Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models.
Although immunosuppressant immunophilin ligands promote neurite outgrowth in vitro, their neurotrophic activities are clearly independent of their immunosuppressive activity. In the present report, a novel nonimmunosuppressive immunophilin ligand, GPI-1046 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate+ ++) is described. In vitro, GPI-1046 bound to FK506 binding protein-12 and elicited neurite outgrowth from sensory neuronal cultures with picomolar potency with maximal effects comparable to nerve growth factor. In vivo, GPI-1046 stimulated the regeneration of lesioned sciatic nerve axons and myelin levels. In the central nervous system, GPI-1046 promoted protection and/or sprouting of serotonin-containing nerve fibers in somatosensory cortex following parachloroamphetamine treatment. GPI-1046 also induced regenerative sprouting from spared nigrostriatal dopaminergic neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice or 6-hydroxydopamine (6-OHDA) toxicity in rats. The rotational abnormality in 6-OHDA treated rats was alleviated by GPI-1046. These neurotrophic actions in multiple models suggest therapeutic utility for GPI-1046 in neurodegenerative diseases.
Steiner
J P
JP
Department of Neurobiological Research, Guilford Pharmaceuticals Inc., Baltimore, MD 21224, USA.
Hamilton
G S
GS
Ross
D T
DT
Valentine
H L
HL
Guo
H
H
Connolly
M A
MA
Liang
S
S
Ramsey
C
C
Li
J H
JH
Huang
W
W
Howorth
P
P
Soni
R
R
Fuller
M
M
Sauer
H
H
Nowotnik
A C
AC
Suzdak
P D
PD
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002645:Chickens; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects; D009422:Nervous System Diseases / Q000188:drug therapy*; D016501:Neurites / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D016559:Tacrolimus / Q000378:metabolism / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D015259:Dopamine Agents; C104949:GPI 1046; D006360:Heat-Shock Proteins; D011759:Pyrrolidines; D012701:Serotonin; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus