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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2019-2024
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number5
DOIs
StatePublished - Mar 4 1997

Keywords

  • FK506
  • calcineurin
  • cyclophilin
  • cyclosporin A
  • dopamine

ASJC Scopus subject areas

  • General

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