Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of i.p. administration of the neurosteroids, allopregnanolone and pregnenolone sulfate, were studied in WAG/Rij rats, a genetic model for generalized absence epilepsy. EEG recordings showed that allopregnanolone, a positive modulator of the GABA(A) receptor, in doses ranging from 5 to 20 mg/kg, increased dose-dependently the number- and total duration of spike-wave discharges. Pregnenolone sulfate, a positive modulator of NMDA receptors, also increased those parameters, though only at the highest dose used (100 mg/kg). Significant changes in spike-wave discharges occurred during the first hour post-injection and were not accompanied with behavioral alterations. The obtained data indicate that both these neurosteroids aggravate the spike-wave activity. This finding contrasts with the anti-convulsant effects of some neurosteroids and they point to a different pharmacological profile of epilepsy with convulsive or non-convulsive seizures.
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PMID:Effects of neurosteroids on spike-wave discharges in the genetic epileptic WAG/Rij rat. 1002 63

Pregnenolone sulfate (PS) is an endogenous neurosteroid known to antagonize GABA(A) 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% (CD(50)) and 97% (CD(97)) 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 GABA(A) 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 GABA(A) receptors, and also possibly by effects on NMDA receptors.
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PMID:Convulsant actions of the neurosteroid pregnenolone sulfate in mice. 1041 90

1. Neurosteroid modulation of GABA(A) receptors present on dentate granule cells (DGCs) acutely isolated from epileptic (epileptic DGCs) or control rats (control DGCs) was studied by application of GABA with or without the modulators and by measuring the amplitude of peak whole-cell currents. 2. In epileptic DGCs, GABA efficacy (1394 +/- 277 pA) was greater than in control DGCs (765 +/- 38 pA). 3. Allopregnanolone enhanced GABA-evoked currents less potently in epileptic DGCs (EC50 = 92.7 +/- 13.4 nM) than in control DGCs (EC50 = 12.9 +/- 2.3 nM). 4. Pregnenolone sulfate inhibited GABA-evoked currents with similar potency and efficacy in control and epileptic DGCs. 5. Diazepam enhanced GABA-evoked currents less potently in epileptic (EC50 = 69 +/- 14 nM) compared to the control DGCs (EC50 = 29.9 +/- 5.7 nM). 6. There were two different patterns of zolpidem modulation of GABA(A) receptor currents in the epileptic DGCs. In one group, zolpidem enhanced GABA(A) receptor currents but with reduced potency compared to the control DGCs (EC50 = 134 +/- 20 nM vs. EC50 = 52 +/- 13 nM). In the second group of epileptic DGCs zolpidem inhibited GABA(A) receptor currents, an effect not observed in control DGCs. 7. Epileptic DGCs were more sensitive to Zn2+ inhibition of GABA(A) receptor currents (IC50 = 19 +/- 6 microM) compared to control (IC50 = 94.7 +/- 7.9 microM). 8. This study demonstrates significant differences between epileptic and control DGCs. We conclude that (1) diminished sensitivity of GABA(A) receptors of epileptic DGCs to allopregnanolone can increase susceptibility to seizures; (2) reduced sensitivity to diazepam and zolpidem, and increased sensitivity to Zn2+ indicate that loss of allopregnanolone sensitivity is likely to be due to altered subunit expression of postsynaptic GABA(A) receptors present on epileptic DGCs; and (3) an inverse effect of zolpidem in some epileptic DGCs demonstrates the heterogeneity of GABA(A) receptors present on epileptic DGCs.
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PMID:Diminished allopregnanolone enhancement of GABA(A) receptor currents in a rat model of chronic temporal lobe epilepsy. 1173 78

Pregnenolone sulfate (PS) is an endogenous neurosteroid synthesized by glial cells, which acts as a potent convulsant when injected intracerebroventricularly and intraperitoneally. PS is found in relatively high concentrations in the hippocampus. But its convulsant action in the hippocampus has not been characterized. A range of PS doses were infused directly into the right hippocampus of 42 rats, which were subsequently monitored for behavioral and electrographic seizures. At the highest dose (4 micromol), PS produced status epilepticus (SE) and severe behavioral convulsions. As the dose of PS was reduced, the fraction of rats having SE diminished (ED50 for SE = 2.7 micromol). At doses lower than 300 nmol, PS infusion produced discrete electrographic seizures (ED50 = 68 nmol) associated with mild behavioral seizures. Both the behavioral seizure score (BSS) and the total number of seizures during the observation period changed in a dose-dependent manner. In separate experiments in cultured hippocampal neurons, PS enhanced NMDA-evoked whole-cell currents (EC50 = 16 microM). The results demonstrate that the hippocampus is highly sensitive to the convulsant effects of PS and that the enhancement of NMDA currents could contribute to the convulsant action of PS.
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PMID:Characterization of the convulsant action of pregnenolone sulfate. 1503 45