Increased levels of kynurenic acid in brains of genetically dystonic hamsters.
Recent pharmacological studies have shown antidystonic effects of NMDA and non-NMDA receptor antagonists in an inbred line of Syrian hamsters (dt(sz)) with primary generalized dystonia, i.e. a neurological syndrome of sustained muscle contractions which occurs in the absence of any pathomorphological alterations. This prompted us to examine the levels of kynurenic acid (KYNA), the endogenous broad spectrum antagonist of the excitatory amino acid receptors. The concentrations of KYNA were determined by HPLC in forebrain, cerebellum, brainstem and plasma in dystonic hamsters and age-matched non-dystonic controls. Dystonia in mutant hamsters is transient and disappears completely at the age of 70 days. In order to examine if neurochemical changes are associated with dystonia, KYNA was determined at the age of maximum severity (30 days) and after remission (70 days). The levels of KYNA were significantly increased in forebrain, cerebellum and brainstem (37-130 percent) in dystonic hamsters at the age of maximum severity of dystonia (30 days of life) compared to both a genetically related non-dystonic inbred line and a non-related outbred line of hamsters. The increase of KYNA in brain regions was accompanied by enhanced plasma levels. However, there was no correlation between brain and plasma levels. Since the changes in KYNA levels disappeared in parallel with dystonia (70 days), the present data provide further evidence that abnormal activity of excitatory amino acids may be pathogenetically involved in dystonia in mutant hamsters. With regard to the recent finding of antidystonic effects of glutamate receptor antagonists the increased levels of kynurenic acid may be interpreted as a counteracting process to an overactivity of the glutamatergic system.
Richter
A
A
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Loscher
W
W
Baran
H
H
Gramer
M
M
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D004421:Dystonia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000097:blood / Q000378:metabolism*; D007736:Kynurenic Acid / Q000097:blood / Q000378:metabolism*; D008647:Mesocricetus; D009154:Mutation; D009929:Organ Size; D009994:Osmolar Concentration; D012016:Reference Values; D014018:Tissue Distribution
D018691:Excitatory Amino Acid Antagonists; D007736:Kynurenic Acid