The effects of neurosteroids on picrotoxin-, bicuculline- and NMDA-induced seizures, and a hypnotic effect of ethanol
Section snippets
Subjects
The experiments were carried out on male albino Swiss mice weighing 20–25 g. All animals were acclimated to their home cages for 5 days before testing. They were housed with water and food ad libitum under a 12-h light–dark cycle, and at a controlled temperature (20°C). All experiments were done between 11 AM and 4 PM. The experiments were performed in accordance with the European Communities Council Directive of 24 November 1986 (86/609 EEC). All experimental procedures using animal subjects
Chemoconvulsants
PTX produced seizures and the lethal effect with a LD50=9.92 mg/kg (95% CL, CL=9.05–10.87). Subsequently, the dose of 12 mg/kg (LD85) was selected for further experiments (Fig. 2). In mice, IP and ICV injections of BIC produced convulsions and lethal effect with a respective LD50 of 11.41 mg/kg (CL=10.48–12.43) and 28.91 nmol (CL=18.97–43.99) (Fig. 2). The doses of 13 mg/kg and 54.44 nmol (LD85) were selected for further experiments. In case of NMDA, LD50 was found to be 100.72 mg/kg
Discussion
Both precursors of neurosteroids, PROG and PREG, appeared only marginally active in all examined models of seizures. The potencies of PROG and PREG in inhibiting convulsions were at least two orders of magnitude lower than those of DZP and (+)MK-801. Several factors may contribute to this finding, e.g. peripheral drugs metabolism and limited penetration of their active metabolites to the brain. It is noteworthy that PROG and PREG do not show any appreciable affinity towards GABAA receptors by
Uncited references
[17]
[22]
Acknowledgements
This work was supported by the State Committee for Scientific Research Grant No. 4PO5A06315.
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Progesterone, 5a-dihydropogesterone and allopregnanolone's effects on seizures: A review of animal and clinical studies
2018, SeizureCitation Excerpt :Akula et al. compared progesterone with other anti-seizure drugs in the intravenous PTZ model in mice and concluded that progesterone is more potent than tiagabine, GABA, adenosine, gabapentin and ethanol, but less potent than triazolam, clonazepam, diazepam, phenobarbital, carbamazepine and phenytoin [24]. Progesterone is also less potent than (+)MK-801 and diazepam in protecting against picrotoxin-, bicuculline- and NMDA-induced lethality [29]. Progesterone has also shown pro-seizure effects in one animal model, the WAG/Rij model of absence seizures.
Neurosteroids and potential therapeutics: Focus on pregnenolone
2016, Journal of Steroid Biochemistry and Molecular Biology