Fig. 4.

Confirmed Sig1R-dependent mechanisms of anti-seizure activity of Sig1R agonists and antagonists. (A) High doses of kainic acid suppress the release of GABA from GABAergic interneurons (1) and enhance presynaptic release of glutamate from glutamatergic neurons (2), which, together with kainic acid, activate postsynaptic KainateR (3) and leads to seizures [265]. Sig1R-dependent anti-seizure activity of Sig1R agonists (dextromethorphan, dextrorphan, dimemorfan and carbetapentane) has been pharmacologically confirmed against kainic acid-induced seizures by using Sig1R antagonists (Table 1). Therefore, based on the activity of kainic acid, Sig1R agonists either increase GABA release from GABAergic interneurons (1), block presynaptic glutamate release (2) and/or attenuate KainateR activity (3). (B) High doses of NMDA activate NMDA receptors and induce seizures. Sig1R antagonists (BD-1063, S1RA) can alleviate NMDA-induced seizures. However, they are ineffective against NMDA-induced seizures in Sig1R KO animals thus confirming Sig1R-dependent activity (Table 1). KainateR – kainate receptors; NMDAR – N-methyl-D-aspartate receptors. Created with BioRender.com.