G. De Sarro et al., NMDA and AMPA/kainate receptors are involved in the anticonvulsant activity of riluzole in DBA/2 mice, EUR J PHARM, 408(1), 2000, pp. 25-34
The anticonvulsant activity of riluzole against sound-induced seizures was
studied in the DBA/2 mouse model. Riluzole (0.1-4 mg kg(-1), intraperitonea
l (i.p.)) produced dose-dependent effects with ED50 values for the suppress
ion 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 (N
MDA) with ED50 values of 3.03 and 5.0 mg kg(-1) for tonus and clonus, respe
ctively. Pretreatment with glycine, an agonist to the glycine/NMDA receptor
s, shifted the dose-response effect of riluzole to the right (ED50 = 6.53 a
gainst tonus and 9.34 mg kg(-1) vs, clonus). Similarly, D-serine, an agonis
t at the glycine site, shifted the ED50 of riluzole against the tonic compo
nent 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 induc
ed by administration of alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropioni
c acid (AMPA), an AMPA/kainate receptor agonist (ED50 = 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 do
se-response curve of riluzole to the right (ED50 = 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 f
indings suggest that the anticonvulsant properties of riluzole depend upon
its interaction with neurotransmission mediated by both the glycine/NMDA an
d the AMPA/kainate receptor complex. (C) 2000 Elsevier Science B.V. All rig
hts reserved.