Trophic factor distribution predicts functional recovery in Parkinsonian monkeys

Don M. Gash, Zhiming Zhang, Yi Ai, Richard Grondin, Robert Coffey, Greg A. Gerhardt

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)224-233
Number of pages10
JournalAnnals of Neurology
Volume58
Issue number2
DOIs
StatePublished - Aug 2005

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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