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Titolo:
Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline
Autore:
Kupsch, A; Sautter, J; Gotz, ME; Breithaupt, W; Schwarz, J; Youdim, MBH; Riederer, P; Gerlach, M; Oertel, WH;
Indirizzi:
Humboldt Univ, Charite, Dept Neurol, D-13353 Berlin, Germany Humboldt Univ Berlin Germany D-13353 ept Neurol, D-13353 Berlin, Germany Univ Munich, Klinikum Grosshadern, Dept Neurol, Inst Physiol, Munich, Germany Univ Munich Munich Germany , Dept Neurol, Inst Physiol, Munich, Germany Univ Marburg, Dept Neurol, Med Zentrum Nervenheilkunde, Marburg, Germany Univ Marburg Marburg Germany Zentrum Nervenheilkunde, Marburg, Germany Univ Wurzburg, Dept Psychiat & Psychotherapy, Clin Neurochem, Wurzburg, Germany Univ Wurzburg Wurzburg Germany erapy, Clin Neurochem, Wurzburg, Germany Technion Israel Inst Technol, Fac Med,Ctr Neurodegenerat Dis, Eve Topf & Natl Parkinson Fdn, Rappaport Family Res Inst,Dept Pharmacol, Haifa, Israel Technion Israel Inst Technol Haifa Israel Dept Pharmacol, Haifa, Israel Univ Wurzburg, Dept Toxicol, Wurzburg, Germany Univ Wurzburg Wurzburg Germany urzburg, Dept Toxicol, Wurzburg, Germany
Titolo Testata:
JOURNAL OF NEURAL TRANSMISSION
fascicolo: 8-9, volume: 108, anno: 2001,
pagine: 985 - 1009
SICI:
0300-9564(2001)108:8-9<985:MOAMNI>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
MESENCEPHALIC DOPAMINE NEURONS; LIPID-PEROXIDATION LEVELS; MAO-B INHIBITOR; PARKINSONS-DISEASE; L-DEPRENYL; SUBSTANTIA-NIGRA; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE-INDUCED PARKINSONISM; ALZHEIMERS-DISEASE; COMMON MARMOSET; PARS COMPACTA;
Keywords:
Parkinson's disease; MPTP; MPP+; common marmoset; monoamine-oxidase; A and B; selegiline; TVP-1012; rasagiline;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
110
Recensione:
Indirizzi per estratti:
Indirizzo: Kupsch, A Humboldt Univ, Charite, Dept Neurol, Campus Virchow,Augustenburger Pl 1, D-13353 Berlin, Germany Humboldt Univ Campus Virchow,Augustenburger Pl 1 Berlin Germany D-13353
Citazione:
A. Kupsch et al., "Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline", J NEURAL TR, 108(8-9), 2001, pp. 985-1009

Abstract

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 nonhuman 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, sepa rated by an intervalof 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, whenanimals 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 theneurotoxic 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 and selegiline at the dosages employed equally protect against MPTP-toxicity in the common marmoset, suggesting that selegiline-derived metabolites are not important for the neuroprotective effects of high dose selegiline in the non-human MPTP-primate model in the experimental design employed. However, unexpectedly, high dose treatment with both MAO-inhibitors causeda decrease of the cell sizes of nigral tyrosine hydroxylase positive neurons. It remains to be determined, if this histological observation represents potential adverse effects of high dose treatment with monoamine oxidase inhibitors.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 17/09/19 alle ore 22:49:09