Rapamycin, but not FK506 and GPI-1046, increases neurite outgrowth in PC12cells by inhibiting cell cycle progression

Immunophilin ligands such as rapamycin, FK506 and GPI-1046 have been report ed to increase neurite outgrowth in vitro and to have neuroprotective activ ity in vitro and in vivo. In this study, however, FK506 and GPI-1046 (0.1-1 000 nM) had little effect on neurite outgrowth in PC12 cells in either the presence or absence of nerve growth factor. In contrast, rapamycin markedly increased neurite outgrowth in PC12 cells in the presence of a low concent ration of nerve growth factor (EC50=10 nM). Unlike FK506 and GPI-1046, rapa mycin is an inhibitor of cell cycle progression. Other cell cycle inhibitor s such as ciclopirox and flavopir-idol also increased neurite outgrowth in PC12 cells in the presence of a low concentration of nerve growth factor (E C50=250 nM and 100 nM, respectively). The neuroprotective effects of FK506, rapamycin and GPI-1046 were also tested in a rodent model of permanent foc al cerebral ischemia. FK506 and rapamycin decreased infarct volume by 40% a nd 37%, respectively, whereas GPI-1046 was ineffective. These data do not s upport the previous suggestion that FK506 and GPI-1046 increase neurite out growth of PC12 cells in vitro. Rapamycin increases neurite outgrowth of PC1 2 cells, an effect that can be ascribed to its ability to inhibit cell cycl e progression. The neuroprotective effect of FK506 and rapamycin against ce rebral ischemia is probably not due to differentiation of neuronal precurso rs or stimulation of neuronal regeneration. (C) 2000 Elsevier Science Ltd. All rights reserved.