Skip to main content
Log in

Acetyl-levo-carnitine protects against MPTP-induced parkinsonism in primates

  • Full Papers
  • Published:
Journal of Neural Transmission - Parkinson's Disease and Dementia Section

Summary

Acetyl-levo-carnitine (ALC) protects against 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in the nonhuman primate. ALC pretreated monkeys do not show signs of parkinsonism or electroretinographic changes typical of dopaminergic deficiency when given MPTP. In addition, pilot neurochemical and morphological data confirm a partial protection effect. While MAO-B inhibitors, like L-Deprenyl, are thought to protect dopaminergic neurons from MPTP-induced cell death by preventing the conversion of MPTP to its toxic metabolite MPP+, ALC is not known to have MAO-B affnity. Converging evidence suggests that ALC may affect directly mitochondrial respiration, which is known to be the target of MPP+ and affected in human neurodegenerative diseases, including Parkinson's disease. The results of this study point to new therapeutic avenues for the treatment of these nosologic entities.

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

  • Bahl JJ, Bressler R (1987) The pharmacology of carnitine. Ann Rev Pharmacol Toxicol 27: 257–277

    Article  Google Scholar 

  • Bodis-Wollner I (1990a) Physiological effects of acetyl-levo-carnitine in the central nervous system. Int J Clin Pharmacol Res 10: 109–114

    PubMed  Google Scholar 

  • Bodis-Wollner I (1990b) Visual deficits related to dopamine deficiency in experimental animals and Parkinson's disease patients. Trends Neurosci 13: 296–302

    Article  PubMed  Google Scholar 

  • Bremer J (1983) Carnitine-metabolism and functions. Physiol Rev 63: 1420–1480

    PubMed  Google Scholar 

  • Burlina AP, Sershen H, Debler EA, Lajtha A (1989) Uptake of acetylcarnitine in the brain. Neurochem Res 14: 489–493

    PubMed  Google Scholar 

  • Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (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

    PubMed  Google Scholar 

  • Cohen G, Pasik A, Cohen B, Leist A, Mytilineou C, Yahr MD (1984) Pargyline and deprenyl prevent the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Eur J Pharmacol 106: 209–210

    Article  Google Scholar 

  • Di Lisa F, Toninello A, Bobyleva-Guarriero V, Morbiato S, Siliprandi N (1986) Protective action of L-carnitine on mitochondrial energy linked processes impaired by aging. In: Van Bezooijen CFA, Miglio F, Knook DL (eds) Liver drugs and aging. Eurage, Rijswijg, pp 103–110

    Google Scholar 

  • Falchetto S, Kato G, Provini L (1971) The action of carnitines on cortical neurons. Can J Physiol Pharmacol 49 (1): 1–7

    PubMed  Google Scholar 

  • Fritz IB (1963) Carnitine and its role in fatty acid metabolism. Adv Lipid Res 1: 285–334

    Google Scholar 

  • Ghilardi MF, Bodis-Wollner I, Onofrj MC, Marx MS, Glover A (1988a) Spatial frequency-dependent abnormalities of the pattern electroretinogram and visual evoked potentials in a parkinsonian monkey model. Brain 111: 131–149

    PubMed  Google Scholar 

  • Ghilardi MF, Chung E, Bodis-Wollner I, Dvorzniak M, Glover A, Onofrj M (1988b) Systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration decreases retinal dopamine content in primates. Life Sci 43: 255–262

    Article  PubMed  Google Scholar 

  • Ghilardi MF, Marx MS, Bodis-Wollner I, Camras CB, Glover AA (1989) The effect of intraocular 6-hydroxydopamine on retinal processing of primates. Ann Neurol 25: 357–364

    Article  PubMed  Google Scholar 

  • Harnois C, Marcotte G, Bedard PJ (1987) Alteration of monkey retinal oscillatory potentials after MPTP injection. Doc Ophthalmol 67: 363–369

    Article  PubMed  Google Scholar 

  • Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC (1984) Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 311: 467–469

    PubMed  Google Scholar 

  • Heikkila RE, Nicklas WJ, Vyas I, Duvoisin RC (1985) Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridium ion (MPP+) after their stereotaxic administration to rats. Neurosci Lett 62: 389–394

    Article  PubMed  Google Scholar 

  • Javitch JA, D'Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonian-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 USA 82: 2173–2177

    PubMed  Google Scholar 

  • Javitch JA, Snyder SH (1984) Uptake of MPP(+) by dopamine neurons explains selectivity of parkinsonian-inducing neurotoxin MPTP. Eur J Pharmacol 106: 455–456

    Article  PubMed  Google Scholar 

  • Mizuno Y, Suzuki K, Sone N, Saitoh T (1988) Inhibition of mitochondrial respiration by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mouse brain in vivo. Neurosci Lett 91: 349–353

    Article  PubMed  Google Scholar 

  • Mytilineou C, Cohen G (1984) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine destroys dopamine neurons in explants of rat embryo mesencephalon. Science 225: 529–553

    PubMed  Google Scholar 

  • Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenylpyridine, a metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 36: 2503–2508

    Article  PubMed  Google Scholar 

  • Nicklas WJ, Youngster SK, Kindt MV, Heikkila RE (1987) Molecular mechanisms of MPTP-induced toxicity. IV. MPTP, MPP+ and mitochondrial function. Life Sci 40: 721–729

    Article  PubMed  Google Scholar 

  • Nguyen-Legros J, Savy C (1988) Dopamine innervation of the vertebrate retina: morphological studies. In: Bodis-Wollner I, Piccolino M (eds) Dopaminergic mechanisms of vision. Alan R Liss, New York, pp 1–17

    Google Scholar 

  • Onofrj MC, Ghilardi MF, Bodis-Wollner I, Glover A (1986) L-Acetylcarnitine (LAC) prevents MPTP-induced parkinsonian like syndrome (PS) in the monkey. Neurology 36 [Suppl 1]: 96

    Google Scholar 

  • Parker WD, Boyson SJ, Parks JK (1989) Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol 26: 719–723

    Article  PubMed  Google Scholar 

  • Pasik P, Pasik T, Pecci Saavedra JP (1982) Immunocytochemical localization of serotonin at the ultrastructural level. J Histochem Cytochem 30: 760–764

    PubMed  Google Scholar 

  • Qu ZX, Neff NH, Hadjiconstantinou M (1988) MPP+ depletes retinal dopamine and induces D-1 receptor supersensitivity. Eur J Pharmacol 148: 453–455

    Article  PubMed  Google Scholar 

  • Ramsay RR, Salach JI, Dadgar J, Singer TP (1986) Inhibition of mitochondrial NADH dehydrogenase by pyridine derivatives and its possible relation to experimental and idiopathic parkinsonism. Biochem Biophys Res Comm 135: 269–275

    Article  PubMed  Google Scholar 

  • Reinhard JF Jr, Diliberto EJ Jr, Viveros OH, Daniels AJ (1987) Subcellular compartmentalization of 1-methyl-4-phenylpyridinium with catecholamines in adrenal medullary chromaffin vesicles may explain the lack of toxicity to adrenal chromaffin cells. Proc Natl Acad Sci USA 84: 8160–8164

    PubMed  Google Scholar 

  • Schapira AHV, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem 54: 823–827

    PubMed  Google Scholar 

  • Siliprandi N, Siliprandi D, Ciman M (1965) Stimulation of oxidation of mitochondrial fatty acids and of acetate by acetylcarnitine. Biochem J 96: 777–780

    PubMed  Google Scholar 

  • Snyder JW, Kyle ME, Ferraro TN (1990) L-carnitine delays the killing of cultured hepatocytes by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Arch Biochem Biophys 276: 132–138

    Article  PubMed  Google Scholar 

  • Villa RF, Gorini A, Zanada F, Benzi G (1986) Action of L-acetylcarnitine on different cerebral mitochondrial populations from hippocampus. Arch Int Pharmacodyn Ther 279: 195–211

    PubMed  Google Scholar 

  • Villa L, Turpeenoja L, Benzi G, Stella AMG (1988) Action of L-acetylcarnitine on age-dependent modifications of mitochondrial membrane proteins from rat cerebellum. Neurochem Res 13: 909–916

    Article  PubMed  Google Scholar 

  • Westlund KN, Denney RM, Kochenperger LM, Rose RM, Abell CW (1985) Distinct monoamino oxidase A and B populations in primate brains. Science 230: 181–183

    PubMed  Google Scholar 

  • Wong C, Ishibashi T, Tucker G, Hamasaki D (1985) Responses of the pigmented rabbit retina to NMPTP, a chemical inducer of parkinsonism. Exp Eye Res 40: 509–519

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bodis-Wollner, I., Chung, E., Ghilardi, M.F. et al. Acetyl-levo-carnitine protects against MPTP-induced parkinsonism in primates. J Neural Transm Gen Sect 3, 63–72 (1991). https://doi.org/10.1007/BF02251137

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02251137

Keywords

Navigation