Skip to main content
Log in

Short-term manganese pretreatment partially protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity

  • Original Articles
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that induces parkinsonism in human and non-human primates. Its mechanism of action is not fully elucidated.Recently, the participation of trace metals, such as manganese, on its neurotoxic action has been postulatted. In this work, we studied the effect of manganese administration on the neurochemical consequences of MPTP neurotoxic action. Male Swiss albino mice were treated with manganese chloride (MnCl2 ·4H2O; 0.5 mg/ml or 1.0 mg/ml of drinking water) for 7 days, followed by three MPTP administrations (30 mg/Kg, intraperitoneally). Seven days after the last MPTP administration, mice were sacrificed and dopamine and homovanillic acid contents in corpus striatum were analyzed. Striatal concentration of dopamine was found increased by 60% in mice pretreated with 0.5 mg/ml and 52% in the group treated of 1.0 mg/ml as compared versus animals treated with MPTP only. Hornovanillic acid content in both groups treated with manganese was the same as those in control animals. The results indicate that manganese may interact with MPTP, producing an enhancement of striatal dopamine turnover, as the protective effect of manganese was more pronounced in the metabolite than in the neurotransmitter.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Prohaska, J. R. 1987. Functions of trace elements in brain metabolism. Physiol. Rev. 67:858–901.

    Google Scholar 

  2. Aschner, M., and Aschner, J. L. 1990. Manganese neurotoxicity: mechanisms of blood-brain barrier transport. Neurosci. Biobehav. Rev. 14:169–176.

    Google Scholar 

  3. Mena, I., Horiuchi, K., and López, G. 1974. Factors enhancing entrance of manganese into brain: iron deficiency and age. J. Nucl. Med. 15:516.

    Google Scholar 

  4. Cotzias, G. C., Horiuchi, K., Fuenzalida, S., and Mena, I. 1968. Chronic manganese poisoning: clearance of tissue manganese concentrations with persistence of the neurological picture. Neurology. 18:376–382.

    Google Scholar 

  5. Carl, G. F., Keen, C. L., Gallagher, B. B., Legg, M. S., Lettleton, W. H., Flannery, D. B., and Hurley, L. S. 1986. Association of low blood manganese concentration with epilepsy. Neurology 36: 1584–1587.

    Google Scholar 

  6. Chandra, S. V., and Shukla, G. S. 1981. Concentrations of striatal catecholamines in rats given manganese chloride through drinking water. J. Neurochem. 36:683–687.

    Google Scholar 

  7. Donaldson, J., and La Bella, F. S. 1984. The effects of manganese on the cholinergic receptor in vivo and in vitro may be mediated through modulations of free radicals. Neurotoxicology. 5:105–112.

    Google Scholar 

  8. Eriksson, H., Lenngren, S., Heilbronn, E. 1987. Effect of longterm administration of manganese on biogenic amine levels in discrete striatal regions of rat brain. Arch. Toxicol. 59:426–431.

    Google Scholar 

  9. Bonilla, E. 1980. L-tyrosine hydroxylase activity in the rat brain after chronic oral administration of manganese chloride. Neurobehav. Toxicol. 2:37–41.

    Google Scholar 

  10. Bonilla, E., and Prasad, A. L. N. 1984. Chronic manganese intake and levels of biogenic amines in rat brain. Neurobehav. Toxicol. 6:341–344.

    Google Scholar 

  11. Barbeau, A. 1984. Manganese and extrapyramidal disorders. Neurotoxicology 5:13–36.

    Google Scholar 

  12. Donaldson, J., McGregor, D., and LaBella F. 1982. Manganese neurotoxicity: a model for free radical mediated neurodegeneration? Can. J. Physiol. Pharmacol. 60:1398–1405.

    Google Scholar 

  13. Keen, C. L., Lonnerdal, B., and Hurley, L. S. 1984. Pages 89–132. Manganese, in Frieden, E. (eds.). Biochemistry of the essential ultratrace elements, Plenum Press, New York.

    Google Scholar 

  14. Wedler, F. C., and Denman, R. B. 1984. Glutamine synthetase from bovine brain is a manganese (II) enzyme. Biochemistry 21:6389–6396.

    Google Scholar 

  15. Gupta, R. C., Khandelwal, R. L., and Sulakhe, P. V. 1984. Intrinsic phosphatase activity of bovine brain calcineurin requires a tightly bound trace metal. FEBS Lett. 169:251–255.

    Google Scholar 

  16. Qato, M. K., and Maines, M. D. 1985. Regulation of heme and drug metabolism activities in the brain by manganese. Biochem. Biophys. Res. Commun. 128:18–24.

    Google Scholar 

  17. Drapeau, P., and Nachsen, D. A. 1984. Manganese fluxes and manganese-dependent neurotransmitter release in presynaptic nerve endings isolated from rat brain. J. Physiol. 3348:493–510.

    Google Scholar 

  18. Davis, G. C., Williams, A. C., Markey, S. P., Ebert, M. H., Caine, E. D., Reichert, C. M., and Kopin, I. J. 1979. Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatr. Res. 1:249–254.

    Google Scholar 

  19. Langston, J. W., Ballard, P., Tetrud, J. W., and Irwin, I. 1983. Chronic parkinsonism in humans due to a product of meperidineanalog synthesis. Science. 219:979–980.

    Google Scholar 

  20. Burns, R. S., Chiueh, C. C., Markey, S. P., Ebert, M. H., Jacobowitz, D. M., and Kopin, I. J. 1983. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc. Natl. Acad. Sci. USA. 80:4546–4550.

    Google Scholar 

  21. Jenner, P., Rupniak, N. M. J., Rose, S., Kelly, E., Kilpatrick, G., Lees, A., and Marsden, C. D. 1984. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the common marmoset. Neurosci. Lett. 50:85–90.

    Google Scholar 

  22. Langston, J. W., Forno, L. S., Rebert, C. S., and Irwin, I. 1984. Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)_in the squirrel monkey. Brain Res. 292:390–394.

    Google Scholar 

  23. Hallman, H., Olson, L., and Jonsson, G. 1984. Neurotoxicity of the meperidine analogue N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on brain catecholamine neurons in the mouse. Eur. J. Pharmacol. 97:133–136.

    Google Scholar 

  24. Heikkila, R. E., Hess, A., and Duvoisin, R. C. 1984. Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Science. 224:1451–1453.

    Google Scholar 

  25. Jarvis, M. F., and Wagner, G. C. 1985. Age-dependent effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuropharmacology. 24:581–583.

    Google Scholar 

  26. Adams, J. D. Jr., and Odunze, I. N. 1991. Oxygen free radicals and Parkinson's disease. Free Rad. Biol. Med. 10:161–169.

    Google Scholar 

  27. Chiba, K., Trevor, A., and Castagnoli, N. 1984. Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem. Biophys. Res. Commun. 120:574–578.

    Google Scholar 

  28. Castagnoli, N., Chiba, K., and Trevor, A. J. 1985. Potential bioactivation pathways for the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Life Sci. 36:225–230.

    Google Scholar 

  29. Javitch, J. A., D'Amato, R. J., Strittmatter, S. M., and Snyder, S. H. 1985. Parkinsonism-inducing neurotoxin. N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by dopamine neurons explains selective toxicity. Proc. Natl. Acad. Sci. USA. 82:2173–2177.

    Google Scholar 

  30. Chiba, K., Trevor, A. J., and Castagnoli, N. 1985. Active uptake of MPP+, a metabolite of MPTP by brain synaptosomes. Biochem. Biophys. Res. Commun. 128:1228–1232.

    Google Scholar 

  31. Nicklas, W. J., Vyas, I., and Heikkila, R. E. 1985. Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Life Sci. 36:2503–2508.

    Google Scholar 

  32. Ramsay, R. R., Kowal, A. T., Johnson, M. K., Salach, J. I., and Singer, T. P. 1987. The inhibition site of MPP+, the neurotoxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is near the Q-binding site of NADH dehydrogenase. Arch. Biochem. Biophys. 259:645–649.

    Google Scholar 

  33. Rios, C., and Tapia, R. 1987. Changes in lipid peroxidation induced by 1-methyl-4-phenylpyridinium in mouse brain homogenates. Neurosci. Lett. 77:321–326.

    Google Scholar 

  34. Rojas, P., and Rios, C. 1993. Increased striatal lipid peroxidation after intracerebroventricular MPP+ administration to mice. Pharmacol. Toxicol. 72:364–368.

    Google Scholar 

  35. Dexter, D. T., Carayon, A., Javoy-Agid, F., Agid, Y., Wells Daniels, F. R., Lees, A. J., Jenner, P., and Marsden, C. D. 1991. Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and the other neurodegenerative diseases affecting the basal ganglia. Brain. 114:1953–1975.

    Google Scholar 

  36. Rios, C., Alvarez-Vega, R., and Rojas, P. 1995. Depletion of copper and manganese in brain after MPTP treatment of mice. Pharmacol. Toxicol. 76:348–352.

    Google Scholar 

  37. Haley, T. J., and McCormick, W. G. 1957. Pharmacological effects produced by intracerebral injections of drugs in the conscious mouse. Brit. J. Pharmacol. 12:12–15.

    Google Scholar 

  38. Mihatsch, W., Russ, H., and Przuntek, H. 1988. Intracerebroventricular administration of 1-methyl-4-phenylpyridinium ion in mice: effects of simultaneously administered nomifensine, deprenyl, and 1-t-butyl-4,4-diphenylpiperidine. J. Neural. Transm. 71:177–188.

    Google Scholar 

  39. Glowinski, J., and Iversen, L. L. 1966. Regional studies of catecholamines in the rat brain. Disposition of 3H-norepinephrine, 3H-dopamine, and 3H-DOPA in various regions of the brain. J. Neurochem. 13:655–669.

    Google Scholar 

  40. Garcia, E., Rios, C., and Sotelo, J. 1992. Ventricular injection of nerve growth factor increases dopamine content in the striata of MPTP-treated mice. Neurochem. Res. 17:979–982.

    Google Scholar 

  41. Bonilla, E. 1978. Flameless atomic absorption spectrophotometric determination of manganese in rat brain and other tissues. Clin. Chem. 24:471–474.

    Google Scholar 

  42. Welz, B. 1976. Atomic spectroscopy. Verlag-Chemie, Weinheim, New York.

    Google Scholar 

  43. Steel, R. G. D., and Torrie, J. H. 1980. Principles and procedures of statistics. McGraw-Hill Inc., New York.

    Google Scholar 

  44. Donaldson, J. 1981.The pathophysiology of trace metals: neurotransmitter interaction in the CNS. Trends Pharmacol. Sci. 2:75–78.

    Google Scholar 

  45. Kono, Y., Takahashi, M., and Asada K. 1976. Oxidation of manganous pyrophosphate by superoxide radicals and illuminated spinach chloroplasts. Arch. Biochem. Biophys. 174:454–461.

    Google Scholar 

  46. Archibald, F. S., and Fridovich I. 1981. Manganese, superoxide dismutase and oxygen tolerance in some lactic acid bacteria. J. Bacteriol. 146:928–936.

    Google Scholar 

  47. George, J. D., Rosen, G. M., and Rauckman, E. J. 1980. Lipid peroxidation: the role of hepatic FAD-monooxygenase. Pages 541–562, in Simic M. G. and Kavel, M. (eds.), Autoxidation in food and biological systems. Plenum Publishing Corp., New York.

    Google Scholar 

  48. Donaldson, J., LaBella, F. S., and Gesser D. 1981. Enhanced autoxidation of dopamine as possible basis of manganese neurotoxicity. Neurotoxicology 2:53–64.

    Google Scholar 

  49. Liccione, J. J., Maines, D. M. 1989. Manganese-mediated increase in the rat brain mitochondrial cytochrome P-450 and drug metabolism activity: susceptibility of the striatum. J. Pharmacol. Exp. Ther. 248:222–228.

    Google Scholar 

  50. Maynard, L. S., and Cotzias, G. C. 1955. Partition of Mn among organs and organelles of the rat. J. Biol. Chem. 214:489–495.

    Google Scholar 

  51. Liccione, J.,and Maines, M. 1988. Selective vulnerability of glutathione metabolism and cellular defense mechanisms in rat striatum to manganese. J. Pharmacol. Exp. Ther. 247:156–161.

    Google Scholar 

  52. Kandel, E. R., and Schwartz, J. H. 1985. Pages 268–269. Principles of neural science. Elsevier, New York.

    Google Scholar 

  53. Suzuki, J., Mouri, T., Suzuki, Y., Nishiyama, K., Fujii, N., and Yano, H. 1975. Study of subacute toxicity of manganese dioxide in monkeys. Tokushima J. Exp. Med. 22:5–10.

    Google Scholar 

  54. Fahn, S. 1976. Biochemistry of the basal ganglia. Adv. Neurol. 14:59–89.

    Google Scholar 

  55. Autissier, N., Rochette, L., Dumas, P., Beley, A., Loireau, A., and Bralet, J. 1982. Dopamine and norepinephrine turnover in various regions of the rat brain after chronic MnCl2 administration. Toxicology 24:175–182.

    Google Scholar 

  56. Ramsay, R. R., and Singer, T. P. 1986. 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. 21:7585–7587.

    Google Scholar 

  57. Tholey, G., Ledig, M., Mandel, P., Sargentini, L., Frivold, A. H., Leroy, M., Grippo, A. A., and Wedler, F. C. 1988. Concentrations of physiologically important metal ions in glial cells cultured from chick cerebral cortex. Neurochem. Res. 13:45–50.

    Google Scholar 

  58. Gerlach, M., Riederer, P., Przuntek, H., Youdim, M. B. H. 1991. MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease. Eur. J. Pharmacol. Mol. Pharmacol. 208:273–286.

    Google Scholar 

  59. Scheuhammer, A. M., and Cherian, M. G. 1982. Influence of chronic MnCl2 and EDTA treatment on tissue levels and urinary excretion of trace metals in rats. Arch. Environ. Contam. Toxicol. 11 (4):515–520.

    Google Scholar 

  60. Halliwell, B., and Gutteridge, J. M. C. 1985. Free radicals in biology and medicine. Oxford-Claredon.

  61. Rojas, P., Altagracia M., Kravzov J., and Ríos C. 1993. Amantadine increases striatal dopamine turnover in MPTP-treated mice. Drug. Dev. Res. 29:222–226.

    Google Scholar 

  62. Daniels, A. J., Lysling, K., and Abarca, J. 1981. Uptake and release of manganese by rat striatal slices. Biochem. Pharmacol. 30:1833–1837.

    Google Scholar 

  63. Chandra, S. V., and Shukla, G. S. 1981: Concentrations of striatal catecholamines in rats given manganese chloride through drinking water. J. Neurochem. 36:683–687.

    Google Scholar 

  64. Bonilla, E. 1980. L-tyrosine hydroxylase activity in the rat brain after chronic oral administration of manganese chloride. Neurobehav. Toxicol. 2:37–41.

    Google Scholar 

  65. Miller, D. B., Reinhard, J. F., Daniels, A. J., and O' Callaghan J. P. 1991. Diethyldithiocarbamate potentiates the neurotoxicity of in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and of in vitro 1-methyl-4-phenylpyridinium. J. Neurochem. 57:541–549.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rojas, P., Ríos, C. Short-term manganese pretreatment partially protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Neurochem Res 20, 1217–1223 (1995). https://doi.org/10.1007/BF00995386

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00995386

Key Words

Navigation