Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate : comparison of rasagiline (TVP 1012) with selegiline

• Published in: Journal of Neural Transmission 2001-01, Vol.108 (8-9), p.985-1009
• Main Authors: KUPSCH, A, SAUTTER, J, GÖTZ, M. E, BREITHAUPT, W, SCHWARZ, J, YOUDIM, M. B. H, RIEDERER, P, GERLACH, M, OERTEL, W. H
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology; Animals; Biological and medical sciences; Body Weight - drug effects; Body Weight - physiology; Callithrix; Callithrix jacchus; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dopamine - metabolism; Dopamine Agents - pharmacology; Female; Immunohistochemistry; Indans - chemistry; Indans - pharmacology; Male; Medical sciences; Monoamine Oxidase - drug effects; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - pharmacology; Motor Activity - drug effects; Motor Activity - physiology; Neostriatum - drug effects; Neostriatum - enzymology; Neostriatum - physiopathology; Neurology; Neurons - drug effects; Neurons - metabolism; Norepinephrine - metabolism; Parkinsonian Disorders - drug therapy; Parkinsonian Disorders - enzymology; Parkinsonian Disorders - physiopathology; rasagiline; Selegiline - chemistry; Selegiline - pharmacology; Serotonin - metabolism; Substantia Nigra - drug effects; Substantia Nigra - enzymology; Substantia Nigra - physiopathology
• ISSN: 0300-9564; 1435-1463
• DOI: 10.1007/s007020170018

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Monoamine-oxidase B (MAO-B) has been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease, since selegiline (L-deprenyl), an irreversible MAO-B inhibitor, prevents MPTP-induced neurotoxicity in numerous species including mice, goldfish and drosophyla. However, one disadvantage of this substance relates to its metabolism to (-)-methamphetamine and (-)-amphetamine. Rasagiline (R-(+)-N-propyl-1-aminoindane) is a novel irrevesible MAO-B-inhibitor, which is not metabolized to metamphetamine and/or amphetamine. The present study compared the effects of high doses of selegiline and rasagiline (10 mg/kg body weight s.c.) on MPTP-induced dopaminergic neurotoxicity in a non-human primate (Callithrix jacchus) model of PD. Groups of four monkeys were assigned to the following six experimental groups: Group I: Saline, Group II: Selegiline/Saline, Group III: Rasagiline/Saline, Group IV: MPTP/Saline, Group V: Rasagiline/MPTP, Group VI: Selegiline/MPTP. Daily treatment with MAO-B-inhibitors (either rasagiline or selegiline, 10 mg/kg body weight s.c.) was initiated four days prior to MPTP-exposure (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 hours for a total of four days) and was continued until the end of the experiment, i.e. 7 days after the cessation of the MPTP-injections, when animals were sacrificed. MPTP-treatment caused distinct behavioural, histological, and biochemical alterations: 1. significant reduction of motor activity assessed by clinical rating and by computerized locomotor activity measurements; 2. substantial loss (approx. 40%) of dopaminergic (tyrosine-hydroxylase-positive) cells in the substantia nigra, pars compacta; and 3. putaminal dopamine depletion of 98% and its metabolites DOPAC (88%) and HVA (96%). Treatment with either rasagiline or selegiline markedly attenuated the neurotoxic effects of MPTP at the behavioural, histological, and at the biochemical levels. There were no significant differences between rasagiline/MPTP and selegiline/MPTP-treated animals in respect to signs of motor impairment, the number of dopaminergic cells in the substantia nigra, and striatal dopamine levels. As expected, both inhibitors decreased the metabolism of dopamine, leading to reduced levels of HVA and DOPAC (by >95% and 45% respectively). In conclusion, rasagiline a