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Anticonvulsant Activity of Androsterone and Etiocholanolone

Authors
 Rafal M Kaminski  ;  Herbert Marini  ;  Won-Joo Kim  ;  Michael A Rogawski 
Citation
 EPILEPSIA, Vol.46(6) : 819-827, 2005 
Journal Title
EPILEPSIA
ISSN
 0013-9580 
Issue Date
2005
MeSH
4-Aminopyridine/pharmacology ; Androsterone/blood ; Androsterone/pharmacology* ; Animals ; Anticonvulsants/pharmacology* ; Behavior, Animal/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Electroshock ; Epilepsy/blood ; Etiocholanolone/blood ; Etiocholanolone/pharmacology* ; Hippocampus/drug effects ; Hippocampus/physiopathology ; Humans ; In Vitro Techniques ; Injections, Intraperitoneal ; Male ; Mice ; Motor Activity/drug effects ; Pilocarpine/pharmacology ; Rats ; Rats, Sprague-Dawley ; Seizures/chemically induced ; Seizures/physiopathology ; Seizures/prevention & control* ; Testosterone/blood ; Testosterone/metabolism
Keywords
Androsterone ; Etiocholanolone ; Epiandrosterone ; Pentylenetetrazol ; Pilocarpine ; 4‐Aminopyridine ; 6‐Hz model ; Seizure ; Mouse
Abstract
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 (5alpha-androstan-3alpha-ol-17-one; 5alpha,3alpha-A), a neurosteroid that acts as a positive allosteric modulator of GABA(A) receptors, and its 5beta-epimer etiocholanolone (5beta-androstan-3alpha-ol-17-one; 5beta,3alpha-A)-also may be reduced in epilepsy. 5alpha,3alpha-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 5alpha,3alpha-A and 5beta,3alpha-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 microM 4-aminopyridine (4-AP).
RESULTS: Intraperitoneal injection of 5alpha,3alpha-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). 5beta,3alpha-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 (5alpha,3beta-A) was inactive (ED50, CONCLUSIONS: 5alpha,3alpha-A and 5beta,3alpha-A have anticonvulsant properties. Although of low potency, the steroids are present in high abundance and could represent endogenous modulators of seizure susceptibility.
Files in This Item:
T200501221.pdf Download
DOI
10.1111/j.1528-1167.2005.00705.x
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Won Joo(김원주) ORCID logo https://orcid.org/0000-0002-5850-010X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/151381
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