title: 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.
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia; Riga Stradins University, Dzirciema Str. 16, Riga, LV-1007, Latvia. Electronic address: edijs.vavers@farm.osi.lv.
authors.forename: Edijs
authors.initials: E
authors.lastname: Vavers
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Baiba
authors.initials: B
authors.lastname: Svalbe
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Lasma
authors.initials: L
authors.lastname: Lauberte
authors.affiliation: JSC Grindeks, Krustpils Str. 53, Riga, LV-1057, Latvia.
authors.forename: Ilmars
authors.initials: I
authors.lastname: Stonans
authors.affiliation: JSC Grindeks, Krustpils Str. 53, Riga, LV-1057, Latvia.
authors.forename: Ilga
authors.initials: I
authors.lastname: Misane
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia; Riga Stradins University, Dzirciema Str. 16, Riga, LV-1007, Latvia.
authors.forename: Maija
authors.initials: M
authors.lastname: Dambrova
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Liga
authors.initials: L
authors.lastname: Zvejniece
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology*; D001640:Bicuculline; D003292:Convulsants / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D010433:Pentylenetetrazole; D011437:Propylamines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D016019:Survival Analysis; D000097605:Sigma-1 Receptor
chemical_list: D000081:Acetamides; D000840:Anisoles; D000927:Anticonvulsants; D001640:Bicuculline; D003292:Convulsants; D009025:Morpholines; D010433:Pentylenetetrazole; D011437:Propylamines; D011760:Pyrrolidinones; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C000592155:2-(5-methyl-2-oxo-4-phenylpyrrolidin-1-yl)acetamide; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride
keywords: Anti-convulsive activity; Bicuculline; E1R; NE-100; Pentylenetetrazol; Sigma-1 receptor