are reviewed. cardiovascular; prooxidant; antioxidant TESTOSTERONE 1 IS THE PREDOMINANT and most important androgen, playing a major role in the development of male reproductive tissues (130,135). "Androgen" is a broad term for any natural or synthetic compound that primarily influences the growth and development of the male reproductive system, including the activity of the accessory male sex organs and development of male secondary sex characteristics (21, 135). Androgens are also essential for health and well being, and their beneficial and stimulant effects have been known for a long time, since the seminal studies from Brown-Séquard in the nineteenth century 2 (22, 135): "ь ь ь in the seminal fluid, as secreted by the testicles, a substance or several substances exist which, entering the blood by resorption, have a most essential use in giving strength to the nervous system and to other parts ь ь ь ."Other androgens include androstenedione, 5␣-dihydrotestosterone (DHT), which is produced from testosterone by the enzyme 5␣-reductase, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and synthetic androgens in their many steroid ester variations (e.g., testosterone cypionate, decanoate, undecanoate, enant...

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Oxidative Stress Defines the Neuroprotective or Neurotoxic Properties of Androgens in Immortalized Female Rat Dopaminergic Neuronal Cells

Cited by 65 publications

References 93 publications

Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis

Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis

Neurophysiological Repercussions of Anabolic Steroid Abuse: A Road into Neurodegenerative Disorders

Reactive oxygen species: players in the cardiovascular effects of testosterone

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