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

被引:219
作者
Grondin, R
Zhang, ZM
Yi, A
Cass, WA
Maswood, N
Andersen, AH
Elsberry, DD
Klein, MC
Gerhardt, GA
Gash, DM
机构
[1] Univ Kentucky, Med Ctr, Dept Anat & Neurobiol, Lexington, KY 40536 USA
[2] Univ Kentucky, Med Ctr, Morris K Udall Parkinsons Dis Res Ctr Exellence, Lexington, KY 40536 USA
[3] Medtronic Inc, Medtron Neurol Div, Minneapolis, MN USA
[4] Amgen Inc, Thousand Oaks, CA 91320 USA
关键词
GDNF; Parkinson's disease; dopamine neurones; regeneration; non-human primates;
D O I
10.1093/brain/awf234
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 mug/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.
引用
收藏
页码:2191 / 2201
页数:11
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