Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3α-androstanediol and 17β-estradiol
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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2019, PsychoneuroendocrinologyCitation Excerpt :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).