Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys.
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 micro g/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.
Grondin
Richard
R
Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Rm. 305 Davis Mills Building, 800 Rose Street, Lexington, KY, USA. rcgron0@pop.uky.edu
Zhang
Zhiming
Z
Yi
Ai
A
Cass
Wayne A
WA
Maswood
Navin
N
Andersen
Anders H
AH
Elsberry
Dennis D
DD
Klein
Michael C
MC
Gerhardt
Greg A
GA
Gash
Don M
DM
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000502:physiology; D004334:Drug Administration Schedule; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006719:Homovanillic Acid / Q000378:metabolism; D007260:Infusion Pumps; D007276:Injections, Intraventricular; D008253:Macaca mulatta; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine; D006719:Homovanillic Acid