Immunophilin ligands can prevent progressive dopaminergic degeneration in animal models of Parkinson's disease

Slowing or halting the progressive dopaminergic (DA) degeneration in Parkin son's disease (PD) would delay the onset and development of motor symptoms, prolong the efficacy of pharmacotherapies and decrease drug-induced side-e ffects. We tested the potential of two orally administered novel immunophil in ligands to protect against DA degeneration in two animal models of PD. F irst, in an MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model , we compared an immunophilin ligand (V-10,367) documented to bind the immu nophilin FKBP12 with V-13,661, which does not bind FKBP12. Both molecules c ould prevent the loss of striatal DA innervation in a dose-dependent fashio n during 10 days of oral administration. Second, to determine whether an im munophilin ligand can protect against progressive and slow DA degeneration typical of PD, an intrastriatal 6-hydroxydopamine-infusion rat model was ut ilized. Oral treatment with the FKBP12-binding immunophilin ligand began on the day of lesion and continued for 21 days. At this time point, post mort em analyses revealed that the treatment had prevented the progressive loss of DA innervation within the striatum and loss of DA neurons within the sub stantia nigra, related to functional outcome as measured by rotational beha viour. Notably, DA fibres extending into the area of striatal DA denervatio n were observed only in rats treated with the immunophilin ligand, indicati ng neuroprotection or sprouting of spared DA fibres. This is the first demo nstration that immunophilin ligands can prevent a slow and progressive DA a xonal degeneration and neuronal death in vivo. The effects of orally admini stered structurally related immunophilin ligands in acute and progressive m odels of DA degeneration are consistent with the idea that these compounds may have therapeutic value in PD.