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. 2007 May 1;8(2):213–222. doi: 10.1111/j.1582-4934.2004.tb00276.x

Coenzyme Q10 inhibits mitochondrial complex‐1 down‐regulation and nuclear factor‐kappa B activation

M Ebadi 1,✉, S K Sharma 1, S Wanpen 1, A Amornpan 1
PMCID: PMC6740220  PMID: 15256069

Abstract

We have used control‐homozygous weaver mutant, and ‐heterozygous weaver mutant mice in order to explore the basic molecular mechanism of neurodegeneration and the neuroprotective potential of coenzyme Q10. Homozygous weaver mutant mice exhibited progressive neurodegeneration in the hippocampus, striatum, and cerebellum, and a reduction in the striatal levels of dopamine and coenzyme Qs (Q9 and Q10) without any significant changes in norepinephrine and serotonin. Mitochondrial complex‐1 was down regulated; whereas nuclear factor‐kappa B was up regulated in homozygous weaver mutant mice. Rotenone inhibited complex‐1, enhanced nuclear factor‐kappa B, and caused apoptosis in human dopaminergic (SK‐N‐SH) neurons; whereas nuclear factor‐kappa B antibody suppressed rotenone‐induced apoptosis, suggesting that enhancing coenzyme Q10 synthesis and suppressing the induction of NF‐kappa B, may provide neuroprotection.

Keywords: weaver mutant mice, coenzyme Q10, ubiquinone‐NADH oxidoreductase (Complex‐1), NF‐kappa B, neurodegeneration, neuroprotection

References

  • 1. Ciesielska A., Joniec I., Przybylkowski A., Gromadzdka G., Kurkowska‐Jastrzebska I., Czlonkowska A., Czlonkowski A., Dynamics of expression of the mRNA for cytokines and inducible nitric oxide synthase in a murine model of the Parkinson's disease. Acta Neurobiol Exp (Wars) 63: 117–126, 2003. [DOI] [PubMed] [Google Scholar]
  • 2. Wintermeyer P., Riess O., Schols L., Przuntek H., Miterski B., Epplen J.T., Kruger R., Mutation analysis and association studies of nuclear factor‐kappaB1 in sporadic Parkinson's disease patients. J. Neurol. Transm 109: 1181–1188, 2002. [DOI] [PubMed] [Google Scholar]
  • 3. Hirsch E.C., Hunot S., Nitric oxide, glial cells and neuronal degeneration in parkinsonism. Trends Pharmacol. Sci. 21: 163–165, 2000. [DOI] [PubMed] [Google Scholar]
  • 4. Bringold U., Ghafourifar P., Richter C., Peroxynitrite formed by mitochondrial NO synthase promotes mitochondrial Ca2+ release. Free Radical Biol. Med. 29: 343–348, 2000. [DOI] [PubMed] [Google Scholar]
  • 5. Clarke D.L., Branton R.L., A Role for tumor necrosis factor alpha in death of dopaminergic neurons following neural transplantation. Exp. Neurol. 176: 154–162, 2002. [DOI] [PubMed] [Google Scholar]
  • 6. Kruger R., Hardt C., Tschentscher F., Jackel S., Kuhn W., Muller T., Werner J., Woitalla D., Berg D., Kuhnl N., Fuchs G.A., Santos E.J., Przuntek H., Epplen JT, Schols L., Riess O., Genetic analysis of immunomodulating factors in sporadic Parkinson's disease. J. Neural Transm. 107: 553–562, 2000. [DOI] [PubMed] [Google Scholar]
  • 7. McGuire S.O., Ling Z.D., Lipton J.W., Sortwell C.E., Collier T.J., Carvey P.M., Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopaminergic neurons. Exp Neurol. 169: 219–230, 2001. [DOI] [PubMed] [Google Scholar]
  • 8. Ebadi M., Govitropong P., Sharma S., Muralikrishnan D., Shavali S., Pellet L., Schafer R., Albano C., Josh E., Ubiquinone (Coenzyme Q10) and Mitochondria in Oxidative Stress of Parkinson's Disease. Biological Signals & Receptors. 10: 224–253, 2001. [DOI] [PubMed] [Google Scholar]
  • 9. Ebadi M., Sharma S., Amornpan A., Maanum S., Weaver Mutant Mouse in Progression of Neurodegeneration in Parkinson's Disease In Parkinson's Disease, Eds Ebadi M., Pfeiffer R. CRC Press; (2004). [Google Scholar]
  • 10. Sharma S.K., Carlson E.C., Ebadi M., Neuroprotective actions of Selegiline inhibiting 1‐methyl, 4‐phenyl, pyridinium ion (MPP+) ‐induced apoptosis in SK‐N‐SH neurons, J. Neurocytol., 32: 329–343, 2003. [DOI] [PubMed] [Google Scholar]
  • 11. Roffler‐Tarlov S., Graybiel A.M., The postnatal development of the DA containing innervation of dorsal and ventral striatum: effects of the weaver gene. J. Neurosci., 7: 2364–2372, 1987. [PMC free article] [PubMed] [Google Scholar]
  • 12. Ghetti B., Triarhou L.C., Nigrostriatal aberrations induced by weaver gene are present at birth. Soc. Neurosci. Abstr., 18: 156, 1982b. [Google Scholar]
  • 13. Surmeier D.J., Mermelstein P.G., Goldwitz D., The weaver mutation of GIRK‐2 results in a loss of inwardly rectifying K+ current in cerebellar granule cells, Proc. Natl. Acad. Sci. USA, 93: 11191–11195, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Blum M., Weickert C., Carrasco E., The weaver GIRK2 mutation leads to decreased levels of serum thyroid hormone: charactrization of the effect on midbrain DA‐rgic neuron survival, Exp Neurol., 160: 413–424, 1999. [DOI] [PubMed] [Google Scholar]
  • 15. Zhong J., Deng J., Ghetti B., Lee W.H., Inhibition of insulin‐like growth factor activity contributes to the premature apoptosis of cerebellar granular neurons in weaver mutant mice: in vitro analysis, J. Neuroscience. Res., 70: 36–45, 2002. [DOI] [PubMed] [Google Scholar]
  • 16. Xu S.G., Prasad C., Smith D.E., Neurons exhibiting DA D2 receptor immunoreactivity in the substantia nigra of the mutant weaver mouse. Neuroscience, 89: 191–207, 1999. [DOI] [PubMed] [Google Scholar]
  • 17. Peng J., Wu Z., Wu Y., Hsu M., Stevenson F.F., Boonplueang R., Roffler‐Tarlov S.K., Andersen J.K., Inhibition of caspases protects cerebellar granular cells of the weaver mouse from apoptosis and improves behavioral phenotype, J. Biol. Chem., 277: 44285–44291, 2002. [DOI] [PubMed] [Google Scholar]

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