Systemic administration of the immunophilin ligand GPI 1046 in MPTP-treated monkeys

Systemic administration of immunophilin ligands provides trophic influences to dopaminergic neurons in rodent models of Parkinson's disease (PD) resul ting in the initiation of clinical trials in patients with Parkinson's dise ase. We believe that prior to clinical trials, novel therapeutic strategies should show safety and efficacy in nonhuman models of PD. The present stud y assessed whether oral administration of the immunophilin 3- (3-pyridyl)-1 -propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrollidinecarboxylate (GP I 1046) could prevent the structural and functional consequences of n-methy l-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in nonhuman pri mates. Twenty-five rhesus monkeys received daily oral administration of veh icle (n = 5) or one of four doses of GPI 1046 (0.3 mg/kg, n = 5; 1.0 mg/kg, n = 5; 3.0 mg/kg, n = 5; 10.0 mg/kg, n = 5). Two weeks after starting the drug treatment, all monkeys received a unilateral intracarotid injection of MPTP-HCl (3 mg). Daily drug administration continue for 6 weeks postlesion after which time the monkeys were sacrificed. Monkeys were assessed for pe rformance on a hand reach task, general activity, and clinical dysfunction based on a clinical rating scale. All groups of monkeys displayed similar d eficits on each behavioral measure as well as similar losses of tyrosine hy droxylase (TH)-immuno-reactive (ir) nigral neurons, TH-mRNA, and TH-ir stri atal optical density indicating that in general treatment failed to have ne uroprotective effects. (C) 2001 Academic Press.