Summary:Purpose: Progesterone has been shown to be anticonvulsant in several animal seizure models. The purpose of the present study was to investigate the anticonvulsant actions of progesterone and its primary metabolite 5α-dihydroprogesterone in the amygdala kindling model.Methods: Female Wistar rats were implanted in the right basolateral amygdala with a long-term, bipolar electrode. The subjects were kindled to 30 stage 5 seizures and stability tested. Multiple doses of progesterone and 5α-dihydroprogesterone were then tested for anticonvulsant activity against focal electrographic and generalized convulsive kindled seizures. The time course of progesterone's anticonvulsant action also was examined.Results: Progesterone had a median effective dose (ED 50 ) of 103 mg/kg against generalized convulsions at 15 min after injection. Subjects were not sedated at the time of seizure testing, although sedation developed later (40-60 min after injection). In time-course experiments, it was found that 120 mg/kg of progesterone caused complete suppression of the generalized convulsion from 20 to 160 min after injection. Suppression of the focal discharge also was seen in some animals between 20 and 160 min. 5α-dihydroprogesterone had an ED 50 of 2.9 mg/kg against generalized kindled convulsions and an ED 50 of 4.3 mg/kg against focal afterdischarge 15 min after injection. 5α-dihydroprogesterone did not produce sedation 15 min after injection, or at any later time interval.Conclusions: Progesterone is anticonvulsant only at high doses when tested against amygdala kindled seizures. 5α-dihydroprogesterone is considerably more potent than progesterone. At low, nonsedative doses, it was effective against both the kindled amygdala focal afterdischarge and the generalized convulsion. Key Words: Progesterone-5α-dihydroprogesterone-Allopregnanolone-Kindling-Complex partial seizures.Treatment with anticonvulsant drugs (AEDs) is the most common therapy for epilepsy. Approximately 60% of patients are seizure free while taking AEDs, and a further 20% achieve partial control of their seizures (1). Twenty percent of patients, however, have intractable epilepsyepilepsy that is not responsive to any drug regimen (1). New drugs are needed to help the patients who are partially or completely resistant to the existing agents.Endogenous hormones, including progesterone, have been found to have anticonvulsant effects. In 1942, Selye (2) demonstrated that progesterone, at anesthetic doses, prevented the induction of seizures by pentylenetetrazol (PTZ) in rats. Craig (3) later determined that large doses of progesterone also protected mice against PTZ-induced seizures.The anticonvulsant effects of progesterone have been investigated by recent experimenters, who have addressed progesterone's mechanism of action. Kokate et al. (4) (5) showed progesterone to be effective against PTZ-induced seizures in mice. The same researchers found that progesterone's anticonvulsant actions are due, at least in part, to its metabolites. Progesterone is first m...

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