Journal
PSYCHOPHARMACOLOGY
Volume 231, Issue 17, Pages 3325-3332Publisher
SPRINGER
DOI: 10.1007/s00213-014-3546-x
Keywords
Androsterone; Etiocholanolone; Enantiomer; Six-Hertz test; Pentylenetetrazol test; Maximal electroshock test
Categories
Funding
- National Institute of Neurological Disorders and Stroke of the National Institutes of Health [NS079202]
- National Institute of General Medical Sciences of the National Institutes of Health [GM47969]
Ask authors/readers for more resources
Androsterone [(3 alpha,5 alpha)-3-hydroxyandrostan-17-one; 5 alpha,3 alpha-A] and its 5 beta-epimer etiocholanolone [(3 alpha,5 beta)-3-hydroxyandrostan-17-one; 5 beta,3 alpha-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABA(A) receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5 alpha,3 alpha-A and 5 beta,3 alpha-A, the unnatural enantiomers are more potent at GABA(A) receptors than the natural forms. The aim of this study was to compare the anticonvulsant potencies and time courses of 5 alpha,3 alpha-A and 5 beta,3 alpha-A with their enantiomers in mouse seizure models. Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 h in time course experiments) prior to administration of an electrical stimulus in the 6-Hz or maximal electroshock (MES) seizure tests or the convulsant pentylenetetrazol (PTZ). In the 6-Hz test, the ED50 values of ent-5 alpha,3 alpha-A was 5.0 mg/kg whereas the value for 5 alpha,3 alpha-A was 12.1 mg/kg; the corresponding values in the PTZ seizure test were 22.8 and 51.8 mg/kg. Neurosteroid GABA(A) receptor-positive allosteric modulators are generally weak in the MES seizure test and this was confirmed in the present study. However, the atypical relative potency relationship was maintained with ED50 values of 140 and 223 mg/kg for ent-5 alpha,3 alpha-A and 5 alpha,3 alpha-A, respectively. Similar relationships were obtained for the 5 beta-isomers, except that the enantioselectivity was accentuated. In the 6-Hz and PTZ tests, the ED50 values of ent-5 beta,3 alpha-A were 11.8 and 20.4 mg/kg whereas the values for 5 beta,3 alpha-A were 57.6 and 109.1 mg/kg. Protective activity in the 6-Hz test of ent-5 alpha,3 alpha-A persisted for somewhat longer (5 h) than for 5 alpha,3 alpha-A (4 h); protection by ent-5 beta,3 alpha-A also persisted longer (3 h) than for 5 beta,3 alpha-A (2 h). The unnatural enantiomers of 17-keto androgen class neurosteroids have greater in vivo potency and a longer duration of action than their natural counterparts. The more prolonged duration of action of the unnatural enantiomers could reflect reduced susceptibility to metabolism. Unnatural enantiomers of androgen class neurosteroids could have therapeutic utility and may provide advantages over the corresponding natural isomers due to enhanced potency and improved pharmacokinetic characteristics.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available