Polyamines in a genetic animal model of paroxysmal dyskinesia.
Previous studies suggested that glutamatergic overactivity contributes to the manifestation of dystonia in the dt(sz) mutant hamster, a model of idiopathic paroxysmal dyskinesia in which dystonic episodes occur in response to mild stress. Therefore, the role of polyamines, known as positive modulators of NMDA receptors, was examined in the present study. The levels of polyamines (putrescine, spermidine, spermine) were determined in forebrain, cerebellum and brainstem in dt(sz) hamsters at an age of most marked expression of dystonia (32 days) and in age-matched non-dystonic control hamsters. Spermine was found to be significantly increased in the forebrain (35%) of dystonic animals, while spermidine was unaltered in dystonic brains and only a moderate increase in putrescine (12%) was detected in the cerebellum of dt(sz) mutants. In view of enhanced spermine levels, the effect of the putative polyamine receptor antagonist ifenprodil on the severity of dystonia was examined in dystonic hamsters. Ifenprodil (5-40 mg/kg i.p.) failed to exert a beneficial effect, but even aggravated dystonia in the dt(sz) mutant at higher doses. These data together with previous pharmacological findings in mutant hamsters do not completely exclude a pathophysiological role of enhanced polyamine levels but suggest that overstimulation of NMDA receptors which contain NR2B subunits by enhanced spermine levels is not involved in the dystonic syndrome.
Richter
Angelika
A
Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Free University Berlin, Koserstrasse 20, D-14195 Berlin, Germany. richtera@zedat.fu-berlin.de
Morrison
Lesley D
LD
D000375:Aging; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D016022:Case-Control Studies; D002819:Chorea / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000188:drug therapy; D018683:Excitatory Amino Acid Agents / Q000627:therapeutic use; D009154:Mutation; D010880:Piperidines / Q000627:therapeutic use; D011073:Polyamines / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology; D012720:Severity of Illness Index
D018683:Excitatory Amino Acid Agents; C121001:NR2B NMDA receptor; D010880:Piperidines; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; C010739:ifenprodil