Heparin-binding determinants of GDNF reduce its tissue distribution but are beneficial for the protection of nigral dopaminergic neurons.
Glial cell line-derived neurotrophic factor (GDNF) protects and repairs dopamine neurons. It binds to GDNF family receptor alpha1 (GFRalpha1) and activates receptor tyrosine kinase. Heparan sulphate proteoglycans (HSPGs) also participate in the signalling of GDNF, though binding to HS may hinder the diffusion of infused GDNF. We assessed the importance of heparin-binding determinants in the neuroprotective effects of GDNF in the 6-OHDA rat model of Parkinson's disease. We utilized a truncated, non-heparin-binding Delta38N-GDNF or combined wtGDNF with heparin-binding growth-associated molecule (HB-GAM, pleiotrophin). Tissue diffusion of wtGDNF+/-HB-GAM and Delta38N-GDNF was also compared. A protective effect against ipsilateral d-amphetamine-induced turning was seen with 10 microg wtGDNF, 17 microg HB-GAM+10 microg wtGDNF or 10 microg Delta38N-GDNF at 8 weeks post lesion. This effect was most pronounced with wtGDNF alone. HB-GAM (17 or 50 microg) also reduced rotational behaviour, but did not protect dopaminergic cells. Otherwise, the survival of TH-positive cells in the substantia nigra correlated with the behavioural data. Although Delta38N-GDNF was more widely distributed than wtGDNF (irrespective of its origin), stable in a brain extract, and potent in mitogen-activated kinase assay, it was inferior in vivo. The results imply that GDNF binding to HSs is needed for the optimum neuroprotective effect.
Piltonen
Marjo
M
Division of Pharmacology and Toxicology, Faculty of Pharmacy, P.O. Box 56, FIN-00014 University of Helsinki, Finland. marjo.piltonen@helsinki.fi
Bespalov
Maxim M
MM
Ervasti
Dagmar
D
Matilainen
Tero
T
Sidorova
Yulia A
YA
Rauvala
Heikki
H
Saarma
Mart
M
Männistö
Pekka T
PT
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002352:Carrier Proteins / Q000627:therapeutic use; D016207:Cytokines / Q000627:therapeutic use; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D017384:Sequence Deletion / Q000235:genetics; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000473:pathology*; D014018:Tissue Distribution / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002352:Carrier Proteins; D016207:Cytokines; D051100:Glial Cell Line-Derived Neurotrophic Factor; C066845:pleiotrophin; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D020929:Mitogen-Activated Protein Kinase Kinases; D004298:Dopamine