Androgenic neurosteroids: anti-seizure effects in an animal model of epilepsy.
These studies investigate whether the neurosteroid and 5 alpha-reduced metabolite of testosterone (T), 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-Diol), has anti-seizure effects similar to its parent compound. In experiment 1, ovariectomized (ovx) Long-Evans rats (n = 20) were subcutaneously (s.c.) administered 32 mg/kg kainic acid or saline vehicle 10 min following 0.0, 3.0, or 7.5 mg/kg 3 alpha-Diol in 10% ethanol, propylene glycol vehicle (veh). During 2 h of observation of ictal activity, 3 alpha-Diol (3.0 and 7.5 mg/kg) prior to kainic acid significantly decreased the number and duration of partial and full seizures compared to the 0.0 3 alpha-Diol conditions and produced ictal activity that was comparable to 0.0 mg/kg 3 alpha-Diol no kainic acid controls (procedure controls). Animals that received 7.5 mg/kg 3 alpha-Diol prior to kainic acid had shorter latencies and distances to the hidden platform in a Morris Water Maze task than those that received 0.0 3 alpha-Diol, 1 week following ictal activity. Administration of 3 alpha-Diol (3.0 or 7.5 mg/kg) prior to kainic acid stimulation resulted in a greater number of identifiable neurons in the hilar region of the hippocampus, compared to 0.0 3 alpha-Diol condition. Experiment 2 was conducted to ascertain whether 3 alpha-Diol's anti-seizure effects were comparable to T and possibly a result of metabolism from T. Ovx rats (n = 36) were stereotaxically implanted with bipolar electrodes into the perforant pathway. One hour prior to perforant pathway stimulation, six rats were s.c. injected with either T (7.5 mg/kg), 3 alpha-Diol (7.5 mg/kg), 7.5 mg/kg T + 4MA (a 5 alpha-reductase inhibitor, 17 beta-N,N-diethylcarbamoyl-4-methyl-4aza,5 alpha-androstan-3-one), 4MA alone, 10% propylene glycol vehicle (veh) with perforant pathway stimulation, or veh without perforant pathway stimulation. 3 alpha-Diol and T produced similar seizure activity, water maze performance, and neuronal integrity in the hilar region of the hippocampus that were comparable to unstimulated controls. Because the T and 3 alpha-Diol groups were not different from T + 4MA but tended to be different from 4MA alone on these measures, this suggests that 3 alpha-Diol and T can have similar anti-seizure effects which may be due to actions of neurosteroids.
Frye
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Neuroscience Program, Department of Psychology, Connecticut College, New London 06320, USA.
Reed
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TA
D045930:Anabolic Agents / Q000494:pharmacology*; D015113:Androstane-3,17-diol / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects*; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology*; D004924:Escape Reaction / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects; D007279:Injections, Subcutaneous; D007608:Kainic Acid; D018782:Maze Learning / Q000187:drug effects; D011939:Mental Recall / Q000187:drug effects; D010052:Ovariectomy; D051381:Rats; D020318:Rats, Long-Evans
D045930:Anabolic Agents; D000927:Anticonvulsants; D015113:Androstane-3,17-diol; D007608:Kainic Acid