Metabolic Brain Disease

, Volume 23, Issue 3, pp 335–349 | Cite as

Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice

  • Hironori Yokoyama
  • Ryohei Yano
  • Eriko Aoki
  • Hiroyuki Kato
  • Tsutomu Araki
Original Paper

Abstract

The biochemical and cellular changes that occur following the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are remarkably similar to that seen in idiopathic Parkinson’s disease(PD). There is growing evidence indicating that reactive oxygen species (ROS), reactive nitrogen species (RNS) and inflammation are a major contributor to the pathogenesis and progression of PD. Hence, we investigated whether 7-nitroindazole [neuronal nitric oxide synthase (nNOS) inhibitor], edaravone (free radical scavenger), minocycline [inducible NOS (iNOS) inhibitor], fluvastatin [endothelial NOS (eNOS) activator], pitavastatin (eNOS activator), etodolac [cyclooxygenase-2 (COX-2) inhibitor] and indomethacin (COX inhibitor) can protect against MPTP neurotoxicity in mice under the same conditions. For the evaluation of each drug, the levels of dopamine, DOPAC and HVA were quantified using HPLC with an electrochemical detector. Four administrations of MPTP at 1-h intervals to mice produced marked depletion of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanilic acid) in the striatum after 5days. 7-Nitroindazole prevented dose-dependently a significant reduction in dopamine contents of the striatum 5days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin, pitavastatin, etodolac and indomethacin did not show the neuroprotective effect on MPTP-induced striatal dopamine, DOPAC and HVA depletions after 5days. The present study demonstrates that the overexpression of nNOS may play a major role in the neurotoxic processes of MPTP, as compared with the production of ROS, the overexpression of iNOS, the modulation of eNOS and the involvement of inflammatory response. Thus our pharmacological findings provide further information for progressive neurodegeneration of the nigrostriatal dopaminergic neuronal pathway.

Keywords

Parkinson’s disease MPTP Reactive oxygen species Reactive nitrogen species Inflammation Dopaminergic system Mice 

References

  1. Agid Y (1991) Parkinson’s disease: pathophysiology. Lancet 337:1321–1324PubMedCrossRefGoogle Scholar
  2. Araki T, Tanji H, Fujihara K, Kato H, Itoyama Y (1999) Increases in [3H]FK-506 and [3H]L-NG-nitro-arginine binding in the rat brain after nigrostriatal dopaminergic denervation. Metab Brain Dis 14:21–31PubMedCrossRefGoogle Scholar
  3. Araki T, Mikami T, Tanji H, Matsubara M, Imai Y, Mizugaki M, Itoyama Y (2001) Biochemical and immunohistological changes in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse. Eur J Pharm Sci 12:231–238PubMedCrossRefGoogle Scholar
  4. Bauer MK, Lieb K, Schulze-Osthoff K, Berger M, Gebicke-Haerter PJ, Bauer J, Fiebich BL (1997) Expression and regulation of cyclooxygenase-2 in rat microglia. Eur J Biochem 243:726–731PubMedCrossRefGoogle Scholar
  5. Beal MF (2003) Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Ann NY Acad Sci 991:120–131PubMedCrossRefGoogle Scholar
  6. Beckman JS, Beckman TW, Chen J (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 87:1620–1624PubMedCrossRefGoogle Scholar
  7. Beckman JS, Ischiropoulos H, Zhu L (1992) Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite. Arch Biochem Biophys 298:438–445PubMedCrossRefGoogle Scholar
  8. Bernheimer H, Birkmayer W, Hornykeiwicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20:415–455PubMedCrossRefGoogle Scholar
  9. Bredt DS, Snyder SH (1990) Isolation of nitric oxide synthase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A 87:682–685PubMedCrossRefGoogle Scholar
  10. Bredt DS, Snyder SH (1994) Nitric oxide: a physiologic messenger molecule. Ann Rev Biochem 63:175–195PubMedCrossRefGoogle Scholar
  11. Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC (2002) Protective action of the peroxisome proxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson’s disease. J Neurochem 82:615–624PubMedCrossRefGoogle Scholar
  12. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909PubMedCrossRefGoogle Scholar
  13. Dawson TM, Snyder SH (1994) Gases as biological messengers: nitric oxide and carbon monoxide in the brain. J Neurosci 14:5147–5159PubMedGoogle Scholar
  14. Dawson VL, Dawson TM, London ED, Bredit DS, Snyder SH (1991) Nitric oxide mediates glutamate neurotoxicity in primary cultures. Proc Natl Acad Sci U S A 88:6268–6371Google Scholar
  15. Dehmer T, Lindenau J, Haid S, Dichgans J, Schultz JB (2000) Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. J Neurochem 74:2213–2216PubMedCrossRefGoogle Scholar
  16. Di Monte DA, Royland JE, Anderson A, Castagnoli K, Castagoli Jr N , Langston JW (1997) Inhibition of monoamine oxidase contributes to the protective effect of 7-nitroindazole against MPTP neurotoxicity. J Neurochem 69:1771–1773PubMedCrossRefGoogle Scholar
  17. Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK (1998) Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 95:8880–8885PubMedCrossRefGoogle Scholar
  18. Feng ZH, Wang TG, Li DD, Fung P, Wilson BC, Liu B, Ali SF, Langenbach R, Hong JS (2002) Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4- phenyl-,2,3,6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra. Neurosci Lett 329:354–358PubMedCrossRefGoogle Scholar
  19. Hantraye P, Brouillet E, Ferrante R, Pafi S, Dolan R, Matthews RT, Beal MF (1996) Inhibition of neuronal nitric oxide synthase prevents MPTP-induced Parkinsonism in baboons. Nat Med 2:1017–1021PubMedCrossRefGoogle Scholar
  20. Hasegawa E, Takeshige K, Oishi T, Murai Y, Minakami S (1990) 1-Methylphenylpyridinium (MPP+) induces NADH-dependent superoxideformation and enhances NADH-dependent lipid peroxidation in bovine heart submitochondrial particles. Biochem Biophys Res Commun 170:1049–1055PubMedCrossRefGoogle Scholar
  21. Hirsh E, Graybiel AM, Agid YA (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 334:345–348CrossRefGoogle Scholar
  22. Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP (2003) The role of glial reaction and inflammation in Parkinson’s disease. Ann NY Acad Sci 991:214–228PubMedCrossRefGoogle Scholar
  23. Hurley SD, O'Banion MK, Song DD, Arana FS, Olschowka JA, Haber SN (2003) Microglial response is poorly correlated with neurodegeneration following chronic, low-dose MPTP-administration in monkeys. Exp Neurol 184:659–668PubMedCrossRefGoogle Scholar
  24. Ignarro LJ (1990) Biosynthesis and metabolism of endothelium-derived nitric oxide. Ann Rev Pharmacol Toxicol 30:535–560CrossRefGoogle Scholar
  25. Ischiropoulos H, Zhu L, Chen J (1992) Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Arch Biochem Biophys 298:431–437PubMedCrossRefGoogle Scholar
  26. Kurosaki R, Akasak M, Michimata M, Matsubara M, Ima Y, Araki T (2003) Effects of Ca2+ antagonists on motor activity and the dopaminergic system in aged mice. Neurobiol Aging 24:315–319PubMedCrossRefGoogle Scholar
  27. Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeration in the MPTP model of Parkinson disease. Nat Med 5:1403–1409PubMedCrossRefGoogle Scholar
  28. Lonart G, Johanson KM (1992) Inhibitory effects of nitric oxide on the uptake of [3H]dopamine and [3H]glutamate by striatal synaptosomes. J Neurochem 63:2108–2117CrossRefGoogle Scholar
  29. Marletta MA (1994) Nitric oxide synthase: aspects concerning structure and catalysis. Cell 78:927–930PubMedCrossRefGoogle Scholar
  30. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia and positive for HLS-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291PubMedGoogle Scholar
  31. Minghetti L, Walsh DT, Levi G, Perry VH (1999) In vivo expression of cyclooxygenase-2 in rat brain following intraparenchymal injection of bacterial endotoxin and inflammatory cytokines. J Neuropathol Exp Neurol 58:1184–1191PubMedCrossRefGoogle Scholar
  32. Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43:109–142PubMedGoogle Scholar
  33. Muramatsu Y, Kurosaki R, Watanabe H, Michimata M, Matsubara M, Imai Y, Araki T (2003) Cerebral alterations in a MPTP-mouse model of Parkinson’s disease-an immunocytochemical study. J Neural Transm 110:1129–1144PubMedCrossRefGoogle Scholar
  34. Murphy S, Simmons ML, Agullo L, Garcia A, Feinstein DL, Galea E, Reis DJ, Minc-Colomb D, Schwartz JP (1993) Synthesis of nitric oxide in CNS glial cells. Trends Neurosci 16:323–328PubMedCrossRefGoogle Scholar
  35. Nathan C, Xie QW (1994) Nitric oxide synthases: roles, tolls, and controls. Cell 78:915–918PubMedCrossRefGoogle Scholar
  36. O’Banion MK (1999) COX-2 and Alzheimer’s disease: potential roles in inflammation and neurodegeneration. Expert Opin Invest Drugs 8:1521–1536CrossRefGoogle Scholar
  37. Pasinetti GM (1998) Cyclooxygenase and inflammation in Alzheimer’s disease: experimental approaches and clinical interventions. J Neurosci Res 54:1–6PubMedCrossRefGoogle Scholar
  38. Ravina BM, Fagan SC, Hart RG, Hovinga CA, Murphy DD, Dawson TM, Marler JR (2003) Neuroprotective agents for clinical trials in Parkinson’s disease: a systematic assessment. Neurology 60:1234–1240PubMedGoogle Scholar
  39. Rice-Evans CA (1994) Formation of free radicals and mechanisms of action in normal biochemical processes and pathological states. In: Rice-Evans CA, Burdon RH (eds) Free radical damage and its control. Elsevier, Amsterdam, pp 131–153CrossRefGoogle Scholar
  40. Samuelsson B (1991) Arachidonic acid metabolism: role in inflammation. Z Rheumatol Suppl 50:3–6Google Scholar
  41. Schulz JB, Matthews RT, Muqit MMK (1995) Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice. J Neurochem 64:936–939PubMedCrossRefGoogle Scholar
  42. Selley ML (2005) Simvastatin prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced striatal dopamine depletion and protein tyrosine nitration in mice. Brain Res 1037:1–6PubMedCrossRefGoogle Scholar
  43. Smith WL, DeWitt DL, Garavitro RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182PubMedCrossRefGoogle Scholar
  44. Sriram K, Pai KS, Boyd MR, Ravindranath V (1997) Evidence for generation of oxidative stress in brain by MPTP: in vitro and in vivo studies in mice. Brain Res 749:44–52PubMedCrossRefGoogle Scholar
  45. Teismann P, Tieu K, Choi DK, Wu DC, Naini A, Hunot S, Vila M, Jackson-Lewis V, Przedborski S (2003) Cyclooxygenase-2 is instrumental in Parkinson’s disease. Proc Natl Acad Sci U S A 100:5473–5478PubMedCrossRefGoogle Scholar
  46. Tipton KF, Singer TP (1993) Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds. J Neurochem 61:1191–1206PubMedCrossRefGoogle Scholar
  47. Watanabe Y, Kato H, Araki T (2008) Protective action of neuronal nitric oxide synthase inhibitor in the MPTP mouse model of Parkinson’s disease. Metab Brain Dis 23:51–69PubMedCrossRefGoogle Scholar
  48. Wenzel SE (1997) Arachidonic acid metabolites: mediators of inflammation in asthma. Pharmacotherapy 17:3S–12SPubMedGoogle Scholar
  49. Wu DC, Jakson-Lewis M, Vila M, Tieu K, Teismann C, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763–1771PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Hironori Yokoyama
    • 1
  • Ryohei Yano
    • 1
  • Eriko Aoki
    • 1
  • Hiroyuki Kato
    • 2
  • Tsutomu Araki
    • 1
  1. 1.Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical SciencesThe University of TokushimaTokushimaJapan
  2. 2.Department of Neurology, Organized Center of Clinical MedicineInternational University of Health and WelfareTochigiJapan

Personalised recommendations