Summary
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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Andringa G (2000) Evaluation of new treatment strategies of Parkinson’s disease in animal models: the therapeutic efficacy of the dopamine D1 antagonist SKF 83959 and the neuroprotective agent CGP 3466B. Print Partners Ipskamp, Enschede, Netherlands, 99–115
Andringa G, Vermeulen RJ, Drukarch B, Renier WO, Stoof JC, Cools AR (1999a) The validity of the pre-treated, unilaterally MPTP-treated monkey as model of Parkinson’s disease: a detailed behavioral analysis of the therapeutic and undesired effects of the D2 agonist LY 171555 and the D1 agonist SKF 81927. Beh Pharmacol 10(2): 163–173
Andringa G, Lubbers L, Drukarch B, Stoof JC, Cools AR (1999b) The predictive validity of the drug-naive bilaterally MPTP-treated monkey as model of Parkinson’s disease: effects of L-DOPA and the D1 agonist SKF 82958. Beh Pharmacol 10(2): 175182
Anglade P, Vyas S, Javoy AF, Herrero MT, Michel PP, Marquez J, Mouatt PA, Ruberg M, Hirsch EC, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12: 25–31
Birkmayer W, Hornykiewicz O (1961) Der L-Dopa bei der Parkinson-Akinese. Wien Klin Wochenschr 73: 787
Booij J, Andringa G, Rijks LJM, Vermeulen RJ, De Bruin C, Boer GJ, Janssen AGM, Van Royen EA (1997) [123I]FP-CIT binds to the dopamine transporter as assessed by biodistribution studies in rats and SPECT studies in MPTP-lesioned monkeys. Synapse 27: 183–190
Carlile GW, Chalmers-Redman RM, Tatton NA, Pong A, Borden KE, Tatton WG (2000) Reduced apoptosis after nerve growth factor and serum withdrawal: Conversion of tetrameric glyceraldehyde-3-phosphate dehydrogenase to a dimer. Mol Pharmacol 57(1): 2–12
Dunnett SB, Bjorklund A (1999) Prospects for new restorative and neuroprotective treatments in Parkinson’s disease. Nature 24, 399 (6738 Suppl): A32–39
Ehringer H, Hornykiewicz O (1960) Verteilung von Noradrenalin and Dopamin (3Hydroxytyramin) im Gehirn des Menschen and ihr Verhalten bei Erkrankungen des extrapyramidalen Systems. Klin Wochenschr 38: 1236–1239
Gelowitz DL, Paterson IA (1999) Neuronal sparing and behavioural effects of the antiapoptotic drug, (-)Deprenyl, following kainic acid administration. Pharmacol Biochem Behav 62: 255–262
Guttman M, Fibiger HC, Jakubovic A, Calne DB (1990) Intracarotid 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine administration: Biochemical and behavioural observations in a primate model of hemiparkinsonism. J Neurochem 54: 13291334
Hirsch EC (1999) Mechanism and consequences of nerve cell death in Parkinson’s disease. J Neural Transm suppl 56: 127–137
Huebscher KJ, Lee J, Rovelli G, Ludin B, Matus A, Stauffer D, Furst P (1999) Protein isoaspartyl methyltransferase protects from Bax-induced apoptosis. Gene 240(2): 333–341
Kato AC, Bernheim L, Waldmeier P, Sagot Y, (1997) CGP 3466B, a dibenzoxepine derivate, increases life-span in an animal model of motoneuron disease. Soc Neurosci Abstr 23(554) (abstr no 215.14)
Koutsilieri E, Chen TS, Rausch WD, Riederer P (1996) Selegiline is neuroprotective in primary brain cultures treated with 1-methyl-4-phenylpyridinium. Eur J Pharmacol 306: 181–186
Kragten E, Lalande I, Zimmermann K, Roggo S, Schindler P, Muller D, van Oostrum J, Waldmeier P, Furst P (1998) Glyceraldehyde-3-phosphate dehydrogenase, the putative target of the antiapoptotic compounds CGP 3466 and R-(-)-deprenyl. J Biol Chem 273: 5821–5828
Kurlan R, Kim MH, Gash DM (1991) Oral levodopa dose-response study in MPTPinduced hemiparkinsonian monkeys: assessment with a new rating scale for monkey parkinsonism. Mov Disord 6(2): 111–118
Langston JW, Langston EB, Irwin I (1984) MPTP-induced parkinsonism in human and non-human primates — clinical and experimental aspects. Acta Neurol Scand Suppl 100: 49–54
Mochizuki H, Goto K, Mori H, Mizuno Y (1996) Histochemical detection of apoptosis in Parkinson’s disease. J Neurol Sci 137: 120–123
Nutt JG (1990) Levodopa induced dyskinesia: review, observations and speculation. Neurology 40: 340–345
Offen D, Hochman A, Gorodin S, Ziv I, Shirvan A, Barzilai A, Melamed E, Olanow CW (1999) Oxidative stress and neuroprotection in Parkinson’s disease: implications from studies on dopamine-induced apoptosis. Adv Neurol 80: 265–269
Paterson IA, Fennig CJ, Gelowitz DL, Waldmeier P, Boulton AA (1998a) CGP3466 prevents neuronal death in models of ischaemia and seizure in vivo. J Neurochem 70 Suppl 1: S6C (Abstract)
Paterson IA, Waldmeier P, Boulton AA (1998b) CGP 3466 and CGP 3466B prevent cytosine arabinoside-induced apoptosis in cultures of cerebellar neurones. J Neurochem 70 Suppl 1: S11B (Abstract)
Roy E, Bedard PJ (1993) Deprenyl increases survival of rat foetal nigral neurones in culture. Neuroreport 4: 1183–1186
Smith RD, Zhang Z, Kurlan R, McDermott M, Gash DM (1993) Developing a stable bilateral model of parkinsonism in rhesus monkeys. Neuroscience 52: 7–16
Sunaga K, Takahashi H, Chuang DM, Ishitani R (1995) Glyceraldehyde-3-phosphate dehydrogenase is over-expressed during apoptotic death of neuronal cultures and is recognized by a monoclonal antibody against amyloid plaques from Alzheimer’s brain. Neurosci Lett 200: 133–136
Tatton NA, Maclean-Fraser A, Tatton WG, Perl DP, Olanow CW (1998) A fluorescent double-labeling method to detect and confirm apoptotic nuclei in Parkinson’s disease. Ann Neurol 44 Suppl 1: S142–S148
Waldmeier P, Boulton AA, Cools AR, Kato AC, Tatton WG (2000) Neurorescuing effects of the GAPDH ligand CGP 3466B. J Neural Transm Suppl 6
Yu PH, Davis BA, Boulton AA (1992) Aliphatic propargylamines: potent, selective, irreversible monoamine oxidase B inhibitors. J Med Chem 35: 3705–3713
Authors’ address: A. R. Cools, Department of Psychoneuropharmacology, P.O. Box. 9101, Faculty of Medicine, University of Nijmegen, 6500 HB, Nijmegen, The Netherlands. Email: A.Cools@pnf.kun.nl
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2000 Springer-Verlag Wien
About this paper
Cite this paper
Andringa, G., Cools, A.R. (2000). The neuroprotective effects of CGP 3466B in the best in vivo model of Parkinson’s disease, the bilaterally MPTP-treated rhesus monkey. In: Riederer, P., et al. Advances in Research on Neurodegeneration. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6301-6_14
Download citation
DOI: https://doi.org/10.1007/978-3-7091-6301-6_14
Publisher Name: Springer, Vienna
Print ISBN: 978-3-211-83537-1
Online ISBN: 978-3-7091-6301-6
eBook Packages: Springer Book Archive