title: Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models.
abstract: 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.
authors.affiliation: Department of Neurobiological Research, Guilford Pharmaceuticals Inc., Baltimore, MD 21224, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Steiner
authors.forename: G S
authors.initials: GS
authors.lastname: Hamilton
authors.forename: D T
authors.initials: DT
authors.lastname: Ross
authors.forename: H L
authors.initials: HL
authors.lastname: Valentine
authors.forename: H
authors.initials: H
authors.lastname: Guo
authors.forename: M A
authors.initials: MA
authors.lastname: Connolly
authors.forename: S
authors.initials: S
authors.lastname: Liang
authors.forename: C
authors.initials: C
authors.lastname: Ramsey
authors.forename: J H
authors.initials: JH
authors.lastname: Li
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.forename: P
authors.initials: P
authors.lastname: Howorth
authors.forename: R
authors.initials: R
authors.lastname: Soni
authors.forename: M
authors.initials: M
authors.lastname: Fuller
authors.forename: H
authors.initials: H
authors.lastname: Sauer
authors.forename: A C
authors.initials: AC
authors.lastname: Nowotnik
authors.forename: P D
authors.initials: PD
authors.lastname: Suzdak
mesh_terms: 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
chemical_list: 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