Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism

Ahlbom, Eva; Prins, Gail S.; Ceccatelli, Sandra

doi:10.1016/s0006-8993(00)03155-3

Cited by 235 publications

(201 citation statements)

References 39 publications

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“…18 Contrarily, testosterone was reported to protect cerebellar granule cells from oxidative stress-induced cell death through a receptor-mediated mechanism. 19 Conflicting findings reveal the need to address molecular signaling pathways with testosterone supplementation. …”

Section: Discussionmentioning

confidence: 99%

Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells

Hwang¹,

Liao²,

Lin³

et al. 2011

Asian J Androl

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Testosterone replacement therapy has benefits for aging men and those with hypogonadism. However, the effects of exogenous testosterone on Leydig cells are still unclear and need to be clarified. In this report, we demonstrate that testosterone supplementation can reduce oxidative damage in Leydig cells. The TM3 Leydig cell line was used as an in vitro cell model in this study. Cytoprotective effects were identified with 100-nmol l 21 testosterone treatment, but cytotoxic effects were found with o500-nmol l 21 testosterone supplementation. Significantly reduced reactive oxygen species (ROS) generation, lipid peroxide contents and hypoxia induction factor (HIF)-1a stabilization and activation were found with 100-nmol l 21 testosterone treatment. There was a 1.72-fold increase in ROS generation in the 500-nmol l 21 compared to the 100-nmol l 21 testosterone treatment. A 1.58-fold increase in steroidogenic acute regulatory protein (StAR) expression was found in 50-nmol l 21 testosterone-treated cells (P,0.01). Chemically induced hypoxia was attenuated by testosterone supplementation. Leydig cells treated with low-dose testosterone supplementation showed cytoprotection by decreasing ROS and lipid peroxides, increasing StAR expression and relieving hypoxia stress as demonstrated by HIF-1a stabilization. Increased oxidative damage was found with o500-nmol l 21 testosterone manipulation. The mechanism governing the differential dose effects of testosterone on Leydig cells needs further investigation in order to shed light on testosterone replacement therapy. INTRODUCTIONTestosterone plays an important role in normal growth and development of male sex organs. It is also known to be a key player in glucose homeostasis and lipid metabolism. 1 More recently, gonadotrophinreleasing hormones I and II were demonstrated to stimulate testosterone production in murine Leydig cells. 2 In the testes, Leydig cells synthesize and secrete testosterone in response to luteinizing hormone, which is counter-regulated by feedback influences of testosterone and its metabolites. Testosterone levels notably decline with aging; 3,4 however, a recent report showed no correlation between androgen receptor (AR) polymorphism and the serum concentrations of total and free testosterone in elderly men. 5 The mechanism by which aged Leydig cells lose their steroidogenic function remains unclear. It was proposed that decreases in testosterone levels with aging may reflect reactive oxygen species (ROS) elevation and further disruption of the ability of Leydig cells to produce testosterone. 6,7 Mitochondrial respiration, which typically consumes about 90% of the oxygen utilized by cells, is considered to be the major source of cellular ROS. 8 ROS cause tissue damage by a variety of mechanisms including DNA damage, lipid peroxidation, protein oxidation and carbonylation, depletion of cellular thiols and activation of proinflammatory cytokine release. Mitochondrial-derived ROS were implicated in a number of disease and disorders, including neurodegenerat...

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Section: Discussionmentioning

confidence: 99%

Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells

Hwang¹,

Liao²,

Lin³

et al. 2011

Asian J Androl

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“…Another paper (Guzmán et al, 2005) showed a similar antitumoral effect caused by testosterone in rat brain. Ex-vivo studies have also found this hormone to protect cerebellum cells in cell cultures induced to death by oxidative stress (Ahlbom et al, 2001). …”

Section: G1mentioning

confidence: 99%

Lipid peroxidation in rats treated with vincristine sulphate and nandrolone decanoate

Martins

Lopes

Mazzanti

et al. 2011

Arq. Bras. Med. Vet. Zootec.

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Brain and serum lipid peroxidation was studied in rats treated with vincristine sulphate and different doses of nandrolone decanoate. Thirty rats were distributed into six groups (n=5). The treatments were applied once a week for two weeks. Sample collection was performed in the third week. Treatments during the first week were: G1 (control) -physiologic solution, G2-vincristine sulphate (4mg/m 2 ), G3-physiologic solution, G4-physiologic solution, G5-vincristine sulphate (4mg/m 2 ), and G6-vincristine sulphate (4mg/m 2 ). In the second week, they were: G1 (control) -physiologic solution, G2-physiologic solution, G3-nandrolone decanoate (1.8mg/kg -1 ), G4-nandrolone decanoate (10mg/kg -1 ), G5-nandrolone decanoate (1.8mg/kg -1 ), and G6-nandrolone decanoate (10mg/kg -1 ). Lipid peroxidation increased with the isolated use of vincristine and nandrolone decanoate, and with vincristine associated to the highest dose of the ester as well. These results suggest that vincristine sulphate and nandrolone decanoate increase free radical production. Therapeutic dose of nandrolone decanoate when associated with vincristine sulphate proved to be beneficial, as it was able to protect the organism from damaging processes involved in free radical production.Keywords: rat, anabolic androgenic steroid, chemotherapeutic, free radicals, brain, blood serum RESUMO Este estudo teve por objetivo detectar a peroxidação lipídica presente no cérebro e no soro de ratos tratados com sulfato de vincristina e diferentes doses de decanoato de nandrolona. Trinta ratos foram distribuídos em seis grupos (n=5). Os tratamentos foram aplicados uma vez por semana, durante duas semanas, e a coleta de amostras foi realizada na terceira semana. Na primeira semana, os tratamentos consistiram de: G1(controle) -solução fisiológica; G2 -sulfato de vincristina (4mg/m 2 ); G3 -solução fisiológica; G4 -solução fisiológica; G5 -sulfato de vincristina (4mg/m 2 ) e G6 -sulfato de vincristina (4mg/m 2 ). Na segunda semana: G1(controle)-

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“…Androgen receptors are present in cultured PN 7 cerebellar granule cells. Treatment with androgens reduces susceptibility to oxidative stress, an effect inhibited by the androgen receptor antagonist flutamide (47). However, not all steroid effects on cerebellar development are mediated through traditional steroid receptors.…”

Section: Other Steroid Playersmentioning

confidence: 99%

Steroids, sex and the cerebellar cortex: implications for human disease

Dean

McCarthy

2008

Cerebellum

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Neurosteroids play an important role in the development of the cerebellum. In particular, estradiol and progesterone appear capable of inducing increases in dendritic spine density during development, and there is evidence that both are synthesized de novo in the cerebellum during critical developmental periods. In normal neonates and adults, there are few differences in the cerebellum between the sexes and most studies indicate that hormone and receptor levels also do not differ significantly during development. However, the sexes do differ significantly in risk of neuropsychological diseases associated with cerebellar pathology, and in animal models there are noticeable sex differences in the response to insult and genetic mutation. In both humans and animals, males tend to fare worse. Boys are more at risk for autism and Attention Deficit Hyperactivity Disorder than girls, and schizophrenia manifests at an earlier age in men. In rats males fare worse than females after perinatal exposure to polychlorinated biphenyls, and male mice heterozygous for the staggerer and reeler mutation show a more severe phenotype. Although very recent evidence suggests that differences in neurosteroid levels between the sexes in diseased animals may play a role in generating different disease phenotypes, the reason this hormonal difference occurs in diseased but not normal animals is currently unknown.

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Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism

Cited by 235 publications

References 39 publications

Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells

Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells

Lipid peroxidation in rats treated with vincristine sulphate and nandrolone decanoate

Steroids, sex and the cerebellar cortex: implications for human disease

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