Elsevier

Neuroscience

Volume 129, Issue 1, 2004, Pages 195-207
Neuroscience

Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3α-androstanediol and 17β-estradiol

https://doi.org/10.1016/j.neuroscience.2004.08.002Get rights and content

Abstract

Testosterone modulates seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here, testosterone modulation of seizure susceptibility is hypothesized to occur through its conversion to neurosteroids with “anticonvulsant” and “proconvulsant” actions, and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17β-estradiol. Reduction of testosterone by 5α-reductase generates 5α-dihydrotestosterone (DHT), which is then converted to 3α-androstanediol (3α-Diol), a powerful GABAA receptor-modulating neurosteroid with anticonvulsant properties. Systemic doses of testosterone decreased seizure threshold in rats and increased the incidence and severity of pentylenetetrazol (PTZ)-induced seizures in mice. These proconvulsant effects of testosterone were associated with increases in plasma 17β-estradiol and 3α-Diol concentrations. Pretreatment with letrozole, an aromatase inhibitor that blocks the conversion of testosterone to 17β-estradiol, significantly inhibited testosterone-induced exacerbation of seizures. The 5α-reductase inhibitor finasteride significantly reduced 3α-Diol levels and also blocked letrozole's ability to inhibit the proconvulsant effects of testosterone. The 5α-reduced metabolites of testosterone, DHT and 3α-Diol, had powerful anticonvulsant activity in the PTZ test. Letrozole or finasteride had no effect on seizure protection by DHT and 3α-Diol, but indomethacin partially reversed DHT actions. 3α-Diol but not 3β-androstanediol, a GABAA receptor-inactive stereoisomer, suppressed 4-aminopyridine-induced spontaneous epileptiform bursting in rat hippocampal slices. Thus, testosterone-derived neurosteroids 3α-Diol and 17β-estradiol could contribute to the net cellular actions of testosterone on neural excitability and seizure susceptibility.

Section snippets

Animals

Male Swiss-Webster mice (25–30 g) and Sprague–Dawley rats (150–250 g) were purchased from Taconic (Germantown, NY, USA). Animals were allowed to acclimatize with access to food and water ad libitum for a 48-h period before use and were group-housed under a 12-h light/dark cycle in an environmentally controlled animal facility. Mice and rats were used for s.c. and i.v. PTZ seizure tests, respectively. All procedures were carried out under strict compliance with the NIH Guide for the Care and Use

Testosterone-induced reduction of PTZ seizure threshold in rats: Correlation with plasma 17β-estradiol and 3α-diol levels

The effect of testosterone on seizure susceptibility was determined by the i.v. PTZ threshold test, which provides a sensitive, graded measure of various seizure signs. The mean threshold values for one seizure sign—forelimb clonus—are presented in Fig. 2A. Systemic administration of testosterone (10–200 mg/kg s.c.) in rats caused a dose-dependent reduction of the PTZ seizure threshold. The highest testosterone dose tested (200 mg/kg) caused an approximately 25% decrease in seizure threshold (P

Discussion

The principal observations of this study are: (1) testosterone facilitates proconvulsant seizure activity in the PTZ test in rats and mice; (2) testosterone conversion to 17β-estradiol contributes to the proconvulsant activity of testosterone; and (3) testosterone-derived 5α-reduced neurosteroid 3α-Diol mediates the anticonvulsant activity of testosterone.

Acknowledgments

The expert assistance of Ms Leigh Ann Apanites, Sarah Timberlake and Dr. Yuan-Shen Chan is gratefully acknowledged. I thank Drs. Cynthia Harden and Ashok Shetty for providing helpful comments on the manuscript. Supported partially by NC State CVM grant.

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      Aromatization of testosterone leads to formation of 17β-estradiol which is believed to have proconvulsive activity (Reddy, 2004). Inhibition of aromatase-mediated conversion to estradiol significantly attenuates the convulsant action of testosterone in tonic-clonic convulsions induced by PTZ (Reddy, 2004). Acute inhibition of testosterone aromatization by letrozole exerts anticonvulsant effect against KA-induced seizures (Iqbal et al., 2018) and development of PTZ- induced kindling in mice (Rashid et al., 2015).

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