Sains Malaysiana 45(9)(2016): 1363–1370

Tocotrienol-Rich Fraction Supplementation Modulates Antioxidant Enzymes Activity and Reduces DNA Damage in APPswe/PS1dE9 Alzheimer’s Disease Mouse Model

(Suplementasi Fraksi Kaya Tokotrienol Memodulasi Aktiviti Enzim Antioksidan dan Mengurangkan Kerosakan DNA pada APPswe/PS1dE9 Model Mencit Penyakit Alzheimer)

 

H.A. DAMANHURI1,2*, N.I. ABDUL RAHIM1, W.N.W. NASR1I, J.K. TAN1, S. MAKPOL1,

M. MAZLAN3, I. TOOYAMA4 & W.Z. WAN NGAH1,2

 

1Biochemistry Department, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaakob Latif, 56000 Cheras, Kuala Lumpur, Federal Territory, Malaysia

 

2UKM Medical Molecular Biology Institute, Jalan Yaakob Latif, 56000 Cheras

Kuala Lumpur, Federal Territory, Malaysia

 

3Faculty of Medicine, Universiti Teknologi MARA, Jalan Hospital, 47000 Sungai Buloh, Selangor Darul Ehsan, Malaysia

 

4Molecular Neuroscience Research Centre, Shiga University of Medical Sciences,

Seta Tsukinowacho, Otsu 520-2192, Shiga, Japan

 

Diserahkan: 21 Disember 2015/Diterima: 29 April 2016

 

ABSTRACT

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by deterioration of the brain functions that result in impairment of memory, cognition and behavioural functions. Oxidative stress is well known to be one of the causative factors for AD. Thus this disease is potentially modulated by natural antioxidants such as vitamin E. The aim of this study was to evaluate the effect of tocotrienol-rich fraction (TRF) supplementation on antioxidant enzymes and DNA damage using APPswe/PS1dE9 transgenic mouse model of AD. Animals were supplemented with TRF (200 mg/kg) or alpha-tocopherol (αT) (200 mg/kg) for six months starting from nine months old. We found that superoxide dismutase (SOD) activity in AD mouse was decreased by supplementation of TRF and αT as compared with AD control mouse with no significant differences in glutathione peroxidise (GPx) activity in all groups. TRF supplementation significantly increased catalase (CAT) activity. The level of DNA damage of AD mouse shows significant decrease with supplementation of TRF and αT. In conclusion, TRF was able to modulate antioxidant enzymes activity and decreased the level of DNA damage of AD transgenic mouse model.

 

Keywords: Alzheimer’s disease; oxidative status; tocotrienol-rich fraction

 

 

ABSTRAK

Penyakit Alzheimer (AD) adalah gangguan progresif neurodegeneratif yang boleh dicirikan dengan kemerosotan fungsi otak yang mengakibatkan kerosakan ingatan, kognitif dan fungsi tingkah laku. Tekanan oksidatif terkenal sebagai salah satu faktor penyebab AD. Oleh itu penyakit ini berpotensi dimodulasikan oleh antioksidan semula jadi seperti vitamin E. Kajian ini bertujuan menilai kesan suplementasi fraksi kaya tokotrienol (TRF) ke atas enzim antioksidan dan kerosakan DNA menggunakan APPswe/PS1dE9 model mencit transgenik AD. Model haiwan ini telah diberi suplementasi TRF (200 mg/kg) atau αT (200 mg/kg) selama enam bulan dari usia sembilan bulan. Keputusan menunjukkan aktiviti SOD menurun pada mencit AD yang telah disuplementasi dengan TRF dan αT berbanding dengan mencit AD kawalan. Tiada perbezaan signifikan dalam aktiviti GPx dalam semua kumpulan. Manakala mencit AD yang diberi suplementasi TRF menunjukkan peningkatan ketara dalam aktiviti CAT. Daripada segi kerosakan DNA, suplementasi TRF dan αT menunjukkan penurunan ketara pada mencit AD. Kesimpulannya, TRF berpotensi untuk memodulasi aktiviti enzim antioksidan dan mengurangkan tahap kerosakan DNA model mencit transgenik AD.

 

Kata kunci: Fraksi kaya tokotrienol; penyakit Alzheimer; status oksidatif

RUJUKAN

Abd Hamid, N.A., Hasrul, M.A., Ruzanna, R.J., Ibrahim, I.A., Baruah, P.S., Mazlan, M., Yusof, Y.A. & Ngah, W.Z. 2011. Effect of vitamin E (Tri E(R)) on antioxidant enzymes and DNA damage in rats following eight weeks exercise. Nutrition Journal 10: 37.

Abdul Hafid, S.R., Chakravarthi, S., Nesaretnam, K. & Radhakrishnan, A.K. 2013. Tocotrienol-adjuvanted dendritic cells inhibit tumor growth and metastasis: A murine model of breast cancer. PLoS One 8(9): e74753.

Aliahmat, N.S., Noor, M.R., Yusof, W.J., Makpol, S., Ngah, W.Z. & Yusof, Y.A. 2012. Antioxidant enzyme activity and malondialdehyde levels can be modulated by Piper betle, tocotrienol rich fraction and Chlorella vulgaris in aging C57BL/6 mice. Clinics (Sao Paulo) 67(12): 1447-1454.

Alzheimer’s Disease International. 2013. Policy Brief for Heads of Government: The Global Impact of Dementia 2013-2050. London: Alzheimer’s Disease International.

Anderson, A.J., Su, J.H. & Cotman, C.W. 1996. DNA damage and apoptosis in Alzheimer’s disease: Colocalization with c-Jun immunoreactivity, relationship to brain area, and effect of postmortem delay. Journal of Neuroscience 16(5): 1710-1719.

Butterfield, D.A., Reed, T., Newman, S.F. & Sultana, R. 2007. Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer’s disease and mild cognitive impairment. Free Radical Biology & Medicine 43(5): 658-677.

Chauhan, V. & Chauhan, A. 2006. Oxidative stress in Alzheimer’s disease. Pathophysiology 13(3): 195-208.

Chin, S.F., Ibahim, J., Makpol, S., Abdul Hamid, N.A., Abdul Latiff, A., Zakaria, Z., Mazlan, M., Mohd Yusof, Y.A., Abdul Karim, A. & Wan Ngah, W.Z. 2011. Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: A randomized controlled study. Nutrition Metabolism (Lond) 8(1): 42.

Chin, S.F., Hamid, N.A., Latiff, A.A., Zakaria, Z., Mazlan, M., Yusof, Y.A., Karim, A.A., Ibahim, J., Hamid, Z. & Ngah, W.Z. 2008. Reduction of DNA damage in older healthy adults by Tri E Tocotrienol supplementation. Nutrition 24(1): 1-10.

De Leo, M.E., Borrello, S., Passantino, M., Palazzotti, B., Mordente, A., Daniele, A., Filippini, V., Galeotti, T. & Masullo, C. 1998. Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer’s disease. Neuroscience Letters 250(3): 173-176.

Feng, Y. & Wang, X. 2012. Antioxidant therapies for Alzheimer’s disease. Oxidative Medicine and Cellular Longevity 2012: 472932.

Grand, J.H., Caspar, S. & Macdonald, S.W. 2011. Clinical features and multidisciplinary approaches to dementia care. Journal of Multidiscipinary Healthcare 4: 125-147.

Hafid, S.R., Radhakrishnan, A.K. & Nesaretnam, K. 2010. Tocotrienols are good adjuvants for developing cancer vaccines. BMC Cancer 10: 5.

Hensley, K., Carney, J.M., Mattson, M.P., Aksenova, M., Harris, M., Wu, J.F., Floyd, R.A. & Butterfield, D.A. 1994. A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: Relevance to Alzheimer disease. Proceedings of the National Academy of Sciences USA 91(8): 3270-3274.

Hong, X., Liu, J., Zhu, G., Zhuang, Y., Suo, H., Wang, P., Huang, D., Xu, J., Huang, Y., Yu, M., Bian, M., Sheng, Z., Fei, J., Song, H., Behnisch, T. & Huang, F. 2013. Parkin overexpression ameliorates hippocampal long-term potentiation and β-amyloid load in an Alzheimer’s disease mouse model. Human Molecular Genetics 23(4): 1056-1072.

Jankowsky, J.L., Fadale, D.J., Anderson, J., Xu, G.M., Gonzales, V., Jenkins, N.A., Copeland, N.G., Lee, M.K., Younkin, L.H., Wagner, S.L., Younkin, S.G. & Borchelt, D.R. 2004. Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: Evidence for augmentation of a 42-specific γ secretase. Human Molecular Genetics 13(2): 159-170.

Jankowsky, J.L., Slunt, H.H., Ratovitski, T., Jenkins, N.A., Copeland, N.G. & Borchelt, D.R. 2001. Co-expression of multiple transgenes in mouse CNS: A comparison of strategies. Biomolecular Engineering 17(6): 157-165.

Jiao, Y., Zhang, Y., Wei, Y., Liu, Z., An, W. & Guo, M. 2012. Direct observation of internalization and ROS generation of amyloid β-Peptide in neuronal cells at subcellular resolution. ChemBioChem 13: 2335-2338.

Kuhad, A., Bishnoi, M., Tiwari, V. & Chopra, K. 2009. Suppression of NF-κβ signaling pathway by tocotrienol can prevent diabetes associated cognitive deficits. Pharmacology Biochemistry and Behavior 92(2): 251-259.

Lesuisse, C., Xu, G., Anderson, J., Wong, M., Jankowsky, J., Holtz, G., Gonzalez, V., Wong, P.C.Y., Price, D.L., Tang, F., Wagner, S. & Borchelt, D.R. 2001. Hyper-expression of human apolipoprotein E4 in astroglia and neurons does not enhance amyloid deposition in transgenic mice. Human Molecular Genetics 10(22): 2525-2537.

Lovell, M.A., Ehmann, W.D., Butler, S.M. & Markesbery, W.R. 1995. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology 45(8): 1594-1601.

Lyras, L., Cairns, N.J., Jenner, A., Jenner, P. & Halliwell, B. 1997. An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s Disease. Journal of Neurochemistry 68(5): 2061-2069.

Makpol, S., Yeoh, T.W., Ruslam, F.A., Arifin, K.T. & Yusof, Y.A. 2013. Comparative effect of Piper betle, Chlorella vulgaris and tocotrienol-rich fraction on antioxidant enzymes activity in cellular ageing of human diploid fibroblasts. BMC Complementary and Alternative Medicine 13: 210.

Makpol, S., Durani, L.W., Chua, K.H., Mohd Yusof, Y.A. & Ngah, W.Z. 2011. Tocotrienol-rich fraction prevents cell cycle arrest and elongates telomere length in senescent human diploid fibroblasts. Journal of Biomedicine and Biotechnology 2011: 506171.

Mao, P., Manczak, M., Calkins, M.J., Truong, Q., Reddy, T.P., Reddy, A.P., Shirendeb, U., Lo, H.H., Rabinovitch, P.S. & Reddy, P.H. 2012. Mitochondria-targeted catalase reduces abnormal APP processing, amyloid beta production and BACE1 in a mouse model of Alzheimer’s disease: Implications for neuroprotection and lifespan extension. Human Molecular Genetics 21(13): 2973-2990.

Marcus, D.L., Thomas, C., Rodriguez, C., Simberkoff, K., Tsai, J.S., Strafaci, J.A. & Freedman, M.L. 1998. Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease. Experimental Neurology 150(1): 40-44.

Mecocci, P., Polidori, M.C., Cherubini, A., Ingegni, T., Mattioli, P., Catani, M., Rinaldi, P., Cecchetti, R., Stahl, W., Senin, U. & Beal, M.F. 2002. Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease. Archives of Neurology 59(5): 794-798.

Moneim, A.E. 2015. Oxidant/antioxidant imbalance and the risk of Alzheimer’s disease. Current Alzheimer Research 12(4): 335-349.

Mullaart, E., Boerrigter, M.E., Ravid, R., Swaab, D.F. & Vijg, J. 1990. Increased levels of DNA breaks in cerebral cortex of Alzheimer’s disease patients. Neurobiology of Aging 11(3): 169-173.

Nagapan, G., Meng Goh, Y., Shameha Abdul Razak, I., Nesaretnam, K. & Ebrahimi, M. 2013. The effects of prenatal and early postnatal tocotrienol-rich fraction supplementation on cognitive function development in male offspring rats. BMC Neuroscience 14: 77.

Nakashima, H., Ishihara, T., Yokota, O., Terada, S., Trojanowski, J.Q., Lee, V.M. & Kuroda, S. 2004. Effects of alpha-tocopherol on an animal model of tauopathies. Free Radical Biology & Medicine 37(2): 176-186.

Padurariu, M., Ciobica, A., Hritcu, L., Stoica, B., Bild, W. & Stefanescu, C. 2010. Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer’s disease. Neuroscience Letters 469(1): 6-10.

Perrin, R., Briancon, S., Jeandel, C., Artur, Y., Minn, A., Penin, F. & Siest, G. 1990. Blood activity of Cu/Zn superoxide dismutase, glutathione peroxidase and catalase in Alzheimer’s disease: A case-control study. Gerontology 36(5-6): 306-313.

Rahman, A.A., Makpol, S., Jamal, R., Harun, R., Mokhtar, N. & Ngah, W.Z. 2014. Tocotrienol-rich fraction, [6]-gingerol and epigallocatechin gallate inhibit proliferation and induce apoptosis of glioma cancer cells. Molecules 19(9): 14528- 14541.

Resende, R., Moreira, P.I., Proenca, T., Deshpande, A., Busciglio, J., Pereira, C. & Oliveira, C.R. 2008. Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radical Biology & Medicie 44(12): 2051-2057.

Rinaldi, P., Polidori, M.C., Metastasio, A., Mariani, E., Mattioli, P., Cherubini, A., Catani, M., Cecchetti, R., Senin, U. & Mecocci, P. 2003. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiology of Aging 24(7): 915-919.

Rodriguez, C., Mayo, J.C., Sainz, R.M., Antolin, I., Herrera, F., Martin, V. & Reiter, R.J. 2004. Regulation of antioxidant enzymes: A significant role for melatonin. Journal of Pineal Research 36(1): 1-9.

Schrag, M., Mueller, C., Zabel, M., Crofton, A., Kirsch, W.M., Ghribi, O., Squitti, R. & Perry, G. 2013. Oxidative stress in blood in Alzheimer’s disease and mild cognitive impairment: A meta-analysis. Neurobiology of Disease 59: 100-110.

Sen, C.K., Khanna, S. & Roy, S. 2006. Tocotrienols: Vitamin E beyond tocopherols. Life Science 78(18): 2088-2098.

Sen, C.K., Khanna, S., Roy, S. & Packer, L. 2000. Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp60(c-Src) kinase activation and death of HT4 neuronal cells. The Journal of Biological Chemistry 275(17): 13049-13055.

Singh, N.P., McCoy, M.T., Tice, R.R. & Schneider, E.L. 1988. A simple technique for quantitation of low levels of DNA damage in individual cells. Experimental Cell Research 175: 184-191.

Smith, D.G., Cappai, R. & Barnham, K.J. 2007. The redox chemistry of the Alzheimer’s disease amyloid beta peptide. Biochimica et Biophysica Acta 1768(8): 1976-1990.

Srivastava, J.K. & Gupta, S. 2006. Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells. Biochemical and Biophysical Research Communications 346(2): 447-453.

Taib, I.S., Budin, S.B., Ghazali, A.R., Jayusman, P.A., Louis, S.R. & Mohamed, J. 2015. Palm oil tocotrienol-rich fraction attenuates testicular toxicity induced by fenitrothion via an oxidative stress mechanism. Toxicology Research 4(1): 132-142.

Taridi, N.M., Abd Rani, N., Abd Latiff, A., Ngah, W.Z. & Mazlan, M. 2014. Tocotrienol rich fraction reverses age-related deficits in spatial learning and memory in aged rats. Lipids 49(9): 855-869.

Taridi, N.M., Yahaya, M.F., Teoh, S.L., Latiff, A.A., Ngah, W.Z., Das, S. & Mazlan, M. 2011. Tocotrienol rich fraction (TRF) supplementation protects against oxidative DNA damage and improves cognitive functions in Wistar rats. Clinical Terapeuthics 162(2): 93-98.

Wang, X., Wang, W., Li, L., Perry, G., Lee, H.G. & Zhu, X. 2014. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochimica et Biophysica Acta 1842: 1240-1247.

Yap, W.N., Chang, P.N., Han, H.Y., Lee, D.T., Ling, M.T., Wong, Y.C. & Yap, Y.L. 2008. Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways. British Journal of Cancer 99(11): 1832-1841.

Zhang, W., Bai, M., Xi, Y., Hao, J., Liu, L., Mao, N., Su, C., Miao, J. & Su, C. 2012. Early memory deficits precede plaque deposition in APPswe/PS1dE9 mice: Involvement of oxidative stress and cholinergic dysfunction. Free Radical Biology & Medicine 52: 1443-1452.

Zhang, J.S., Zhang, S.J., Li, Q., Liu, Y.H., He, N., Zhang, J., Zhou, P.H., Li, M., Guan, T. & Liu, J.R. 2015. Tocotrienol-rich fraction (TRF) suppresses the growth of human colon cancer xenografts in balb/C nude mice by the Wnt pathway. Plos One 10(3): e0122175.

Zhao, Y. & Zhao, B. 2013. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxidative Medicine and Cellular Longevity 2013: 316523.

 

 

*Pengarang untuk surat-menyurat; email: hanafi.damanhuri@ppukm.ukm.edu.my

 

 

 

 
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