ANALYSIS OF THE NEUROTROPHIC EFFECTS OF GPI-1046 ON NEURON SURVIVAL AND REGENERATION IN CULTURE AND IN-VIVO

The putative neurotrophic effects of the immunophilin ligand GPI-1046 were evaluated in established experimental systems of neuron survival and axon growth in vitro and in vivo. GPI-1046 marginally increased ne urite outgrowth of chick dorsal root ganglia in culture under conditio ns where a very robust effect of nerve growth factor was seen. GPI-104 6 failed to protect dopaminergic neurons from 1-methyl-1-phenylpyridin ium in culture or to protect cultured cortical neurons from experiment ally induced apoptosis in vitro. In adult rats in vivo, daily administ ration of GPI-1046 (10 mg/kg, s.c.) for three days enhanced the maxima l regeneration distance of both motor and large myelinated sensory axo ns measured using an electrophysiological assay. However, derailed mor phometric analysis of these animals failed to provide evidence for an increase in axon numbers in GPI-1046-treated animals. The ability of G PI-1046 to promote the recovery of dopaminergic function following uni lateral 6-hydroxydopamine lesions of the substantia nigra was also tes ted in rats. In the first study, the duration of amphetamine (3 mg/kg, s.c.)-induced circling, but not the maximal number of rotations, was significantly reduced in animals treated with GPI-1046 for five days ( 10 mg/k/day). In a second study, testing the effects of delayed GPI-10 46 administration, chronic treatment with GPI-1046 (10 mg/kg/day) for two weeks, beginning one month after surgery, did not alter circling r esponses. Morphometric analysis failed to reveal any changes in either the density of tyrosine hyroxylase-positive fibres in dopaminergic ta rget areas or in cell numbers in the substantia nigra in both experime nts. Thus, while GPI-1046 produced marginal effects on neurite outgrow th in dorsal root ganglia cultures and on functional paramaters of ner ve regeneration ill vivo; we failed to obtain evidence in support of t he notion of a general neuroprotective effect of the compound or for a n effect on morphologic nerve regeneration in vivo. (C) 1998 IBRO. Pub lished by Elsevier Science Ltd.