Effects of intrastriatal GDNF on the response of dopamine neurons to 6-hydroxydopamine: time course of protection and neurorestoration.
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 (9μg) or its vehicle. Six hours later, animals received 6-OHDA (4 μg) 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.
Pittsburgh Institute for Neurodegenerative Diseases and Center for Neuroscience, University of Pittsburgh, PA, USA.
Ann D
AD
Cohen
Michael J
MJ
Zigmond
Amanda D
AD
Smith
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents