Antiparkinsonian trophic action of glial cell line-derived neurotrophic factor and transforming growth factor β1 is enhanced after co-infusion in rats.
The objective was to analyze functional effects of the combination of GDNF and TGF-β1 in the retrograde model of Parkinsonism in rats, based on the intrastriatal infusion of 6-hydroxydopamine, which leads to protracted and progressive cell death in the substantia nigra. Hemiparkinsonian rats were implanted with osmotic minipumps 2 months after striatal lesion, pumps delivering GDNF alone (10 ng/day), TGF-β1 alone (2 ng/day), or a GDNF and TGF-β1 combination. The findings confirmed that GDNF alone has potent dopaminotrophic effects but they also revealed, for the first time, that GDNF and TGF-β1 co-infusion led to stronger trophic effects relative to the infusion of GDNF alone. TGF-β1 allowed further reducing dopamine receptor hypersensitivity, and potentiated GDNF-mediated effects. This cooperation could be accounted for by the recruitment of GFRα1 on striatal membranes, and by enhanced expression and activation of TH through augmented pSer31TH and pSer40TH. Co-infusion induced striatal sprouting, as revealed by augmentation of p21-Arc, stathmin, and synaptophysin, and led to a reliable recovery of phenotypic expression of TH in surviving nigral neurons. Functional recovery and improvement of TH signal in the nigrostriatal system were long-lasting and sustained, remaining after cessation of trophic infusion.
Gonzalez-Aparicio
Ramiro
R
Departamento de Fisiologia Medica y Biofisica, Universidad de Sevilla, Av. Sanchez Pizjuan 4, 41009 Sevilla, Spain.
Flores
Juan A
JA
Fernandez-Espejo
Emilio
E
D000465:Algorithms; D000661:Amphetamine; D000818:Animals; D000978:Antiparkinson Agents; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000494:pharmacology*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000096:biosynthesis; D007150:Immunohistochemistry; D015918:Infusion Pumps, Implantable; D008297:Male; D008845:Microinjections; D017072:Neostriatum; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior; D013565:Sympatholytics; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000494:pharmacology*
D000978:Antiparkinson Agents; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D013565:Sympatholytics; D053773:Transforming Growth Factor beta1; D016627:Oxidopamine; D000661:Amphetamine; D001058:Apomorphine