TY - JOUR
T1 - The activity of selective sigma-1 receptor ligands in seizure models in vivo
AU - Vavers, Edijs
AU - Svalbe, Baiba
AU - Lauberte, Lasma
AU - Stonans, Ilmars
AU - Misane, Ilga
AU - Dambrova, Maija
AU - Zvejniece, Liga
N1 - Funding Information:
The current work was supported by the grant from the Latvian Council of Science (108/2012).
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - 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 25 mg/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 50 mg/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 50 mg/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.
AB - 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 25 mg/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 50 mg/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 50 mg/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.
KW - Anti-convulsive activity
KW - Bicuculline
KW - E1R
KW - NE-100
KW - Pentylenetetrazol
KW - Sigma-1 receptor
UR - http://www.scopus.com/inward/record.url?scp=85017187523&partnerID=8YFLogxK
U2 - 10.1016/j.bbr.2017.04.008
DO - 10.1016/j.bbr.2017.04.008
M3 - Article
C2 - 28389336
AN - SCOPUS:85017187523
SN - 0166-4328
VL - 328
SP - 13
EP - 18
JO - Behavioural Brain Research
JF - Behavioural Brain Research
ER -