A novel immunophilin ligand: distinct branching effects on dopaminergic neurons in culture and neurotrophic actions after oral administration in an animal model of Parkinson's disease.
Protection or regeneration of the dopaminergic (DA) system would be of significant therapeutic value for Parkinson's disease. Immunophilin ligands, such as FK506, can produce neurotrophic effects in vitro and in vivo, but their immunosuppressive effects make them unsuitable for neurological application. This study demonstrates that a novel, nonimmunosuppressive immunophilin ligand (V-10,367) increased the number of neurites extended by tyrosine hydroxylase positive (TH+) DA neurons in embryonic day 14 primary DA neuronal cultures. In contrast, the immunosuppressive immunophilin ligand FK506 increased the length of TH+ neurites. After oral administration in MPTP-treated mice, V-10,367 completely protected against MPTP-induced loss of striatal TH+ axonal density, while FK506 did not. These experiments demonstrate that nonimmunosuppressive immunophilin ligands specifically increase neurite branching in primary DA neuronal culture and possess neurotrophic actions in vivo with potential application to neurodegenerative disease.
Costantini
L C
LC
Neuroregeneration Laboratory, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02178, USA. Costanti@helix.mgh.harvard.edu
Chaturvedi
P
P
Armistead
D M
DM
McCaffrey
P G
PG
Deacon
T W
TW
Isacson
O
O
D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D020104:Immunophilins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008024:Ligands; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000187:drug effects / Q000201:enzymology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D007166:Immunosuppressive Agents; D008024:Ligands; D011725:Pyridines; C108850:V 10367; D014446:Tyrosine 3-Monooxygenase; D020104:Immunophilins; D004298:Dopamine