NEUROTROPHIC ACTIONS OF NONIMMUNOSUPPRESSIVE ANALOGS OF IMMUNOSUPPRESSIVE DRUGS FK506, RAPAMYCIN AND CYCLOSPORINE-A

We show that the nonimmunosuppressive analogues of the immunosuppressi ve drugs FK506, rapamycin and cyclosporin A promote neurite outgrowth both in PC12 cells and sensory neuronal cultures of dorsal root gangli a with potencies resembling their immunosuppressive homologues. Neurot rophic potencies of the immunophilin ligands resemble their potencies in binding to and inhibiting the rotamase activity of FKBP-12 or cyclo philin. Since nonimmunosuppressive immunophilin ligands, which are dev oid of calcineurin inhibitory activity, are equally neurotrophic, inhi bition of calcineurin activity is not the mediator of the neurotrophic effects. The immunophilin ligands are neurotrophic in intact animals. FK506 and L-685,818 (the C18-hydroxy, C21-ethyl derivative of FK506) treatment of rats with crushed sciatic nerves enhances both functional and morphologic recovery. The striking potency of these agents, their bioavailability and the dissociation of neurotrophic from immunosuppr essant actions argue for their therapeutic relevance in the treatment of neurodegenerative diseases.