Prodystonic effects of riluzole in an animal model of idiopathic dystonia related to decreased total power in the red nucleus?
The effects of riluzole (2-amino-6-trifluoromethoxy benzothiazole) on the severity of dystonia were examined in mutant hamsters (dtsz), an animal model of idiopathic dystonia in which dystonic attacks can be age dependently induced by mild stress. Previous studies in hamsters have shown antidystonic activity of various glutamate receptor antagonists whereas lamotrigine, considered as an inhibitor of glutamate release, exerted prodystonic effects. The latter, unexpected, finding prompted us to investigate riluzole which is thought to possess antiglutamatergic properties with mechanisms similar to those of lamotrigine. Riluzole (2, 5, 10 or 20 mg/kg i.p.) dose dependently decreased the latency to onset of dystonic attacks. A dose of 10 or 20 mg/kg significantly increased the severity of dystonia. Even in dtsz hamsters older than 70 days, i.e., after spontaneous remission of age-dependent dystonia, riluzole (10 or 20 mg/kg) provoked severe long-lasting (> 4 h) dystonic attacks. At a dose of 20 mg/kg, riluzole provoked short-lasting (< 1 h) dystonic disturbances also in non-dystonic control hamsters. Electroencephalographic recordings from depth electrodes in the red nucleus, where recent studies have shown abnormal neural activity before and during dystonic attacks in dtsz hamsters, revealed that riluzole (10 mg/kg) tended to cause a further decrease of the total power in dtsz hamsters and significantly reduced the total power in control animals. This finding may indicate that the prodystonic effects of riluzole are related to alterations of rubrospinal activity. With regard to antidystonic effects of glutamate receptor antagonists demonstrated in previous studies, the prodystonic effects of riluzole and, as shown by recent experiments, of lamotrigine also, may be due to the lack of selectivity of these drugs to inhibit glutamate release.
Richter
A
A
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany. arichter@pharma.tiho-hannover.de
Gernert
M
M
Löscher
W
W
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006224:Cricetinae; D004195:Disease Models, Animal; D004421:Dystonia / Q000139:chemically induced*; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D000077213:Lamotrigine; D018696:Neuroprotective Agents / Q000494:pharmacology; D019782:Riluzole / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology
D000978:Antiparkinson Agents; D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D014227:Triazines; D018698:Glutamic Acid; D019782:Riluzole; D000077213:Lamotrigine