Differential in vivo effects of neurturin and glial cell-line-derived neurotrophic factor.
Glial cell-line derived neurotrophic factor (GDNF) and neurturin (NTN) are structurally homologous, and they seem to produce similar effects in vitro. Tissue distributions of their respective receptors, GFR alpha-1 and GFR alpha-2, reveal overlapping but distinct patterns of expression, which implies that the in vivo actions of GDNF and NTN may be different. In the present study, a direct comparison of the in vivo effects of GDNF and NTN was performed using osmotic minipumps delivering either GDNF or NTN over a 30-day period into rat lateral cerebral ventricles. Amphetamine-induced activity levels were increased in both NTN- and GDNF-treated animals, with higher activity levels achieved by GDNF than NTN. The increase in amphetamine-induced activity levels persisted for 2 weeks and returned to control levels at the end of the third week. NTN-treated rats showed higher dopamine levels in the mediodorsal striatum, relative to the ventrolateral striatum. In contrast, no significant change in the regional distribution of dopamine levels was observed in GDNF treated or control animals. On the other hand, an increase in ventrolateral and mediodorsal striatal dopamine utilization was apparent in GDNF-treated animals, while NTN-treated animals showed increased levels of dopamine utilization only in the ventrolateral striatum. With respect to potential adverse effects, GDNF administration resulted in weight loss and the emergence of allodynia. No weight loss or allodynia was detectable with chronic NTN administration. These results suggest that although GDNF and NTN share structural and functional similarities, they may have differential effects in vivo.
Hoane
M R
MR
CytoTherapeutics, Inc., Lincoln, Rhode Island 02865, USA.
Gulwadi
A G
AG
Morrison
S
S
Hovanesian
G
G
Lindner
M D
MD
Tao
W
W
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D007276:Injections, Intraventricular; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D051101:Neurturin; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D029721:Drosophila Proteins; C495041:Gdnf protein, rat; C494989:Gfra1 protein, rat; C494992:Gfra2 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D051101:Neurturin; C495057:Nrtn protein, rat; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D000661:Amphetamine; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D004298:Dopamine