title: The testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors.
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 (5alpha-androstan-3alpha,17beta-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 GABA(A) receptor modulator. In whole-cell recordings from acutely dissociated hippocampus CA1 pyramidal cells, androstanediol (but not its 3beta-epimer) produced a concentration-dependent enhancement of GABA-activated currents (EC(50) of 5 microM). At 1 microM, androstanediol produced a 50% potentiation of GABA responses. In the absence of GABA, androstanediol has moderate direct effects on GABA(A) receptor-mediated currents at high concentrations. Systemic doses of androstanediol (5-100 mg/kg), but not its 3beta-epimer, caused dose-dependent suppression of behavioral and electrographic seizures in mouse hippocampus kindling, which is a model of temporal lobe epilepsy. The ED(50) value for antiseizure effects of androstanediol was 50 mg/kg, which did not produce sedation/motor toxicity. At high (2x ED(50)) 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 microM) are within the range of concentrations that modulate GABA(A) 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 GABA(A) receptor modulator and that androstanediol may play a key role in men with epilepsy, especially during the age-related decline in androgen levels.
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, 228 Reynolds Medical Bldg., College Station, TX 77843-1114, USA. reddy@medicine.tamhsc.edu
authors.forename: Doodipala Samba
authors.initials: DS
authors.lastname: Reddy
authors.forename: Kuihuan
authors.initials: K
authors.lastname: Jian
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D015113:Androstane-3,17-diol / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000187:drug effects; D003627:Data Interpretation, Statistical; D005071:Evoked Potentials / Q000187:drug effects; D005485:Flutamide / Q000494:pharmacology; D018757:GABA Modulators; D006624:Hippocampus / Q000502:physiology; D066298:In Vitro Techniques; D007696:Kindling, Neurologic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011597:Psychomotor Performance / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects*; D012640:Seizures / Q000517:prevention & control; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000726:Androgen Antagonists; D018757:GABA Modulators; D011963:Receptors, GABA-A; D015113:Androstane-3,17-diol; D005680:gamma-Aminobutyric Acid; D005485:Flutamide