TCH346 prevents motor symptoms and loss of striatal FDOPA uptake in bilaterally MPTP-treated primates.
The neuroprotective efficacy of the propargylamine TCH346 was studied in the primate model of Parkinson's disease, the bilaterally MPTP-treated monkey. Male rhesus monkeys received 2.5 mg MPTP into the left carotid artery and, 8 weeks later, 1.25 mg MPTP into the right carotid artery. Starting 2 h after the second MPTP infusion, either 0.014 mg/kg TCH346 or its solvent was subcutaneously injected twice per day for 14 days. The first MPTP treatment induced mild Parkinson symptoms, reduced right limb movements, and reduced FDOPA uptake in the left striatum. The second MPTP treatment made Parkinson symptoms worse, reduced left limb movements, and reduced FDOPA uptake in the right striatum of solvent-treated monkeys. In contrast, the second MPTP treatment did not further worsen motor symptoms and did not decrease FDOPA uptake in the right striatum of TCH346-treated monkeys. Although the effects of the second MPTP treatment were largely prevented, the effects of the first MPTP treatment were not reversed by TCH346. Immunohistochemical examination confirmed the dramatic loss of dopamine cells in vehicle-treated monkeys and the preservation of these neurons in the right brain side of the TCH346-treated animals. In conclusion, systemic administration of TCH346 prevented motor symptoms and nigrostriatal degeneration induced by MPTP in primates.
Andringa
Gerda
G
Department of Psychoneuropharmacology, University of Nijmegen, Nijmegen, The Netherlands. G.Andringa@vumc.nl
Eshuis
Silvia
S
Perentes
Elias
E
Maguire
R Paul
RP
Roth
Daniel
D
Ibrahim
Merdol
M
Leenders
Klaus L
KL
Cools
Alexander R
AR
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008253:Macaca mulatta; D008297:Male; D019957:Motor Skills Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D011437:Propylamines / Q000494:pharmacology / Q000627:therapeutic use*
D011437:Propylamines; C009054:propargylamine; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D010293:Pargyline