Anticonvulsant activity of androsterone and etiocholanolone

Purpose: Men with epilepsy often have sexual or reproductive abnormalities that are attributed to alterations in androgen levels, including subnormal free testosterone. Levels of the major metabolites of testosterone-androsterone (5 alpha-androstan-3 alpha-ol-17-one; 5 alpha,3 alpha-A), a neurosteroid that acts as a positive allosteric modulator of GABA(A) receptors, and its 5 epimer etiocholanolone (5 beta-androstan-3 alpha-ol-17-one; 5 beta,3 alpha-A)-also may be reduced in epilepsy. 5 alpha,3 alpha-A has been found in adult brain, and both metabolites, which also can be derived from androstenedione, are present in substantial quantities in serum along with their glucuronide and sulfate conjugates. This study sought to determine whether these endogenous steroid metabolites can protect against seizures. Methods: The anticonvulsant activity of 5 alpha,3 alpha-A and 5 beta,3 alpha-A was investigated in electrical and chemoconvulsant seizure models in mice. The steroids also were examined for activity against extracellularly recorded epileptiform discharges in the CA3 region of the rat hippocampal slice induced by perfusion with 55 mu M 4-aminopyridine (4-AP). Results: Intraperitoneal injection of 5 alpha,3 alpha-A-protected mice in a dose-dependent fashion from seizures in the following models (ED50, dose in mg/kg protecting 50% of animals): 6-Hz electrical stimulation (29.1), pentylenetetrazol (43.5), pilocarpine (105), 4-AP (215), and maximal electroshock (224). 5 beta,3 alpha-A also was active in the 6-Hz and pentylenetetrazol models, but was less potent (ED50 values, 76.9 and 139 mg/kg, respectively), whereas epiandrosterone (5 alpha,3 beta-A) was inactive (ED50, <= 300 mg/kg). 5 alpha,3 beta-A (10-100 mu M) also inhibited epileptiform discharges in a concentration-dependent fashion in the in vitro slice model, whereas 5 beta,3 alpha-A was active but of lower potency, and 5 alpha,3 beta-A was inactive. Conclusions: 5 alpha,3 alpha-A and 5 beta,3 alpha-A have anticonvulsant properties. Although of low potency, the steroids are present in high abundance and could represent endogenous modulators of seizure susceptibility.