Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on Parkinson’s disease

Year 2019, Volume: 5 Issue: 1, 48 - 54, 04.04.2019

Havvanur Akbulut Elif Köylüoğlu Oytun Erbaş

Abstract

Parkinson's disease is a chronic movement disorder seen frequently in adults and caused by the destruction of dopaminergic neurons. Its symptoms are tremor, rigidity, balance disorder, and bradykinesia. The current medications of the disease cure the symptoms; none of them stops neurodegeneration. Various modellings are performed on experimental animals for Parkinson's disease research. The main substance used in these modellings is 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a synthetic toxin. MPTP is a neurotoxic agent that appeared unintentionally during the production of illicit drugs. MPTP converts to 1-methyl-4-phenyl-4-propionoxypiperidine in the body. This substance produces most of the biochemical, pathological, and clinical features similar to Parkinson's disease in an acute and irreversible way and this experimental Parkinson model leads many researchers. In this review, we discussed MPTP’s discovery, metabolism, neurodegeneration mechanisms, and use in treatment in light of the literature.

Keywords

1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine, 1-methyl-4-phenyl-4-propionoxypiperidine, experimental Parkinson model, Parkinson’s disease

1-metil-4-fenil-1,2,3,6-tetrahidropiridinin (MPTP) Parkinson hastalığı üzerindeki etkileri

Abstract

Parkinson hastalığı erişkinlerde sık görülen, dopaminerjik nöronların zarar görmesi sonucunda gelişen kronik bir hareket bozukluğudur. Belirtileri tremor, rijidite, denge bozukluğu ve bradikinezidir. Hastalığın mevcut ilaçları semptomları tedavi eder; hiçbiri nörodejenerasyonu durdurmaz. Parkinson hastalığı araştırmaları için deney hayvanları üzerinde çeşitli modellemeler yapılır. Bu modellemelerde kullanılan maddelerin başında sentetik bir toksin olan 1-metil-4-fenil-1,2,3,6-tetrahidropiridin (MPTP) gelir. MPTP, yasadışı uyuşturucu üretimi sırasında istemeden ortaya çıkmış nörotoksik bir maddedir. MPTP, vücutta 1-metil-4-fenil-4-propiyonoksipiperidine dönüşür. Bu madde Parkinson hastalığına benzer biyokimyasal, patolojik ve klinik özelliklerin çoğunu akut ve geri dönüşümsüz bir şekilde meydana getirir ve bu deneysel Parkinson modeli birçok araştırmacıya yol gösterir. Bu derlemede, MPTP’nin keşfi, metabolizması, nörodejenerasyon mekanizmaları ve tedavide kullanımı literatür ışığında tartışıldı.

Keywords

1-metil-4-fenil-1, 2, 3, 6-tetrahidropiridin, 1-metil-4-fenil-4-propiyonoksipiperidin, deneysel Parkinson modeli, Parkinson hastalığı

References

• 1. Türkiye Parkinson Hastalı¤ı Derne¤i. Available from: http://parkinsondernegi.com/parkinson-nedir/ 2. Murat K. Available from: http://norolojiklinigi.info/parkinson-hastaligi/ 3. Available from: http://www.saglik.im/parkinson-hastaligi/ 4. Rose S, Nomoto M, Jackson EA, Gibb WR, Jaehnig P, Jenner P, et al. Age-related effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets. Eur J Pharmacol 1993;230:177-85. 5. Irwin I, DeLanney LE, Langston JW. MPTP and aging. Studies in the C57BL/6 mouse. Adv Neurol 1993;60:197-206. 6. Ovadia A, Zhang Z, Gash DM. Increased susceptibility to MPTP toxicity in middle-aged rhesus monkeys. Neurobiol Aging 1995;16:931-7. 7. Forno LS, DeLanney LE, Irwin I, Langston JW. Similarities and differences between MPTP-induced parkinsonsim and Parkinson's disease. Neuropathologic considerations. Adv Neurol 1993;60:600-8. 8. Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, et al. Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1979;1:249-54. 9. Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D. Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 1999;46:598-605. 10. Moratalla R, Quinn B, DeLanney LE, Irwin I, Langston JW, Graybiel AM. Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A 1992;89:3859-63. 11. Sirinathsinghji DJ, Kupsch A, Mayer E, Zivin M, Pufal D, Oertel WH. Cellular localization of tyrosine hydroxylase mRNA and cholecystokinin mRNA-containing cells in the ventral mesencephalon of the common marmoset: effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Brain Res Mol Brain Res 1992;12:267-74. 12. Varastet M, Riche D, Maziere M, Hantraye P. Chronic MPTP treatment reproduces in baboons the differential vulnerability of mesencephalic dopaminergic neurons observed in Parkinson's disease. Neuroscience 1994;63:47-56. 13. Hirsch E, Graybiel AM, Agid YA. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 1988;334:345-8. 14. Herrero MT, Hirsch EC, Kastner A, Ruberg M, Luquin MR, Laguna J, et al. Does neuromelanin contribute to the vulnerability of catecholaminergic neurons in monkeys intoxicated with MPTP? Neuroscience 1993;56:499-511. 15. Zecca L, Tampellini D, Gerlach M, Riederer P, Fariello RG, Sulzer D. Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour. Mol Pathol 2001;54:414-8. 16. D’Amato RJ, Lipman ZP, Snyder SH. Selectivity of the parkinsonian neurotoxin MPTP: toxic metabolite MPP+ binds to neuromelanin. Science 1986;231:987-9. 17. Forno LS, Langston JW, DeLanney LE, Irwin I, Ricaurte GA. Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann Neurol 1986;20:449-55. 18. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 2000;3:1301-6. 19. Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990;249:1436-8. 20. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 1998;339:1105-11. 21. Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature 1996;380:252-5. 22. Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 2000;290:767-73. 23. Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci U S A 1985;82:2173-7. 24. Mayer RA, Kindt MV, Heikkila RE. Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport. J Neurochem 1986;47:1073-9. 25. Bezard E, Gross CE, Fournier MC, Dovero S, Bloch B, Jaber M. Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter. Exp Neurol 1999;155:268-73. 26. Haber SN, Ryoo H, Cox C, Lu W. Subsets of midbrain dopaminergic neurons in monkeys are distinguished by different levels of mRNA for the dopamine transporter: comparison with the mRNA for the D2 receptor, tyrosine hydroxylase and calbindin immunoreactivity. J Comp Neurol 1995;362:400-10. 27. Liu Y, Roghani A, Edwards RH. Gene transfer of a reserpine-sensitive mechanism of resistance to N-methyl-4-phenylpyridinium. Proc Natl Acad Sci U S A 1992;89:9074-8. 28. Ramsay RR, Singer TP. Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, by mitochondria. J Biol Chem 1986;261:7585-7. 29. Klaidman LK, Adams JD Jr, Leung AC, Kim SS, Cadenas E. Redox cycling of MPP+: evidence for a new mechanism involving hydride transfer with xanthine oxidase, aldehyde dehydrogenase, and lipoamide dehydrogenase. Free Radic Biol Med 1993;15:169-79. 30. Takahashi N, Miner LL, Sora I, Ujike H, Revay RS, Kostic V, et al. VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc Natl Acad Sci U S A 1997;94:9938-43. 31. Miller GW, Gainetdinov RR, Levey AI, Caron MG. Dopamine transporters and neuronal injury. Trends Pharmacol Sci 1999;20:424-9. 32. Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 1985;36:2503-8. 33. Chan P, DeLanney LE, Irwin I, Langston JW, Di Monte D. Rapid ATP loss caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mouse brain. J Neurochem 1991;57:348-51. 34. Fabre E, Monserrat J, Herrero A, Barja G, Leret ML. Effect of MPTP on brain mitochondrial H2O2 and ATP production and on dopamine and DOPAC in the striatum. J Physiol Biochem 1999;55:325-31. 35. Takubo H, Kondo T, Mori H, Miyake T, Suda K, Yokochi M, et al. A 62-year-old man with familial parkinsonism with the onset at 24 years of the age. No To Shinkei 1996;48:587-97. [Abstract] 36. Hasegawa E, Kang D, Sakamoto K, Mitsumoto A, Nagano T, Minakami S, et al. A dual effect of 1-methyl-4-phenylpyridinium (MPP+)-analogs on the respiratory chain of bovine heart mitochondria. Arch Biochem Biophys 1997;337:69-74. 37. Jackson-Lewis V, Jakowec M, Burke RE, Przedborski S. Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration 1995;4:257-69. 38. Mandir AS, Przedborski S, Jackson-Lewis V, Wang ZQ, Simbulan-Rosenthal CM, Smulson ME, et al. Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Proc Natl Acad Sci U S A 1999;96:5774-9. 39. Saporito MS, Thomas BA, Scott RW. MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo. J Neurochem 2000;75:1200-8. 40. Vila M, Jackson-Lewis V, Vukosavic S, Djaldetti R, Liberatore G, Offen D, et al. Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Proc Natl Acad Sci U S A 2001;98:2837-42. 41. Tatton NA, Kish SJ. In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining. Neuroscience 1997;77:1037-48. 42. Duan W, Zhu X, Ladenheim B, Yu QS, Guo Z, Oyler J, et al. p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism. Ann Neurol 2002;52:597-606. 43. Trimmer PA, Smith TS, Jung AB, Bennett JP Jr. Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity. Neurodegeneration 1996;5:233-9. 44. Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD, editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th ed. Philadelphia: Lippincott-Raven; 1999. 45. Emborg ME. Nonhuman primate models of Parkinson's disease. ILAR J 2007;48:339-55. 46. Blandini F, Armentero MT. Animal models of Parkinson's disease. FEBS J 2012;279:1156-66. 47. Morin N, Jourdain VA, Di Paolo T. Modeling dyskinesia in animal models of Parkinson disease. Exp Neurol 2014;256:105-16. 48. Porras G, Li Q, Bezard E. Modeling Parkinson’s disease in primates: The MPTP model. Cold Spring Harb Perspect Med 2012;2:a009308. 49. Przedborski S, Jackson-Lewis V, Naini AB, Jakowec M, Petzinger G, Miller R, et al. The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety. J Neurochem 2001;76:1265-74. 50. Ashkan K, Wallace BA, Mitrofanis J, Pollo C, Brard PY, Fagret D, et al. SPECT imaging, immunohistochemical and behavioural correlations in the primate models of Parkinson's disease. Parkinsonism Relat Disord 2007;13:266-75. 51. Liu Y, Yue F, Tang R, Tao G, Pan X, Zhu L, et al. Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([(18)F]AV-133). Neurosci Bull 2014;30:409-16. 52. Nagai Y, Obayashi S, Ando K, Inaji M, Maeda J, Okauchi T, et al. Progressive changes of pre- and post-synaptic dopaminergic biomarkers in conscious MPTP-treated cynomolgus monkeys measured by positron emission tomography. Synapse 2007;61:809-19. 53. Imbert C, Bezard E, Guitraud S, Boraud T, Gross CE. Comparison of eight clinical rating scales used for the assessment of MPTP-induced parkinsonism in the Macaque monkey. J Neurosci Methods 2000;96:71-6. 54. Kurlan R, Kim MH, Gash DM. Oral levodopa dose-response study in MPTP-induced hemiparkinsonian monkeys: assessment with a new rating scale for monkey parkinsonism. Mov Disord 1991;6:111-8. 55. Seo J, Lee Y, Kim BS, Park J, Yang S, Yoon HJ, et al. A non-human primate model for stable chronic Parkinson's disease induced by MPTP administration based on individual behavioral quantification. J Neurosci Methods 2019;311:277-87.