The neuroprotective effects of CGP 3466B in the best in vivo model of Parkinson's disease, the bilaterally MPTP-treated rhesus monkey.
The propargylamine CGP 3466B prevents dopamine cell death both in vitro and in rodent models of Parkinson's disease. The present study investigates the efficacy of this compound to prevent the behavioral consequences of dopaminergic cell death in the best animal model of Parkinson's disease, the bilaterally MPTP-treated monkey. Rhesus monkeys were bilaterally treated with MPTP, using a two-step procedure: 2.50 mg MPTP was infused into the left carotid artery followed by a second bolus of 1.25 mg into the right carotid artery, 8 weeks later. Subcutaneous injection of either 0.014 mg/kg CGP 3466B (n = 4) or its solvent (distilled water; n = 4), twice daily for fourteen days, started two hours after the second MPTP infusion. A Parkinson rating scale was assessed for the evaluation of the effects. After the first MPTP treatment, the monkeys developed mild to moderate parkinsonian symptoms. The second MPTP treatment strongly increased the severity of Parkinson scores in all control monkeys, as assessed on day 3, 7, 14, 21, 28 and 35 after the second MPTP treatment. In contrast, CGP 3466B nearly completely prevented the increase of parkinsonian symptoms after the second MPTP treatment. The therapeutic effects of CGP 3466B were still present after a washout period of 3 weeks, implying that the effects were not symptomatic. These data are the first to show that the systemic administration of CGP 3466B is able to prevent the development of MPTP-induced motor symptoms in primates. This compound may have great value for inhibiting the progression of the neurodegenerative process in patients with Parkinson's disease.
Andringa
G
G
Department of Psychoneuropharmacology, Faculty of Medicine, University of Nijmegen, The Netherlands.
Cools
A R
AR
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010082:Oxepins / Q000494:pharmacology*; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology*; D011437:Propylamines / Q000494:pharmacology*
D018696:Neuroprotective Agents; D010082:Oxepins; D011437:Propylamines; C111178:dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine; C009054:propargylamine; D010293:Pargyline