Skip to main content
SpringerLink
Log in

Role of Lipoamide Dehydrogenase and Metallothionein on 1-Methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced Neurotoxicity

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

Abstract

In the present study, we investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on lipoamide dehydrogenase activity and metallothionein content. Lipoamide dehydrogenase is a flavoprotein enzyme, which reduces lipoamide and low molecular weight thiols. This enzyme has also been involved in the conversion of ubiquinone (coenzyme Q-10, oxidized form) to ubiquinol (reduced form). Lipoamide dehydrogenase activity was measured spectrophotometrically following its incubation with different doses of MPTP, MPP+, and divalent metals. MPTP at higher concentrations inhibited the lipoamide dehydrogenase activity, whereas it’s potent toxic metabolite 1-methyl-4-phenylpyridinium (MPP+) had a similar effect at lower concentration. Calcium and copper did not affect the enzyme activity at any of the doses tested, whereas, zinc dose dependently enhanced the lipoamide dehydrogenase activity. Additionally, levels of metallothionein in the mouse nigrostriatal system were measured by cadmium affinity method following administration of MPTP. Metallothionein content was significantly reduced in the substantia nigra (SN), and not in the nucleus caudatus putamen (NCP) following a single administration of MPTP (30 mg/kg, i.p.). Our results suggests that both lipoamide dehydrogenase activity and metallothionein levels may be critical for dopaminergic neuronal survival in Parkinson’s disease and provides further insights into the neurotoxic mechanisms involved in MPTP-induced neurotoxicity.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Thomas B, Muralikrishnan D, Mohanakumar KP (2000) In vivo hydroxyl radical generation in the striatum following systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Brain Res 85:221–224

    Article  Google Scholar 

  2. Chiueh CC, Burns RS, Markey SP et al (1985) Primate model of parkinsonism: selective lesion of nigrostriatal neurons by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine produces an extrapyramidal syndrome in rhesus monkeys. Life Sci 36:213–218

    Article  PubMed  CAS  Google Scholar 

  3. Ebadi M, Leuschen MP, El Refaey H et al (1996) The antioxidant properties of zinc and metallothionein. Neurochem Int 29:159–166

    Article  PubMed  CAS  Google Scholar 

  4. Sziraki I, Mohanakumar KP, Rauhala P et al (1998) Manganese: a transition metal protects nigrostriatal neurons from oxidative stress in the iron-induced animal model of parkinsonism. Neuroscience 85:1101–1111

    Article  PubMed  CAS  Google Scholar 

  5. Dawson R, Felheim R, Nguyen S (1995) Mechanism of sodium nitroprusside-mediated inhibition of aromatic amino acid decarboxylase activity. Pharmacology 50:74–85

    Article  PubMed  CAS  Google Scholar 

  6. Salach JI, Singer TP, Castagnoli N et al (1984) Oxidation of the neurotoxic amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by monoamine oxidase A and B and suicide inactivation of the enzyme by MPTP. Biochem Biophys Res Commun 125:831–835

    Article  PubMed  CAS  Google Scholar 

  7. Heikkila RE, Nicklas WJ, Vyas I, Duvoisin RC (1985) Dopaminergic toxicity of rotenone and 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Neurosci Lett 62:389–394

    Article  PubMed  CAS  Google Scholar 

  8. Hoppel CL, Grinblatt D, Kwok HC et al (1987) Inhibition of mitochondrial respiration by analogs of 4-phenylpyridine and 1-methyl-4-phenylpyridinium cation (MPP+) the neurotoxic metabolite of MPTP. Biochem Biophys Res Commun 148:684–693

    Article  PubMed  CAS  Google Scholar 

  9. Singer TP, Ramsay RR, McKeown K et al (1988) Mechanism of the neurotoxicity of 1-methyl-4-phenylpyridinium (MPP+), the toxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Toxicology 49:17–23

    Article  PubMed  CAS  Google Scholar 

  10. Poirier J, Donaldson J, Barbeau A (1985) The specific vulnerability of the substantia nigra to MPTP is related to the presence of transition metals. Biochem Biophys Res Commun 128:25–33

    Article  PubMed  CAS  Google Scholar 

  11. Varadarajan S, Yatin S, Aksenova M et al (2000) Alzheimer’s amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol 130:184–208

    Article  PubMed  CAS  Google Scholar 

  12. Dhanasekaran M, Ren J (2005) The emerging role of coenzyme Q-10 in aging, neurodegeneration, cardiovascular disease, cancer and diabetes mellitus. Curr Neurovasc Res 2:447–459

    Article  PubMed  CAS  Google Scholar 

  13. Schulz JB, Lindenau J, Seyfried J et al (2000) Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 267:4904–4911

    Article  PubMed  CAS  Google Scholar 

  14. Olsson JM, Xia L, Eriksson LC et al (1999) Ubiquinone is reduced by lipoaminde dehydrogenase and this reaction is potently stimulated by zinc. FEBS lett 448:190–192

    Article  PubMed  CAS  Google Scholar 

  15. Battino M, Gorini A, Villa RF et al (1995) Coenzyme Q content in synaptic and non-synaptic mitochondria from different brain regions in the ageing rat. Mech Ageing Dev 78:173–187

    Article  PubMed  CAS  Google Scholar 

  16. Maulik N, Yoshida T, Engelman RM et al (2000) Dietary coenzyme Q (10) supplement renders swine hearts resistant to ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 278:1084–1090

    Google Scholar 

  17. Favit A, Nicoletti F, Scapagnini U et al (1992) Ubiquinone protects cultured neurons against spontaneous and excitotoxin-induced degeneration. J Cerebr Blood Fl met 12:638–645

    CAS  Google Scholar 

  18. Matthews RT, Yang L, Browne S et al (1998) Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. P Natl Acad Sci USA 95:8892–8897

    Article  CAS  Google Scholar 

  19. Kumari MV, Hiramatsu M, Ebadi M (1998) Free radical scavenging actions of metallothionein isoforms I and II. Free Radical Res 29:93–101

    Article  CAS  Google Scholar 

  20. Rojas P, Rojas-Castaneda J, Vigueras RM et al (2000) MPTP decreases MT-I mRNA in mouse striatum. Neurochem Res 25:503–509

    Article  PubMed  CAS  Google Scholar 

  21. Bartsch R, Klein D, Summer KH (1990) The Cd-Chelex assay: a new sensitive method to determine metallothionein containing zinc and cadmium. Arch Toxicol 67:177–180

    Article  Google Scholar 

  22. Klivenyi P, Starkov AA, Calingasan NY et al (2004) Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity. J Neurochem 88:1352–60

    Article  PubMed  CAS  Google Scholar 

  23. Abell CW, Shen RS, Gessner W et al (1984) Inhibition of dihydropteridine reductase by novel 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine analogs. Science 224:405–407

    Article  PubMed  CAS  Google Scholar 

  24. Hadjiconstantinou M, Neff NH (1990) Differential recovery of dopamine synthetic enzymes following MPTP and the consequences of GM1 ganglioside treatment. Eur J Pharmacol 181:137–139

    Article  PubMed  CAS  Google Scholar 

  25. Thiffault C, Aumont N, Quinon R et al (1995) Effect of MPTP and L-deprenyl on antioxidant enzymes and lipid peroxidation levels in mouse brain. J Neurochem 65:2725–2733

    Article  PubMed  CAS  Google Scholar 

  26. Bray TM, Bettger WJ (1990) The physiological role of zinc as an antioxidant. Free radical Biol Med 8:281–291

    Article  CAS  Google Scholar 

  27. Rogers JM, Lonerdal B, Hurley LS et al (1987) Iron and Zinc concentrations and 59Fe retention in developing fetuses of zinc-deficient rats. J Nutr 117:1875–1882

    PubMed  CAS  Google Scholar 

  28. Ebadi M, Hiramatsu M, Burke WJ et al (1998) Metallothionein isoforms provide neuroprotection against 6-hydroxydopamine-generated hydroxyl radicals and superoxide anions. Proc West Pharmacol Soc 41:155–158

    PubMed  CAS  Google Scholar 

  29. Mohanakumar KP, Muralikrishnan D, Thomas B (2000) Neuroprotection by sodium salicylate against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. Brain Res 864:281–290

    Article  PubMed  CAS  Google Scholar 

  30. Muralikrishnan D, Ebadi M (2001) SKF-38393, a dopamine receptor agonist, attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. Brain Res 892:241–247

    Article  PubMed  CAS  Google Scholar 

  31. Fariello RG, Ghirardi O, Peschechera A et al (1987) Transient nigral ubiquinone depletion after single MPTP administration in mice. Neuropharmacology 26:1799–1802

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  33. Mochizuki H, Imai H, Endo K et al (1994) Iron accumulation in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian monkeys. Neurosci Lett 168:251–253

    Article  PubMed  CAS  Google Scholar 

  34. Olanow CW, Good PF, Shinotoh H et al (1996) Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study. Neurology 46:492–498

    PubMed  CAS  Google Scholar 

  35. Mohanakumar KP, De Bartolomeis A, Wu RM et al (1994) Ferrous-citrate complex and nigral degeneration: Evidence for free radical formation and lipid peroxidation. Ann N Y Acad Sci 738:392–399

    Article  PubMed  CAS  Google Scholar 

  36. Muralikrishnan D, Mohanakumar KP (1998) Neuroprotection by bromocriptine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice. FASEB J 12:905–912

    PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This study was supported by Department of Pharmacal Sciences, Auburn University, Auburn AL.

Author information

Authors and Affiliations

  1. Division of Pharmacology and Toxicology, Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA

    Muralikrishnan Dhanasekaran, Senthilkumar S. Karuppagounder, Subramaniam Uthayathas & Vishnu Suppiramaniam

  2. Department of Pharmacology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58201, USA

    Christian B. Albano, Lori Pellet, Holly Brown-Borg & Manuchair Ebadi

Authors
  1. Muralikrishnan Dhanasekaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian B. Albano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lori Pellet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Senthilkumar S. Karuppagounder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Subramaniam Uthayathas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vishnu Suppiramaniam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Holly Brown-Borg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manuchair Ebadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Muralikrishnan Dhanasekaran.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dhanasekaran, M., Albano, C.B., Pellet, L. et al. Role of Lipoamide Dehydrogenase and Metallothionein on 1-Methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced Neurotoxicity. Neurochem Res 33, 980–984 (2008). https://doi.org/10.1007/s11064-007-9468-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-007-9468-9

Keywords

Search

Navigation