Nanomolar concentrations of anabolic–androgenic steroids amplify excitotoxic neuronal death in mixed mouse cortical cultures

Orlando, Rosamaria; Caruso, Alessandra; Molinaro, Gemma; Motolese, Marta; Montorsi, Francesco; Togna, G.; Melchiorri, Daniela; Nicoletti, Ferdinando; Bruno, Valeria

doi:10.1016/j.brainres.2007.06.047

Cited by 58 publications

(57 citation statements)

References 62 publications

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“…Exposure of mixed cultures of mouse cortical cells to testosterone induced concentrationdependent increase in NMDA-induced neurotoxicity, as demonstrated by increases on trypan blue-labeling and the release of lactate-dehydrogenase [99]. This effect was further increased when aromatase inhibitors were co-administered to the culture medium, corroborating the hypothesis that testosterone-induced neuroprotection was at least partially mediated by further conversion into estrogen.…”

Section: Excitotoxicitysupporting

confidence: 61%

“…This effect was further increased when aromatase inhibitors were co-administered to the culture medium, corroborating the hypothesis that testosterone-induced neuroprotection was at least partially mediated by further conversion into estrogen. In addition, co-administration of flutamide significantly attenuated the increased excitotoxicity induced by high concentrations of testosterone, highlighting the role exerted by the overactivation of AR in this regard [99]. In keeping with this, exposure of neuronal cells to nor-testosterone (i.e., nandrolone) and stanozolol increased NDMAinduced neurotoxicity in a concentration-dependent and aromatase-independent way, given that inhibition of aromatase did not attenuate this effect [99].…”

Section: Excitotoxicitymentioning

confidence: 77%

“…Within physiological ranges, testosterone exhibited neuroprotective effects against neurotoxicity induced by kainic acid, an agonist of AMPA receptors and its conversion into estrogen by aromatase is thought to have a key role in this protection [99]. However, as previously stated, most of ASs are poorly converted into estrogen by aromatase, especially class II and III AS.…”

Section: Excitotoxicitymentioning

confidence: 83%

“…In addition, co-administration of flutamide significantly attenuated the increased excitotoxicity induced by high concentrations of testosterone, highlighting the role exerted by the overactivation of AR in this regard [99]. In keeping with this, exposure of neuronal cells to nor-testosterone (i.e., nandrolone) and stanozolol increased NDMAinduced neurotoxicity in a concentration-dependent and aromatase-independent way, given that inhibition of aromatase did not attenuate this effect [99]. As a result, AS-induced potentiation in the glutamate signaling substantially increased the peak of calcium concentration induced by glutamate, whereas the return to calcium baseline levels was prolonged [16].…”

Section: Excitotoxicitymentioning

confidence: 87%

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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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Section: Excitotoxicitysupporting

confidence: 61%

Section: Excitotoxicitymentioning

confidence: 77%

Section: Excitotoxicitymentioning

confidence: 83%

Section: Excitotoxicitymentioning

confidence: 87%

See 2 more Smart Citations

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

Seara¹,

Fortunato²,

Carvalho³

et al. 2018

Sex Hormones in Neurodegenerative Processes and Diseases

View full text Add to dashboard Cite

show abstract

“…A review has shown that their prolonged use could result in sexual dysfunction and reproductive disorders while less frequently genotoxic, hepatotoxic, neurotoxic, and cardiovascular effects were also observed (2,5,10,16,19,20,26). With this in mind, the question as to the extent these compounds can indeed exert adverse effects on humans is a hot issue.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic effects of the synthetic oestrogens and androgens on Balb/c 3T3 and HepG2 cells

Minta

Radko

Stypuła-Trębas

et al. 2014

Bulletin of the Veterinary Institute in Pulawy

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The aim of the study was to test and compare the cytotoxic potential of two synthetic oestrogens: diethylstilboestrol (DES) and ethinyloestradiol (EE2) and two androgens: testosterone propionate (TP) and trenbolone (TREN) on two cell lines. The fibroblast cell line Balb/c 3T3 and the hepatoma cell line HepG2 were selected. To get more insight into the mode of toxic action, four methods were used, which evaluated different biochemical endpoints: mitochondrial activity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay), lysosomal activity (neutral red uptake assay), total protein content, and lactate dehydrogenase release. Cytotoxicity was assessed after 24, 48, and 72 h exposure to eight concentrations ranging from 0.78 to 100 µg/mL. Concentration-and time-dependent effects were observed. Depending on the line and assay used, half maximal effective concentration after 72 h (EC50-72h) values ranged as follows: DES 1-13.7 µg/mL (Balb/c 3T3) and 3.7-5.2 µg/mL (HepG2); EE2 2.1-14.3 µg/mL (Balb/c 3T3) and 1.8-7.8 µg/mL (HepG2); TP-14.9-17.5 µg/mL (Balb/c 3T3), and 63.9-100 µg/mL (HepG2); and TREN 11.3-31.4 µg/mL (Balb/c 3T3) and 12.5-59.4 µg/mL (HepG2). The results revealed that oestrogens were more toxic than androgens and the most affected endpoint was mitochondrial activity. In contrast to oestrogens, for which EC50-72h values were similar in both lines and by all assays used, Balb/c 3T3 cells were more sensitive than HepG2 cells to TP.

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Neurotoxic properties of the anabolic androgenic steroids nandrolone and methandrostenolone in primary neuronal cultures

Caraci

Pistarà

Corsaro

et al. 2011

J of Neuroscience Research

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Anabolic-androgenic steroid (AAS) abuse is associated with multiple neurobehavioral disturbances. The sites of action and the neurobiological sequels of AAS abuse are unclear at present. We investigated whether two different AASs, nandrolone and methandrostenolone, could affect neuronal survival in culture. The endogenous androgenic steroid testosterone was used for comparison. Both testosterone and nandrolone were neurotoxic at micromolar concentrations, and their effects were prevented by blockade of androgen receptors (ARs) with flutamide. Neuronal toxicity developed only over a 48-hr exposure to the steroids. The cell-impermeable analogues testosterone-BSA and nandrolone-BSA, which preferentially target membrane-associated ARs, were also neurotoxic in a time-dependent and flutamide-sensitive manner. Testosterone-BSA and nandrolone-BSA were more potent than their parent compounds, suggesting that membrane-associated ARs were the relevant sites for the neurotoxic actions of the steroids. Unlike testosterone and nandrolone, toxicity by methandrostenolone and methandrostenolone-BSA was insensitive to flutamide, but it was prevented by the glucocorticoid receptor (GR) antagonist RU-486. Methandrostenolone-BSA was more potent than the parent compound, suggesting that its toxicity relied on the preferential activation of putative membrane-associated GRs. Consistently with the evidence that membrane-associated GRs can mediate rapid effects, a brief challenge with methandrostenolone-BSA was able to promote neuronal toxicity. Activation of putative membrane steroid receptors by nontoxic (nanomolar) concentrations of either nandrolone-BSA or methandrostenolone-BSA became sufficient to increase neuronal susceptibility to the apoptotic stimulus provided by β-amyloid (the main culprit of AD). We speculate that AAS abuse might facilitate the onset or progression of neurodegenerative diseases not usually linked to drug abuse.

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Nanomolar concentrations of anabolic–androgenic steroids amplify excitotoxic neuronal death in mixed mouse cortical cultures

Cited by 58 publications

References 62 publications

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

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

Cytotoxic effects of the synthetic oestrogens and androgens on Balb/c 3T3 and HepG2 cells

Neurotoxic properties of the anabolic androgenic steroids nandrolone and methandrostenolone in primary neuronal cultures

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