Validation of a rodent model of Parkinson's Disease: evidence of a therapeutic window for oral Sinemet.
Behavioral measures of parkinsonism that are more clinically relevant than rotometry have been developed for rats with severe unilateral dopamine depletions, and the validity of these measures is supported by reports that these parkinsonian symptoms are attenuated by drugs that are effective in the clinical setting. Although the therapeutic gold standard, L-DOPA:carbidopa (Sinemet), effectively attenuates parkinsonian symptoms, the beneficial effects of this drug are limited by the dyskinesias that it produces at higher doses. The range of effective doses, from the minimum dose that produces beneficial effects to the dose that produces intolerable dyskinesias, is referred to as the "therapeutic window." It would be extremely valuable to assess, preclinically, the effects of novel treatments on the therapeutic window for Sinemet. The results of the present study support the validity of nondrug-induced measures of parkinsonian symptoms in dopamine-depleted rats. Neurological measures revealed large behavioral deficits in the affected forelimb analogous to the deficits exhibited in Parkinson's disease patients, and these deficits were significantly attenuated with some doses of oral Sinemet (30-40 mg/kg). These drug effects on measures of parkinsonism were specific to performance with the affected limb. At slightly higher doses (50 mg/ kg), the rats were untestable due to severe dyskinesias. The results of the present study suggest that it is possible to investigate the therapeutic potential of novel treatments as well as their effects on the therapeutic window of oral Sinemet in this rodent model of Parkinson's disease.
Lindner
M D
MD
CytoTherapeutics, Inc., Provicence, RI 02906, USA. MLINDNER@CTYO.COM
Plone
M A
MA
Francis
J M
JM
Emerich
D F
DF
D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D002230:Carbidopa / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004409:Dyskinesia, Drug-Induced / Q000209:etiology; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D010302:Parkinson Disease, Secondary / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013239:Stereotyped Behavior / Q000187:drug effects
D000978:Antiparkinson Agents; D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa