Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced Parkinsonian monkeys

Richard Grondin, Zhiming Zhang, Ai Yi, Wayne A. Cass, Navin Maswood, Anders H. Andersen, Dennis D. Elsberry, Michael C. Klein, Greg A. Gerhardt, Don M. Gash

Research output: Contribution to journalArticlepeer-review

244 Scopus citations

Abstract

The powerful trophic effects that glial cell line-derived neurotrophic factor (GDNF) exerts on midbrain dopamine neurones suggest its use in treating Parkinson's disease. However, some important questions remain about the possible therapeutic applications of GDNF. Here we demonstrate that the chronic infusion of 5 or 15 gg/day GDNF into the lateral ventricle or the striatum, using programmable pumps, promotes restoration of the nigrostriatal dopaminergic system and significantly improves motor functions in rhesus monkeys with neural deficits modelling the terminal stages of Parkinson's disease. The functional improvements were associated with pronounced upregulation and regeneration of nigral dopamine neurones and their processes innervating the striatum. When compared with vehicle recipients, these functional improvements were associated with (i) >30% bilateral increase in nigral dopamine neurone cell size; (ii) >20% bilateral increase in the number of nigral cells expressing the dopamine marker tyrosine hydroxylase; (iii) >70 and >50% bilateral increase in dopamine metabolite levels in the striatum and the pallidum, respectively; (iv) 233 and 155% increase in dopamine levels in the periventricular striatal region and the globus pallidus, respectively, on the lesioned side; and (v) a five-fold increase in tyrosine hydroxylase-positive fibre density in the periventricular striatal region on the lesioned side. In addition, chronic GDNF treatment did not induce the side-effects generally associated with chronic administration of levodopa, the most widely used treatment for Parkinson's disease. Thus, the results suggest that the prolonged and controlled delivery of GDNF into the brain could be used to intervene in long-term neurodegenerative disease processes like Parkinson's disease. Additional studies are required to determine the potential differences between chronic, intraventricular and intraputamenal (or intranigral) delivery of GDNF to maximize the efficacy of infusion treatments.

Original languageEnglish
Pages (from-to)2191-2201
Number of pages11
JournalBrain
Volume125
Issue number10
DOIs
StatePublished - Oct 1 2002

Bibliographical note

Funding Information:
We wish to thank Robin Avison, Tracy Barber, LiYa Liu, Erin Manning, Melody Smith, Sherry Bailey, Michael Harned and Michael Manning for technical support with collecting the data. We also thank Susan Tucker for artwork. Supported by USPHS NIH grants NS39787, AG13494 and MH01245. R.G. was supported by a postdoctoral fellowship award from the Fond de la Recherche en Santé du Québec (FRSQ).

Keywords

  • Dopamine neurones
  • GDNF
  • Non-human primates
  • Parkinson's disease
  • Regeneration

ASJC Scopus subject areas

  • Clinical Neurology

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