Glial cell line-derived neurotrophic factor-levodopa interactions and reduction of side effects in parkinsonian monkeys.
Glial cell line-derived neurotrophic factor (GDNF) stimulates the nigrostriatal 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 GDNF-Sinemet interactions in parkinsonian rhesus monkeys. Both GDNF and Sinemet, when given alone, significantly improved total parkinsonian scores. The response to Sinemet did not change after intracerebroventricular vehicle injections. In contrast, there was a functional interaction between GDNF and levodopa. When comparing the levodopa dose response 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 parkinsonian animals included vomiting, dykinesias, dystonias, and stereotypic movements. Combined GDNF-Sinemet treatment significantly reduced 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 could be of therapeutic value in treating parkinsonism, by producing a greater functional response and by mitigating adverse responses to Sinemet treatment.
Miyoshi
Y
Y
Department of Anatomy and Neurobiology, University of Kentucky, College of Medicine, Lexington, USA.
Zhang
Z
Z
Ovadia
A
A
Lapchak
P A
PA
Collins
F
F
Hilt
D
D
Lebel
C
C
Kryscio
R
R
Gash
D M
DM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D002230:Carbidopa / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007276:Injections, Intraventricular; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D008253:Macaca mulatta; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D013239:Stereotyped Behavior / Q000187:drug effects
D000978:Antiparkinson Agents; D004338:Drug Combinations; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D002230:Carbidopa