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

  1. Peter D. Suzdak*

    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.

    Footnotes

      • ↵ To whom reprint requests should be addressed.

      • Solomon Snyder, Johns Hopkins University School of Medicine, Baltimore, MD

    • ABBREVIATIONS

      GPI-1046,
      3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
      MPTP,
      1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;
      6-OHDA,
      6-hydroxy dopamine;
      TH,
      tyrosine hydroxylase;
      PCA,
      parachloroamphetamine;
      FKBP,
      FK506 binding protein;
      GAP-43,
      growth-associated protein of 43 kDa
      • Received December 1, 1996.
      • Accepted December 23, 1996.

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