GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR-LEVODOPA INTERACTIONS ANDREDUCTION OF SIDE-EFFECTS IN PARKINSONIAN MONKEYS

Glial cell line-derived neurotrophic factor (GDNF) stimulates the nigr ostriatal dopaminergic pathway and improves motor functions in animal models of parkinsonism. Sinemet is currently the most widely used drug for treating Parkinson's disease. The present study has evaluated GDN F-Sinemet interactions in parkinsonian rhesus monkeys. Both GDNF and S inemet, when given alone, significantly improved total parkinsonian sc ores, The response to Sinemet did not change after intracerebroventric ular vehicle injections. In contrast, there was a Functional interacti on between GDNF and levodopa. When comparing the levodopa dose respons e before and after GDNF treatment, significant behavioral improvements were seen after trophic factor administration at every levodopa dose Level except 500 mg. Adverse responses to Sinemet treatment alone in p arkinsonian animals included vomiting, dykinesias, dystonias, and ster eotypic movements. Combined GDNF-Sinemet treatment significantly reduc ed the occurrence of these levodopa-induced side effects, with a >90% decrease in adverse responses seen at the mid-Sinemet (250 mg levodopa -25 mg carbidopa) dose level, The only side effect from GDNF treatment was a transitory weight loss, Thus, combined GDNF-Sinemet treatment c ould be of therapeutic value in treating parkinsonism, by producing a greater Functional response and by mitigating adverse responses to Sin emet treatment.