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) resulting in the initiation of clinical trials in patients with Parkinson's disease. We believe that prior to clinical trials, novel therapeutic strategies should show safety and efficacy in nonhuman models of PD. The present study assessed whether oral administration of the immunophilin 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrollidinecarboxylate (GPI 1046) could prevent the structural and functional consequences of n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in nonhuman primates. Twenty-five rhesus monkeys received daily oral administration of vehicle (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 performance on a hand reach task, general activity, and clinical dysfunction based on a clinical rating scale. All groups of monkeys displayed similar deficits on each behavioral measure as well as similar losses of tyrosine hydroxylase (TH)-immunoreactive (ir) nigral neurons, TH-mRNA, and TH-ir striatal optical density indicating that in general treatment failed to have neuroprotective effects.
Emborg
M E
ME
Research Center for Brain Repair, Rush Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.
Shin
P
P
Roitberg
B
B
Sramek
J G
JG
Chu
Y
Y
Stebbins
G T
GT
Hamilton
J S
JS
Suzdak
P D
PD
Steiner
J P
JP
Kordower
J H
JH
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries; D007839:Functional Laterality; D005684:Gait; D020104:Immunophilins / Q000378:metabolism; D007269:Injections, Intra-Arterial; D008253:Macaca mulatta; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000201:enzymology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D011187:Posture; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D013378:Substantia Nigra / Q000378:metabolism; D014158:Transcription, Genetic; D014202:Tremor / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
C104949:GPI 1046; D011759:Pyrrolidines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D020104:Immunophilins