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NeuroMolecular Medicine

, Volume 16, Issue 1, pp 106–118 | Cite as

Curcumin Nanoparticles Attenuate Neurochemical and Neurobehavioral Deficits in Experimental Model of Huntington’s Disease

  • Rajat Sandhir
  • Aarti Yadav
  • Arpit Mehrotra
  • Aditya Sunkaria
  • Amandeep Singh
  • Sadhna Sharma
Original Paper

Abstract

Till date, an exact causative pathway responsible for neurodegeneration in Huntington’s disease (HD) remains elusive; however, mitochondrial dysfunction appears to play an important role in HD pathogenesis. Therefore, strategies to attenuate mitochondrial impairments could provide a potential therapeutic intervention. In the present study, we used curcumin encapsulated solid lipid nanoparticles (C-SLNs) to ameliorate 3-nitropropionic acid (3-NP)-induced HD in rats. Results of MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay and succinate dehydrogenase (SDH) staining of striatum revealed a marked decrease in Complex II activity. However, C-SLN-treated animals showed significant increase in the activity of mitochondrial complexes and cytochrome levels. C-SLNs also restored the glutathione levels and superoxide dismutase activity. Moreover, significant reduction in mitochondrial swelling, lipid peroxidation, protein carbonyls and reactive oxygen species was observed in rats treated with C-SLNs. Quantitative PCR and Western blot results revealed the activation of nuclear factor-erythroid 2 antioxidant pathway after C-SLNs administration in 3-NP-treated animals. In addition, C-SLN-treated rats showed significant improvement in neuromotor coordination when compared with 3-NP-treated rats. Thus, the results of this study suggest that C-SLNs administration might be a promising therapeutic intervention to ameliorate mitochondrial dysfunctions in HD.

Keywords

Curcumin Huntington’s disease Mitochondria Nanoparticles 3-Nitropropionic acid 

Notes

Acknowledgments

The authors acknowledge the financial assistance received from the Department of Science and Technology and the University Grants Commission under the PURSE and SAP programs.

Conflict of interest

There is no conflict of interest.

References

  1. Abu-Taweel, G. M., Ajarem, J. S., & Ahmad, M. (2013). Protective effect of curcumin on anxiety, learning behaviour, neuromuscular activities, brain neurotransmitters and oxidative stress enzymes in cadmium intoxicated mice. Journal of Behavioral and Brain Sciences, 3, 74–84.CrossRefGoogle Scholar
  2. Alexi, T., Hughes, P. E., Faull, R. L., & Williams, C. E. (1998). 3-Nitropropionic acid’s lethal triplet: Cooperative pathways of neurodegeneration. NeuroReport, 9(11), R57–R64.CrossRefPubMedGoogle Scholar
  3. Al-Omar, F. A., Nagi, M. N., Abdulgadir, M. M., Al Joni, K. S., & Al-Majed, A. A. (2006). Immediate and delayed treatments with curcumin prevents forebrain ischemia-induced neuronal damage and oxidative insult in the rat hippocampus. Neurochemical Research, 31(5), 611–618.CrossRefPubMedGoogle Scholar
  4. Alston, T. A., Mela, L., & Bright, H. J. (1977). 3-Nitropropionate, the toxic substance of Indigofera, is a suicide inactivator of succinate dehydrogenase. Proceedings of the National Academy of Sciences, USA, 74(9), 3767–3771.CrossRefGoogle Scholar
  5. Bharath, S., Hsu, M., Kaur, D., Rajagopalan, S., & Andersen, J. K. (2002). Glutathione, iron and Parkinson’s disease. Biochemical Pharmacology, 64(5–6), 1037–1048.CrossRefPubMedGoogle Scholar
  6. Bizat, N., Hermel, J. M., Boyer, F., Jacquard, C., Creminon, C., Ouary, S., et al. (2003). Calpain is a major cell death effector in selective striatal degeneration induced in vivo by 3-nitropropionate: Implications for Huntington’s disease. Journal of Neuroscience, 23(12), 5020–5030.PubMedGoogle Scholar
  7. Bogdanov, M. B., Ferrante, R. J., Kuemmerle, S., Klivenyi, P., & Beal, M. F. (1998). Increased vulnerability to 3-nitropropionic acid in an animal model of Huntington’s disease. Journal of Neurochemistry, 71(6), 2642–2644.CrossRefPubMedGoogle Scholar
  8. Boissier, J. R., & Simon, P. (1965). Action of caffeine on the spontaneous motility of the mouse. Archives Internationales de Pharmacodynamie et de Therapie, 158(1), 212–221.PubMedGoogle Scholar
  9. Brouillet, E., Guyot, M. C., Mittoux, V., Altairac, S., Conde, F., Palfi, S., et al. (1998). Partial inhibition of brain succinate dehydrogenase by 3-nitropropionic acid is sufficient to initiate striatal degeneration in rat. Journal of Neurochemistry, 70(2), 794–805.CrossRefPubMedGoogle Scholar
  10. Browne, S. E., Bowling, A. C., MacGarvey, U., Baik, M. J., Berger, S. C., Muqit, M. M., et al. (1997). Oxidative damage and metabolic dysfunction in Huntington’s disease: Selective vulnerability of the basal ganglia. Annals of Neurology, 41(5), 646–653.CrossRefPubMedGoogle Scholar
  11. Browne, S. E., Ferrante, R. J., & Beal, M. F. (1999). Oxidative stress in Huntington’s disease. Brain Pathology, 9(1), 147–163.CrossRefPubMedGoogle Scholar
  12. Chan, D. C. (2006). Mitochondria: Dynamic organelles in disease, aging, and development. Cell, 125(7), 1241–1252.CrossRefPubMedGoogle Scholar
  13. Cheng, A. L., Hsu, C. H., Lin, J. K., Hsu, M. M., Ho, Y. F., Shen, T. S., et al. (2001). Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Research, 21(4B), 2895–2900.Google Scholar
  14. Cirillo, G., Maggio, N., Bianco, M. R., Vollono, C., Sellitti, S., & Papa, M. (2010). Discriminative behavioral assessment unveils remarkable reactive astrocytosis and early molecular correlates in basal ganglia of 3-nitropropionic acid subchronic treated rats. Neurochemistry International, 56(1), 152–160.CrossRefPubMedGoogle Scholar
  15. Dhillon, N., Aggarwal, B. B., Newman, R. A., Wolff, R. A., Kunnumakkara, A. B., Abbruzzese, J. L., et al. (2008). Phase II trial of curcumin in patients with advanced pancreatic cancer. Clinical Cancer Research, 14(14), 4491–4499.CrossRefPubMedGoogle Scholar
  16. Duran-Vilaregut, J., Manich, G., Del Valle, J., Camins, A., Pallas, M., Vilaplana, J., et al. (2012). Expression pattern of ataxia telangiectasia mutated (ATM), p53, Akt, and glycogen synthase kinase-3beta in the striatum of rats treated with 3-nitropropionic acid. Journal of Neuroscience Research, 90(9), 1803–1813.CrossRefPubMedGoogle Scholar
  17. Fang, M., Jin, Y., Bao, W., Gao, H., Xu, M., Wang, D., et al. (2012). In vitro characterization and in vivo evaluation of nanostructured lipid curcumin carriers for intragastric administration. International Journal of Nanomedicine, 7, 5395–5404.CrossRefPubMedCentralPubMedGoogle Scholar
  18. Fiske, C. H., & Subbarow, Y. (1925). The colorimetric determination of phosphorus. Journal of Biological Chemistry, 66, 375–400.Google Scholar
  19. Forsmark-Andree, P., Lee, C. P., Dallner, G., & Ernster, L. (1997). Lipid peroxidation and changes in the ubiquinone content and the respiratory chain enzymes of submitochondrial particles. Free Radical Biology and Medicine, 22(3), 391–400.CrossRefPubMedGoogle Scholar
  20. Frautschy, S. A., & Cole, G. M. (2009). Bioavailable curcuminoid formulations for treating Alzheimer’s disease and other age-realted disorders. United States. US 2009/0324703 A1.Google Scholar
  21. Gould, T. J., Bowenkamp, K. E., Larson, G., Zahniser, N. R., & Bickford, P. C. (1995). Effects of dietary restriction on motor learning and cerebellar noradrenergic dysfunction in aged F344 rats. Brain Research, 684(2), 150–158.CrossRefPubMedGoogle Scholar
  22. Green, D. R., & Kroemer, G. (2004). The pathophysiology of mitochondrial cell death. Science, 305(5684), 626–629.CrossRefPubMedGoogle Scholar
  23. Griffiths, D. E., & Houghton, R. L. (1974). Studies on energy-linked reactions: Modified mitochondrial ATPase of oligomycin-resistant mutants of Saccharomyces cerevisiae. European Journal of Biochemistry, 46(1), 157–167.CrossRefPubMedGoogle Scholar
  24. Guerrieri, F., Capozza, G., Fratello, A., Zanotti, F., & Papa, S. (1993). Functional and molecular changes in FoF1 ATP-synthase of cardiac muscle during aging. Cardioscience, 4(2), 93–98.PubMedGoogle Scholar
  25. Guyot, M. C., Hantraye, P., Dolan, R., Palfi, S., Maziere, M., & Brouillet, E. (1997). Quantifiable bradykinesia, gait abnormalities and Huntington’s disease-like striatal lesions in rats chronically treated with 3-nitropropionic acid. Neuroscience, 79(1), 45–56.CrossRefPubMedGoogle Scholar
  26. Hamilton, B. F., & Gould, D. H. (1987). Nature and distribution of brain lesions in rats intoxicated with 3-nitropropionic acid: A type of hypoxic (energy deficient) brain damage. Acta Neuropathologica, 72(3), 286–297.CrossRefPubMedGoogle Scholar
  27. Hayes, J. D., & McMahon, M. (2001). Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. Cancer Letters, 174(2), 103–113.CrossRefPubMedGoogle Scholar
  28. Henderson, J. M., Schleimer, S. B., Allbutt, H., Dabholkar, V., Abela, D., Jovic, J., et al. (2005). Behavioural effects of parafascicular thalamic lesions in an animal model of parkinsonism. Behavioural Brain Research, 162(2), 222–232.CrossRefPubMedGoogle Scholar
  29. Hickey, M. A., Zhu, C., Medvedeva, V., Lerner, R. P., Patassini, S., Franich, N. R., et al. (2012). Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington’s disease. Molecular Neurodegener, 7, 12.CrossRefGoogle Scholar
  30. Hissin, P. J., & Hilf, R. (1976). A fluorometric method for determination of oxidized and reduced glutathione in tissues. Analytical Biochemistry, 74(1), 214–226.CrossRefPubMedGoogle Scholar
  31. Kakkar, V., & Kaur, I. P. (2011). Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium induced behavioural, biochemical and histopathological alterations in mice brain. Food and Chemical Toxicology, 49(11), 2906–2913.CrossRefPubMedGoogle Scholar
  32. Kakkar, V., Muppu, S. K., Chopra, K., & Kaur, I. P. (2013). Curcumin loaded solid lipid nanoparticles: An efficient formulation approach for cerebral ischemic reperfusion injury in rats. European Journal of Pharmaceutics and Biopharmaceutics, 6411(13), 00059-3.Google Scholar
  33. Kakkar, V., Singh, S., Singla, D., & Kaur, I. P. (2011). Exploring solid lipid nanoparticles to enhance the oral bioavailability of curcumin. Molecular Nutrition & Food Research, 55(3), 495–503.CrossRefGoogle Scholar
  34. King, T. E., & Howard, R. L. (1967). Preparation and properties of soluble NADH dehydrogenase from cardiac muscle. Methods in enzymology (pp. 275–276). New York: Academic Press.Google Scholar
  35. King, T. E., Ohnishi, T., Winter, D. B., & Wu, J. T. (1976). Biochemical and EPR probes for structure-function studies of iron sulfur centers of succinate dehydrogenase. Advances in Experimental Medicine and Biology, 74, 182–227.CrossRefPubMedGoogle Scholar
  36. Kono, Y. (1978). Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Archives of Biochemistry and Biophysics, 186(1), 189–195.CrossRefPubMedGoogle Scholar
  37. Kremer, B. (2002). Clinical neurology of Huntington’s disease. OXFORD MONOGRAPHS ON MEDICAL GENETICS.Google Scholar
  38. Kumar, P., & Kumar, A. (2009). Neuroprotective effect of cyclosporine and FK506 against 3-nitropropionic acid induced cognitive dysfunction and glutathione redox in rat: Possible role of nitric oxide. Neuroscience Research, 63(4), 302–314.CrossRefPubMedGoogle Scholar
  39. Kumar, P., Padi, S. S., Naidu, P. S., & Kumar, A. (2007). Possible neuroprotective mechanisms of curcumin in attenuating 3-nitropropionic acid-induced neurotoxicity. Methods and Findings in Experimental and Clinical Pharmacology, 29(1), 19–25.CrossRefPubMedGoogle Scholar
  40. Kundu, P., Mohanty, C., & Sahoo, S. K. (2012). Antiglioma activity of curcumin-loaded lipid nanoparticles and its enhanced bioavailability in brain tissue for effective glioblastoma therapy. Acta Biomaterialia, 8(7), 2670–2687.CrossRefPubMedGoogle Scholar
  41. La Fontaine, M. A., Geddes, J. W., Banks, A., & Butterfield, D. A. (2000). 3-Nitropropionic acid induced in vivo protein oxidation in striatal and cortical synaptosomes: Insights into Huntington’s disease. Brain Research, 858(2), 356–362.CrossRefPubMedGoogle Scholar
  42. Lee, W. T., & Chang, C. (2004). Magnetic resonance imaging and spectroscopy in assessing 3-nitropropionic acid-induced brain lesions: An animal model of Huntington’s disease. Progress in Neurobiology, 72(2), 87–110.CrossRefPubMedGoogle Scholar
  43. Leventhal, L., Sortwell, C. E., Hanbury, R., Collier, T. J., Kordower, J. H., & Palfi, S. (2000). Cyclosporin A protects striatal neurons in vitro and in vivo from 3-nitropropionic acid toxicity. Journal of Comparative Neurology, 425(4), 471–478.CrossRefPubMedGoogle Scholar
  44. Levine, R. L., Garland, D., Oliver, C. N., Amici, A., Climent, I., Lenz, A. G., et al. (1990). Determination of carbonyl content in oxidatively modified proteins. Methods in Enzymology, 186, 464–478.CrossRefPubMedGoogle Scholar
  45. Lin, M. T., & Beal, M. F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 443(7113), 787–795.CrossRefPubMedGoogle Scholar
  46. Liu, Y., Peterson, D. A., Kimura, H., & Schubert, D. (1997). Mechanism of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. Journal of Neurochemistry, 69(2), 581–593.CrossRefPubMedGoogle Scholar
  47. Lowry, O. H., Rosebrough, N. J., Farr, A. L., & Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry, 193(1), 265–275.PubMedGoogle Scholar
  48. Miao, W., Hu, L., Scrivens, P. J., & Batist, G. (2005). Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway. Journal of Biological Chemistry, 280(21), 20340–20348.CrossRefPubMedGoogle Scholar
  49. Mohammadi-Bardbori, A., Bengtsson, J., Rannug, U., Rannug, A., & Wincent, E. (2012). Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR). Chemical Research in Toxicology, 25(9), 1878–1884.CrossRefPubMedGoogle Scholar
  50. Montoya, A., Price, B. H., Menear, M., & Lepage, M. (2006). Brain imaging and cognitive dysfunctions in Huntington’s disease. Journal of Psychiatry and Neuroscience, 31(1), 21–29.PubMedCentralPubMedGoogle Scholar
  51. Nasr, P., Carbery, T., & Geddes, J. W. (2009). N-methyl-D-aspartate receptor antagonists have variable affect in 3-nitropropionic acid toxicity. Neurochemical Research, 34(3), 490–498.CrossRefPubMedGoogle Scholar
  52. Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95(2), 351–358.CrossRefPubMedGoogle Scholar
  53. Petersen, A., Castilho, R. F., Hansson, O., Wieloch, T., & Brundin, P. (2000). Oxidative stress, mitochondrial permeability transition and activation of caspases in calcium ionophore A23187-induced death of cultured striatal neurons. Brain Research, 857(1–2), 20–29.CrossRefPubMedGoogle Scholar
  54. Pfaffl, M. W., Horgan, G. W., & Dempfle, L. (2002). Relative expression software tool (REST©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Research, 30(9), e36.CrossRefPubMedCentralPubMedGoogle Scholar
  55. Puka-Sundvall, M., Wallin, C., Gilland, E., Hallin, U., Wang, X., Sandberg, M., et al. (2000). Impairment of mitochondrial respiration after cerebral hypoxia-ischemia in immature rats: relationship to activation of caspase-3 and neuronal injury. Brain Research. Developmental Brain Research, 125(1–2), 43–50.CrossRefPubMedGoogle Scholar
  56. Ray, B., Bisht, S., Maitra, A., & Lahiri, D. K. (2011). Neuroprotective and neurorescue effects of a novel polymeric nanoparticle formulation of curcumin (NanoCurc) in the neuronal cell culture and animal model: Implications for Alzheimer’s disease. Journal of Alzheimer’s Disease, 23(1), 61–77.PubMedCentralPubMedGoogle Scholar
  57. Sandhir, R., & Mehrotra, A. (2013). Quercetin supplementation is effective in improving mitochondrial dysfunctions induced by 3-nitropropionic acid: Implications in Huntington’s disease. Biochimica et Biophysica Acta, 1832(3), 421–430.CrossRefPubMedGoogle Scholar
  58. Sandhir, R., Mehrotra, A., & Kamboj, S. S. (2010). Lycopene prevents 3-nitropropionic acid-induced mitochondrial oxidative stress and dysfunctions in nervous system. Neurochemistry International, 57(5), 579–587.CrossRefPubMedGoogle Scholar
  59. Sandhir, R., Sood, A., Mehrotra, A., & Kamboj, S. S. (2012). N-Acetylcysteine reverses mitochondrial dysfunctions and behavioral abnormalities in 3-nitropropionic acid-induced Huntington’s disease. Neurodegenerative Diseases, 9(3), 145–157.CrossRefPubMedGoogle Scholar
  60. Saulle, E., Gubellini, P., Picconi, B., Centonze, D., Tropepi, D., Pisani, A., et al. (2004). Neuronal vulnerability following inhibition of mitochondrial complex II: A possible ionic mechanism for Huntington’s disease. Molecular and Cellular Neuroscience, 25(1), 9–20.CrossRefPubMedGoogle Scholar
  61. Sharma, S., Zhuang, Y., Ying, Z., Wu, A., & Gomez-Pinilla, F. (2009). Dietary curcumin supplementation counteracts reduction in levels of molecules involved in energy homeostasis after brain trauma. Neuroscience, 161(4), 1037–1044.CrossRefPubMedCentralPubMedGoogle Scholar
  62. Sottocasa, G. L., Kuylenstierna, B., Ernster, L., & Bergstrand, A. (1967). An electron-transport system associated with the outer membrane of liver mitochondria. A biochemical and morphological study. Journal of Cell Biology, 32(2), 415–438.CrossRefPubMedGoogle Scholar
  63. Sun, M., Su, X., Ding, B., He, X., Liu, X., Yu, A., et al. (2012). Advances in nanotechnology-based delivery systems for curcumin. Nanomedicine (Lond), 7(7), 1085–1100.CrossRefGoogle Scholar
  64. Tabrizi, S. J., Cleeter, M. W., Xuereb, J., Taanman, J. W., Cooper, J. M., & Schapira, A. H. (1999). Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Annals of Neurology, 45(1), 25–32.CrossRefPubMedGoogle Scholar
  65. Tabrizi, S. J., Workman, J., Hart, P. E., Mangiarini, L., Mahal, A., Bates, G., et al. (2000). Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Annals of Neurology, 47(1), 80–86.CrossRefPubMedGoogle Scholar
  66. Tedeschi, H., & Harris, D. L. (1958). Some observations on the photometric estimation of mitochondrial volume. Biochimica et Biophysica Acta, 28(2), 392–402.CrossRefPubMedGoogle Scholar
  67. Towbin, H., Staehelin, T., & Gordon, J. (1992). Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applications. Biotechnology, 24, 145–149.PubMedGoogle Scholar
  68. Tunez, I., Montilla, P., Del Carmen Munoz, M., Feijoo, M., & Salcedo, M. (2004). Protective effect of melatonin on 3-nitropropionic acid-induced oxidative stress in synaptosomes in an animal model of Huntington’s disease. Journal of Pineal Research, 37(4), 252–256.CrossRefPubMedGoogle Scholar
  69. Wang, H., & Joseph, J. A. (1999). Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radical Biology and Medicine, 27(5–6), 612–616.CrossRefPubMedGoogle Scholar
  70. Williams, J. N., Jr. (1964). A method for the simultaneous quantitative estimation of cytochromes a, B, C1, and C in mitochondria. Archives of Biochemistry and Biophysics, 107, 537–543.CrossRefPubMedGoogle Scholar
  71. Wu, J., Li, Q., Wang, X., Yu, S., Li, L., Wu, X., et al. (2013). Neuroprotection by curcumin in ischemic brain injury involves the Akt/Nrf2 pathway. PLoS ONE, 8(3), e59843. doi: 10.1371/journal.pone.0059843.CrossRefPubMedCentralPubMedGoogle Scholar
  72. Yang, K. Y., Lin, L. C., Tseng, T. Y., Wang, S. C., & Tsai, T. H. (2007). Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS. Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences, 853(1–2), 183–189.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Rajat Sandhir
    • 1
  • Aarti Yadav
    • 1
  • Arpit Mehrotra
    • 1
  • Aditya Sunkaria
    • 1
  • Amandeep Singh
    • 2
  • Sadhna Sharma
    • 2
  1. 1.Department of BiochemistryPanjab UniversityChandigarhIndia
  2. 2.Department of BiochemistryPostgraduate Institute of Medical Education and ResearchChandigarhIndia

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