Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models

• DOI: 10.1073/pnas.94.5.2019
• Publication Date: 2002-07-26T14:31:39Z
• Authors: Joseph P. Steiner; Gregory S. Hamilton; Douglas T. Ross; Heather L. Valentine; Hongzhi Guo; Maureen A. Connolly; Shi Liang; Cynthia Ramsey; Jia-He J. Li; Wei Huang; Pamela Howorth; Rajat Soni; Michael Fuller; Hans Sauer; Alison C. Nowotnik; Peter D. Suzdak
• Keywords: Neurite; Sprouting

Although immunosuppressant immunophilin ligands promote neurite outgrowth in vitro, their neurotrophic activities are clearly independent of immunosuppressive activity. In the present report, a novel nonimmunosuppressive ligand, GPI-1046 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate+ ++) is described. bound to FK506 binding protein-12 and elicited from sensory neuronal cultures with picomolar potency maximal effects comparable nerve growth factor. vivo, stimulated regeneration lesioned sciatic axons myelin levels. central nervous system, promoted protection and/or sprouting serotonin-containing fibers somatosensory cortex following parachloroamphetamine treatment. also induced regenerative spared nigrostriatal dopaminergic neurons 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity mice or 6-hydroxydopamine (6-OHDA) rats. The rotational abnormality 6-OHDA treated rats was alleviated by GPI-1046. These actions multiple models suggest therapeutic utility for neurodegenerative diseases.