Abstract
Testosterone modulates seizure susceptibility, but the underlying mechanisms are obscure. Recently, we demonstrated that testosterone affects seizure activity via its conversion to neurosteroids in the brain. Androstanediol (5α-androstan-3α,17β-diol) is an endogenous neurosteroid synthesized from testosterone. However, the molecular mechanism underlying the seizure protection activity of androstanediol remains unclear. Here, we show that androstanediol has positive allosteric activity as a GABAA receptor modulator. In whole-cell recordings from acutely dissociated hippocampus CA1 pyramidal cells, androstanediol (but not its 3β-epimer) produced a concentration-dependent enhancement of GABA-activated currents (EC50 of 5 μM). At 1 μM, androstanediol produced a 50% potentiation of GABA responses. In the absence of GABA, androstanediol has moderate direct effects on GABAA receptor-mediated currents at high concentrations. Systemic doses of androstanediol (5–100 mg/kg), but not its 3β-epimer, caused dose-dependent suppression of behavioral and electrographic seizures in mouse hippocampus kindling, which is a model of temporal lobe epilepsy. The ED50 value for antiseizure effects of androstanediol was 50 mg/kg, which did not produce sedation/motor toxicity. At high (2× ED50) doses, androstanediol produced complete seizure protection that lasted for up to 3 h after injection. The estimated plasma concentrations of androstanediol producing 50% seizure protection in the kindling model (10.6 μM) are within the range of concentrations that modulate GABAA receptors. These studies suggest that androstanediol could be a neurosteroid mediator of testosterone actions on neuronal excitability and seizure susceptibility via its activity as a GABAA receptor modulator and that androstanediol may play a key role in men with epilepsy, especially during the age-related decline in androgen levels.
Footnotes
This research was supported in part by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS051398].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.169854.
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ABBREVIATIONS:
- ACSF
- artificial cerebrospinal fluid
- AR
- androgen receptor.
- Received May 1, 2010.
- Accepted June 14, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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