Influence of Sigma1R ligands on seizures induced by blockade of the orthosteric site and chloride channel of the GABA_A receptor

Relevance. The role of the Sigma1R chaperone in modulating the effects of allosteric modulators of GABA_A receptors has been previously demonstrated.

However, its influence on processes associated with the orthosteric GABA-binding site and the chloride channel of the receptor remains poorly understood. Despite the established Sigma1R-dependent effect of fabomotizole in the pentylenetetrazole-induced seizure model, the involvement of Sigma1R in its anticonvulsant mechanism under conditions of orthosteric GABA-binding site or chloride channel inhibition remains unclear.

Objective. To evaluate the influence of Sigma1R ligands PRE-084, BD-1047, and fabomotizole on seizure thresholds in mouse models of seizures induced by intravenous administration of bicuculline and picrotoxin.

Materials and Methods. The study was conducted on male ICR mice. Seizures were induced by intravenous infusion of bicuculline or picrotoxin. Fabomotizole (20 mg/kg), PRE-084 (10 and 20 mg/kg), and BD-1047 (10 and 20 mg/kg) were administered intraperitoneally 90 minutes prior to the convulsant. Threshold doses for the onset of clonic jerks, generalized clonic, and tonic seizures were recorded.

Results. An anticonvulsant effect of fabomotizole at a dose of 20 mg/kg was demonstrated, which was attenuated by the Sigma1R chaperone antagonist BD-1047. No intrinsic effects were observed for either the selective Sigma1R agonist PRE-084 or the antagonist BD-1047.

Conclusion. The present study demonstrated that the anticonvulsant action of fabomotizole in bicuculline- and picrotoxin-induced seizure models is mediated by Sigma1R activation. The difference between the pharmacological action of fabomotizole and that of the classical agonist PRE-084 suggests the existence of additional, as yet unstudied, mechanisms of Sigma1R interaction with the GABA_A receptor, which opens new avenues for further research.

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