NMDA and AMPA/kainate receptors are involved in the anticonvulsant activity of riluzole in DBA/2 mice.
The anticonvulsant activity of riluzole against sound-induced seizures was studied in the DBA/2 mouse model. Riluzole (0.1-4 mg kg(-1), intraperitoneal (i.p.)) produced dose-dependent effects with ED(50) values for the suppression of tonic, clonic and wild running phases of 0.72, 1.38 and 2.71 mg kg(-1), respectively. Riluzole also protected DBA/2 mice from seizures induced by an intracerebroventricular (i.c.v.) injection of N-methyl-D-aspartate (NMDA) with ED(50) values of 3.03 and 5.0 mg kg(-1) for tonus and clonus, respectively. Pretreatment with glycine, an agonist to the glycine/NMDA receptors, shifted the dose-response effect of riluzole to the right (ED(50)=6.53 against tonus and 9.34 mg kg(-1) vs. clonus). Similarly, D-serine, an agonist at the glycine site, shifted the ED(50) of riluzole against the tonic component of audiogenic seizures from 0.72 to 1.97, and that against clonus from 1.38 to 2.77 mg kg(-1). Riluzole was also potent to prevent seizures induced by administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), an AMPA/kainate receptor agonist (ED(50)=1.80 and 3.35 mg kg(-1), against tonus and clonus, respectively). Pretreatment with aniracetam, a positive allosteric modulator of AMPA/kainate receptors, shifted the dose-response curve of riluzole to the right (ED(50)=1.78 against tonus and 2.58 mg kg(-1) vs. clonus). The data indicate that riluzole is an effective anticonvulsant drug in the genetic model of seizure-prone DBA/2 mice. Our findings suggest that the anticonvulsant properties of riluzole depend upon its interaction with neurotransmission mediated by both the glycine/NMDA and the AMPA/kainate receptor complex.
De Sarro
G
G
Department of Experimental and Clinical Medicine, Faculty of Medicine and Surgery, University of Catanzaro Magna Graecia, Policlinico Mater Domini, Via T. Campanella, 88100 Catanzaro, Italy. desarro@unicz.it
Siniscalchi
A
A
Ferreri
G
G
Gallelli
L
L
De Sarro
A
A
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018091:Receptors, AMPA / Q000187:drug effects*; D018009:Receptors, Glycine / Q000187:drug effects / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D019782:Riluzole / Q000494:pharmacology*; D012640:Seizures / Q000517:prevention & control
D000927:Anticonvulsants; D018091:Receptors, AMPA; D018009:Receptors, Glycine; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D019782:Riluzole