Effect of 6-hydroxydopamine on striatal GDNF and nigral GFRalpha1 and RET mRNAs in the adult rat.
Exogenous GDNF as well as vectors containing the gene for this trophic factor has been shown to be neuroprotective in animal models of Parkinson's disease. We therefore investigated whether changes in striatal GDNF protein and nigral mRNA levels of its co-receptors GFRalpha1 and RET occur in response to lesions of dopamine (DA) neurons and examined the temporal profile of these changes as they relate to the loss of dopaminergic markers. Rats were lesioned with 6-hydroxydopamine and sacrificed 3 h to 60 days post-infusion. DA tissue levels in the striatum and tyrosine hydroxylase immunoreactivity in the substantia nigra (SN) and ventral tegmental area (VTA) were used to determine the size of the lesions. GDNF protein was measured in the striatum using radioimmunocytochemistry. In situ hybridization was used to determine alterations in the mRNAs of RET and GFRalpha1 in the SN and VTA. We observed no persistent changes in GDNF protein in the striatum in response to 6-hydroxydopamine over the 60-day observation period, suggesting that compensatory changes in this trophic factor do not occur in response to injury. Dramatic decreases in RET and GFRalpha1 were observed in both SN and VTA that were generally correlated with the loss of TH protein and striatal DA content, strongly suggesting that these receptors are located on DA neurons and that the protective effect of GDNF reflects a direct action of the trophic factor on these neurons.
Smith
Amanda D
AD
Department of Neurology, University of Pittsburgh, S-510 Biomedical Science Tower, Pittsburgh, PA 15213, USA. smithad@pitt.edu
Antion
Marci
M
Zigmond
Michael J
MJ
Austin
Mark C
MC
D000818:Animals; D001345:Autoradiography; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D007839:Functional Laterality; D051100:Glial Cell Line-Derived Neurotrophic Factor; D021621:Imaging, Three-Dimensional; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D013565:Sympatholytics / Q000494:pharmacology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
D029721:Drosophila Proteins; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D013565:Sympatholytics; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila