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B6.4 TOPICAL APPLICATION OF NEUROIMMUNOPHILIN LIGAND ANALOGS INDUCES ANAGEN HAIR GROWTH IN C57BL/6J MICE. Marna Ericson, Anna Guanche, Joseph P Steiner*, John Sundberg**, Maria Hordinsky Dept. of Dermatology, U of MN, Minneapolis, MN; Guilford Pharmaceuticals, Inc. Baltimore, MD, **The Jackson Laboratory, Bar Harbor, ME. Topical application of FK506 is associated with hair growth in C57BL/6J telogen mice and in two animal models of alopecia areata, the C3H/HeJ mouse and the Dundee Experimental Bald Rat. This hair growth has been attributed to the immunosuppressive effect of FK506. However, this immunophilin ligand also has neurotrophic effects as FK506 binds to FK Binding Protein-12 (FKBP-12), a cytosolic protein found in both the central and peripheral nervous systems as well as in the immune system. One of our aims is to understand neuronal involvement in hair growth. In this study, we examined the effects of topically applied FK506 and neurotrophic immunophilin ligands, GPI1046 and GPI1511 (Guilford Pharmaceuticals, Baltimore, MD), analogs of FK506, on hair growth in the C57BL/6J mouse model. Both GPI1046 and GPI1511 bind to FKBP-12, as does FK506. However, in contrast to FK506, the analogs lack immunosuppressive capability.Drug was applied 3 times per week for 42 days to mice separated into the following treatment groups: 1 mol-GPI1511, 1 mol-GPI1046, 6 mol-GPI1046, 6 mol GPI1511, 1 mol FK506, vehicle (EtOH) and shaving only. We found that FK506 initiated onset of anagen hair growth within 11 days of application. GPI1046 and GPI1511 also initiated anagen hair growth but not as quickly as FK506. At 42 days of treatment, anagen hair growth was greatest with topically applied 1 mol-GPI1511, 1 mol-GPI1046, and 6 mol-GPI1046 vs. 6 mol GPI1511, 1 mol FK506, vehicle (EtOH) and shaving only. At Day 42, percent hair coverage of the treated area was higher in the GPI1046-, and GPI1511-treated mice as compared to the mice in the FK506, EtOH- or shaved-only groups. GPI1046 and GPI1511 were shown to be pharmacologically active in this assay and showed a similar but delayed onset of anagen hair growth, as did FK506. Both ligands also demonstrated better hair regrowth at the conclusion of the study as compared to FK506. Our results suggest that the peripheral nervous system is important to hair growth in this model. We have recently completed a pilot study evaluating the application of these ligands on xenografts (full thickness human skin grafts from male androgenetic alopecia patients) onto immunodeficient mice. The results of these experiments are currently being evaluated in context of data obtained with topical application of neuroimmunophilin ligand analogs and FK506 to C57BL/6J mice. |
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