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, 5-μM). At 1μM, 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 (10-μM). Systemic doses of androstanediol (5-100 mg/kg), but not its 3β-epimer, caused dose-dependent suppression of behavioral and electrographic seizures in the mouse hippocampus kindling, which is a model of temporal lobe epilepsy. The ED50 for antiseizure effects of androstanediol was 50 mg/kg, which did not produce sedation. At high (2xED50) doses, androstanediol produced complete seizure protection that lasted for up to 3-hr after injection. The estimated plasma concentrations of androstanediol producing 50% seizure protection in the kindling model (10.6μM) 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 may play a key role in men with epilepsy especially during age-related decline in androgen levels.
Footnotes
- Received May 1, 2010.
- Revision received June 14, 2010.
- Accepted June 14, 2010.
- The American Society for Pharmacology and Experimental Therapeutics