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.