Systemic administration of the propargylamine CGP 3466B prevents behavioural and morphological deficits in rats with 6-hydroxydopamine-induced lesions in the substantia nigra.
The ability of CGP 3466B to attenuate the behavioural and morphological consequences of experimentally induced cell death was investigated in a recently updated animal model of Parkinson's disease. 6-Hydroxydopamine was infused bilaterally into the substantia nigra pars compacta of rats that were pretreated with desimipramine. Treatment with CGP 3466B (0.0014-1.4 mg/kg, injected subcutaneously) or its solvent was begun 2 h after the 6-OHDA injection, and maintained twice daily for 14 days. After a washout period of 14 days, changes in motor behaviour were evaluated, using the open field test (analysis of normal and abnormal stepping, e.g.) and the paw test (analysis of retraction time of limbs). Changes in learning and memory were evaluated with the help of the Morris water maze task. Following immunocytochemical staining of tyrosine hydroxylase, the extent of the lesion was quantified using a computerized system. CGP 3466B prevented all deficits produced by 6-hydroxydopamine (6-OHDA), though at different doses. It prevented: abnormal stepping (0.0014-0.014 mg/kg); increased forelimb and hindlimb retraction time (0.014-0.14 mg/kg and 0.0014-0.14 mg/kg, respectively); delayed learning (1.4 mg/kg); and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra (0.0014-0.014 mg/kg). CGP 3466B (0.0014-0.14 mg/kg) induced no deficits in sham-treated rats. CGP 3466B (1.4 mg/kg), however, did not show any benefit on motor deficits in 6-OHDA-lesioned rats, and induced abnormal movements and decreased the tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and the ventral tegmental area of sham-lesioned animals. It is concluded that CGP 3466B prevents all 6-OHDA-induced behavioural and immunocytochemical deficits, though at different doses. CGP 3466B is suggested to be a valuable agent for inhibiting the dopaminergic degeneration in patients with Parkinson's disease.
Andringa
G
G
Department of Psychoneuropharmacology, University of Nijmegen, Nijmegen, The Netherlands. AndringaG@ninds.nih.gov
van Oosten
R V
RV
Unger
W
W
Hafmans
T G
TG
Veening
J
J
Stoof
J C
JC
Cools
A R
AR
D000818:Animals; D000906:Antibodies; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight; D003714:Denervation; D004298:Dopamine / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects; D005684:Gait / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000201:enzymology; D010082:Oxepins / Q000494:pharmacology*; D016627:Oxidopamine; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000276:immunology
D000906:Antibodies; D010082:Oxepins; D011437:Propylamines; D013565:Sympatholytics; C111178:dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine; C009054:propargylamine; D016627:Oxidopamine; D010293:Pargyline; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine