Trophic factor distribution predicts functional recovery in parkinsonian monkeys.
Glial cell line-derived neurotrophic factor (GDNF) promotes the survival, growth, and regeneration of dopamine neurons in the midbrain that degenerate in Parkinson's disease. However, translating successful animal studies into effective clinical therapy for Parkinson's disease has proved difficult. In this article, using pulsed infusion for convection-enhanced delivery of GDNF, we have analyzed two variables hypothesized to be important for achieving efficacy: dose and GDNF distribution in the target tissue. Motor functions were significantly improved in rhesus monkeys with unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism that received midbrain infusion of GDNF for 10 weeks. The volume of distribution of GDNF in the five trophic factor recipients varied more than fivefold, from 59 to 325 mm3, and significantly correlated with motor function improvements. Significant increases were evident in the number of midbrain dopamine neurons immunopositive for tyrosine hydroxylase in both the substantia nigra and ventral tegmental area. Based on neurochemical and quantitative morphological measures, GDNF administration promoted recovery of both the nigrostriatal and ventral tegmental area-nucleus accumbens dopaminergic pathways without producing evident side effects. Increasing the dose threefold did not increase efficacy, suggesting that after achieving a critical threshold, GDNF tissue distribution is more important than dose for trophic stimulation of dopamine neurons.
Gash
Don M
DM
Department of Anatomy and Neurobiology and Morris K. Udall Parkinson's Disease Research Center of Excellence, University of Kentucky, Lexington, KY 40536-0098, USA. dongash@uky.edu
Zhang
Zhiming
Z
Ai
Yi
Y
Grondin
Richard
R
Coffey
Robert
R
Gerhardt
Greg A
GA
D000704:Analysis of Variance; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002452:Cell Count / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry / Q000379:methods; D020267:MPTP Poisoning / Q000188:drug therapy; D008253:Macaca mulatta; D008636:Mesencephalon / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors / Q000008:administration & dosage* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D020127:Recovery of Function; D012044:Regression Analysis; D012720:Severity of Illness Index; D014018:Tissue Distribution; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D014446:Tyrosine 3-Monooxygenase