Novel anticonvulsive effects of progesterone in a mouse model of hippocampal electrical kindling.
Progesterone is a known anticonvulsant, with its inhibitory effects generally attributed to its secondary metabolite, 5α,3α-tetrahydroprogesterone (THP), and THP's enhancement of GABAA receptor activity. Accumulating evidence, however, suggests that progesterone may have non-genomic actions independent of the GABAA receptor. In this study, we explored THP/GABAA-independent anticonvulsive actions of progesterone in a mouse model of hippocampal kindling and in mouse entorhinal slices in vitro. Specifically, we examined the effects of progesterone in kindled mice with or without pretreatments with finasteride, a 5α-reductase inhibitor known to block the metabolism of progesterone to THP. In addition, we examined the effects of progesterone on entorhinal epileptiform potentials in the presence of a GABAA receptor antagonist picrotoxin and finasteride. Adult male mice were kindled via a daily stimulation protocol. Electroencephalographic (EEG) discharges were recorded from the hippocampus or cortex to assess "focal" or "generalized" seizure activity. Kindled mice were treated with intra-peritoneal injections of progesterone (10, 35, 100 and 160mg/kg) with or without finasteride pretreatment (50 or 100mg/kg), THP (1, 3.5, 10 and 30mg/kg), midazolam (2mg/kg) and carbamazepine (50mg/kg). Entorhinal cortical slices were prepared from naïve young mice, and repetitive epileptiform potentials were induced by 4-aminopyridine (100μM), picrotoxin (100μM) and finasteride (1μM). Pretreatment with finasteride did not abolish the anticonvulsant effects of progesterone. In finasteride-pretreated mice, progesterone at 100 and 160mg/kg decreased cortical but not hippocampal afterdischarges (ADs). Carbamazepine mimicked the effects of progesterone with finasteride pretreatments in decreasing cortical discharges and motor seizures, whereas midazolam produced effects similar to progesterone alone or THP in decreasing hippocampal ADs and motor seizures. In brain slices, progesterone at 1μM inhibited entorhinal epileptiform potentials in the presence of picrotoxin and finasteride. We suggest that progesterone may have THP/GABAA-dependent and independent anticonvulsive actions in the hippocampal-kindled mouse model.
Department of Pharmacology and Toxicology, University of Toronto, Canada; Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Canada; University of Toronto Epilepsy Research Program, Canada.
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M
Jeffrey
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Canada.
M
M
Lang
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Canada.
J
J
Gane
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Canada.
E
E
Chow
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Canada; University of Toronto Epilepsy Research Program, Canada.
C
C
Wu
Department of Medicine (Neurology), University of Toronto, Canada; Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Canada; University of Toronto Epilepsy Research Program, Canada. Electronic address: liangz@uhnres.utoronto.ca.
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L
Zhang
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001600:Berberine Alkaloids / Q000494:pharmacology / Q000627:therapeutic use; D002220:Carbamazepine / Q000494:pharmacology / Q000627:therapeutic use; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004567:Electrodes, Implanted / Q000009:adverse effects; D018120:Finasteride / Q000494:pharmacology / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D066298:In Vitro Techniques; D007696:Kindling, Neurologic / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008874:Midazolam / Q000494:pharmacology / Q000627:therapeutic use; D010852:Picrotoxin / Q000494:pharmacology; D011374:Progesterone / Q000627:therapeutic use*; D012640:Seizures / Q000188:drug therapy* / Q000473:pathology*
D000927:Anticonvulsants; D001600:Berberine Alkaloids; D002220:Carbamazepine; D003292:Convulsants; D004338:Drug Combinations; D018120:Finasteride; D008874:Midazolam; D010852:Picrotoxin; D011374:Progesterone; C103306:2,3,10,11-tetrahydroxytetrahydroprotoberberine
5α,3α-tetrahydroprogesterone; 5α-dihydroprogesterone; ACSF; AD; DHP; EEG; THP; afterdischarge; artificial cerebrospinal fluid; electroencephalographic; epilepsy; neurosteroids; seizures