Convulsant actions of the neurosteroid pregnenolone sulfate in mice
| Autor: | Shun Ichi Yamaguchi, Tushar G. Kokate, Jose Llamas, R.Duncan Kirkby, Michael A. Rogawski, Kyungho N. Juhng |
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| Rok vydání: | 1999 |
| Předmět: |
Male
medicine.medical_specialty Neuroactive steroid N-Methylaspartate Convulsants Status epilepticus chemistry.chemical_compound Mice Seizures Internal medicine medicine Animals Pentylenetetrazol Molecular Biology Injections Intraventricular General Neuroscience Allopregnanolone Drug Synergism Receptors GABA-A Dizocilpine Endocrinology nervous system chemistry Pregnenolone Convulsant Pentylenetetrazole Neurology (clinical) Disease Susceptibility medicine.symptom Pregnenolone sulfate Developmental Biology medicine.drug |
| Zdroj: | Brain research. 831(1-2) |
| ISSN: | 0006-8993 |
| Popis: | Pregnenolone sulfate (PS) is an endogenous neurosteroid known to antagonize GABAA receptor-mediated inhibitory responses and potentiate NMDA receptor-mediated excitatory responses in vitro. To assess the actions of the steroid as a modulator of seizure susceptibility in vivo, PS (30–300 nmol) was administered intracerebroventricularly in mice. At doses of 50 to 150 nmol, PS elicited seizures characterized by head jerks, rearing and falling, severe forelimb and hindlimb clonus, opisthotonos and explosive running. The seizures increased in severity and frequency with time and eventually progressed to status epilepticus, tonic hindlimb extension and death. The doses producing convulsions in 50% (CD50) and 97% (CD97) of animals were 92 and 205 nmol, respectively. A subconvulsant dose of PS (50 nmol) significantly increased the convulsant potencies of systemically administered pentylenetetrazol (30–50 mg/kg) and NMDA (50–100 mg/kg). Systemically administered PS at doses as high as 100 mg/kg failed to induce seizures or alter the convulsant potencies of pentylenetetrazol and NMDA. Protection against PS (205 nmol)-induced seizures and lethality was conferred by the GABAA receptor positive allosteric modulators clonazepam and allopregnanolone, and by the NMDA receptor antagonists dizocilpine and (R)-CPP. The overall pharmacological profile suggests that the convulsant actions of PS are mediated predominantly via its effects on GABAA receptors, and also possibly by effects on NMDA receptors. |
| Databáze: | OpenAIRE |
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