Effects of intrastriatal GDNF on the response of dopamine neurons to 6-hydroxydopamine: Time course of protection and neurorestoration

被引:35
作者
Cohen, Ann D. [2 ]
Zigmond, Michael J. [2 ]
Smith, Amanda D. [1 ,2 ,3 ]
机构
[1] Univ Pittsburgh, Dept Neurol, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Ctr Neurosci, Pittsburgh, PA 15213 USA
[3] VA Pittsburgh Healthcare Ctr, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA
关键词
Neuroprotection; Oxidative stress; Parkinson's disease; Striatum; Substantia nigra; Glial cell line derived neurotrophic factor; NEUROTROPHIC FACTOR GDNF; TYROSINE-HYDROXYLASE PHOSPHORYLATION; PARTIAL LESION MODEL; CELL-LINE; PARKINSONS-DISEASE; IN-VIVO; SUBSTANTIA-NIGRA; EXTRACELLULAR DOPAMINE; FACTOR PROMOTES; MESSENGER-RNAS;
D O I
10.1016/j.brainres.2010.11.006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Glial cell line-derived neurotrophic factor (GDNF) protects dopamine (DA) neurons from 6-hydroxydopamine (6-OHDA) toxicity. We have now explored this protection over 8 weeks following toxin administration. Infusion of Fluoro-Gold (FG) into the striatum was followed 1 week later by GDNF (9 mu g) or its vehicle. Six hours later, animals received 6-OHDA (4 mu g) into the same site. 6-OHDA caused a loss of cells in the substantia nigra that expressed both FG and tyrosine hydroxylase (TH) and striatal terminals expressing TH, the high affinity dopamine transporter (DAT), and the vesicular monoamine transporter 2 (VMAT2) as assessed 2-8 weeks later. Loss of FG(+) cells, and striatal DA was completely blocked by GDNF by 2 weeks. In contrast, GDNF only slightly attenuated the loss of TH, DAT, or VMAT2 in the striatum at 2 weeks, but had restored these markers by 4-8 weeks. Thus, GDNF prevents DA cell death and loss of striatal DA content, but several weeks are required to fully restore the dopaminergic phenotype. These results provide insight into the mechanism of GDNF protection of DA neurons, and may help avoid incorrect interpretations of temporary phenotypic changes. (C) 2010 Elsevier B.V. All rights reserved.
引用
收藏
页码:80 / 88
页数:9
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