The activity of selective sigma-1 receptor ligands in seizure models in vivo

Abstract

Sigma-1 receptor (Sig1R) is a ligand-regulated protein which, since its discovery, has been widely studied as a novel target to treat neurological disorders, including seizures. However, the roles and mechanisms of Sig1R in the regulation of seizures are not fully understood. The aim of the present study was to test and compare effects of often used selective Sig1R ligands in models of experimentally induced seizures. The anti-seizure activities and interactions of selective Sig1R agonist PRE-084, selective Sig1R antagonist NE-100 and novel positive allosteric Sig1R modulator E1R were evaluated in pentylenetetrazol (PTZ) and (+)-bicuculline (BIC)-induced seizure models in mice. Sig1R antagonist NE-100 at a dose of 25mg/kg demonstrated pro-convulsive activity on PTZ-induced seizures. Agonist PRE-084 did not change the thresholds of chemoconvulsant-induced seizures. Positive allosteric modulator E1R at a dose of 50mg/kg showed anti-convulsive effects on PTZ- and BIC-induced clonic and tonic seizures. The anti-seizure activity of E1R was blocked by NE-100. Surprisingly, NE-100 at a dose of 50mg/kg induced convulsions, but E1R significantly alleviated the convulsive behaviour induced by NE-100. In conclusion, the selective Sig1R antagonist NE-100 induced seizures that could be partially attenuated by positive allosteric Sig1R modulator. Our results confirm that Sig1R could be a novel molecular target for new anti-convulsive drugs.

Functional and transcriptional characterization of complex neuronal co-cultures

“…Finally, we evaluated whether cell composition dictated the responsiveness of simple and complex systems to the GABA A receptor blocker, bicuculline (BIC). BIC antagonizes GABA-mediated inhibition which results www.nature.com/scientificreports/ in periodic bursting activity or convulsions when administered in vivo 51,52 . BIC is frequently used to evaluate neuronal composition (i.e., evaluate the presence of GABAergic neurons) and network behavior of in vitro systems 23,53 .…”

Allosteric Modulators of Sigma-1 Receptor: A Review

“…The effects of E1R were antagonized by the selective Sig1R antagonist NE-100, thus confirming the Sig1R modulatory activity of E1R in vivo . E1R demonstrated dose-dependent anti-convulsant effects on pentylenetetrazole (PTZ)- and bicuculline (BIC)-induced seizures at doses of 10 and 50 mg/kg (Vavers et al, 2017; Tables 1, 3 ). To verify that Sig1R was involved in the anti-convulsant activity of E1R, the selective Sig1R antagonist NE-100 was used.…”

“…To verify that Sig1R was involved in the anti-convulsant activity of E1R, the selective Sig1R antagonist NE-100 was used. The administration of NE-100 (5 mg/kg) before E1R (10 mg/kg) significantly restored the tonic seizure threshold to the basal level and therefore showed that the anti-seizure effect of E1R was mediated through Sig1R activity (Vavers et al, 2017). The pharmacological activity of E1R demonstrates that it is a selective PAM of Sig1R.…”

“…* NE-100 induced seizures in 100% of animals at a dose of 75 mg/kg (Vavers et al, 2017). Phenytoin, ropizine, SCH23390, and SKF38393 are not included in the table because the seizure modulating activities of these compounds are not shown to be significantly blocked by the selective Sig1R ligands .…”

“…It was demonstrated that the anti-seizure effect of E1R, SOMCL-668, and SKF83959 was blocked by the Sig1R selective antagonists NE-100 and BD-1047 (Guo et al, 2015; Vavers et al, 2017), while the anti-seizure effect of phenytoin was not blocked by BD-1047 (Guo et al, 2015). Moreover, anti-seizure effect of phenytoin is related to the inhibition of voltage-gated sodium channels (Tunnicliff, 1996).…”