The effect of nobiletin on apoptosis in midbrain and neostriatum in a rat model of Parkinson’s disease induced by intranigral injection of lipopolysaccharide

Authors

Abstract

Background and Objective: Nobiletin is a flavonoid in the citrus. The antioxidant, anti-inflammatory and anti-apoptotic properties of nobiletin have been observed in many recent studies. The aim of the present study was to investigate the effect of nobiletin on apoptosis in an experimental model of Parkinson's disease induced by intranigral injection of lipopolysaccharide in the rat.
 
Materials and Methods: Male rats (n = 28) were divided into four groups: sham, sham under treatment with nobiletin, lesion, and lesion treated with nobiletin. To achieve unilateral lesion of the nigrostriatal system, rats received 5 microgram of LPS into the right substantia nigra. Nobiletin was daily administered p.o. at a dose of 10 mg/kg one hour after surgery for one week. At the end of the first week, tissue homogenate was prepared and severity of apoptosis was measured.
 
Results: The results showed that treatment with nobiletin decreases the level of DNA fragmentation in the LPS group as compared to the LPS group in midbrain area (p <0.05).
 
Conclusion: Administration of nobiletin to lipopolysaccharide-induced Parkinsonian rats reduces apoptosis and may be potentially effective for ancillary therapy of Parkinson's disease.
 

Keywords


1. Sanz FJ, Solana-Manrique C, Muñoz-Soriano V, Calap-Quintana P, Moltó MD, Paricio N. Identification of potential therapeutic compounds for Parkinson's disease using Drosophila and human cell models. Free Radical Biology and Medicine 2017;108:683-91. 2. Rizek P, Kumar N, Jog MS. An update on the diagnosis and treatment of Parkinson disease. The Canadian Medical Association Journal 2016;188(16):1157-65. 3. Elbaz A, Bower JH, Maraganore DM, McDonnell SK, Peterson BJ, Ahlskog JE, et al. Risk tables for parkinsonism and Parkinson's disease. Journal of Clinical Epidemiology 2002;55(1):25-31. 4. Boeve BF, Silber MH, Ferman TJ, Lucas JA, Parisi JE. Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Movement disorders: Official Journal of the Movement Disorder Society 2001;16(4):622-30. 5. Lin T-K, Liou C-W, Chen S-D, Chuang Y-C, Tiao M-M, Wang P-W, et al. Mitochondrial dysfunction and biogenesis in the pathogenesis of Parkinson’s disease. Chang Gung Medical Journal 2009;32(6):589-99. 6. Tadibi V, Yosefi B, Taheri H, Taherzadeh J. The impact of a physical therapy regimen on motor function in people with parkinson's disease. J Pajouhesh 2008;18:157-69. 7. Schulze‐Osthoff K, Ferrari D, Los M, Wesselborg S, Peter ME. Apoptosis signaling by death receptors. European Journal of Biochemistry 1998;254(3):439-59. 8. Wang ZB, Liu YQ, Cui YF. Pathways to caspase activation. Cell Biology International 2005;29(7):489-96. 9. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998;281(5381):1322-6. 10. Upadhyay D, Panduri V, Ghio A, Kamp DW. Particulate matter induces alveolar epithelial cell DNA damage and apoptosis: role of free radicals and the mitochondria. American Journal of Respiratory Cell and Molecular Biology 2003;29(2):180-7. 11. Marzetti E, Privitera G, Simili V, Wohlgemuth SE, Aulisa L, Pahor M, et al. Multiple pathways to the same end: mechanisms of myonuclear apoptosis in sarcopenia of aging. The Scientific World Journal 2010;10:340-9. 12. Kim S-E, Ko I-G, Kim B-K, Shin M-S, Cho S, Kim C-J, et al. Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus. Experimental Gerontology 2010;45(5):357-65. 13. Bloem B, Irwin I, Buruma O, Haan J, Roos R, Tetrud J, et al. The MPTP model: versatile contributions to the treatment of idiopathic Parkinson's disease. Journal of the Neurological Sciences 1990;97(2-3):273-93. 14. Lev N, Melamed E, Offen D. Apoptosis and Parkinson's disease. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2003;27(2):245-50. 15. Roth J, Harré E-M, Rummel C, Gerstberger R, Hubschle T. Signaling the brain in systemic inflammation: role of sensory circumventricular organs. Frontiers in Bioscience 2004;9(7):290-300. 16. Yoshigai E, Machida T, Okuyama T, Mori M, Murase H, Yamanishi R, et al. Citrus nobiletin suppresses inducible nitric oxide synthase gene expression in interleukin-1β-treated hepatocytes. Biochemical and Biophysical Research Communications 2013;439(1):54-9. 17. Kimura O, Ohta C, Koga N, Haraguchi K, Kato Y, Endo T. Carrier-mediated uptake of nobiletin, a citrus polymethoxyflavonoid, in human intestinal Caco-2 cells. Food Chemistry 2014;154:145-50. 18. Lee Y-C, Cheng T-H, Lee J-S, Chen J-H, Liao Y-C, Fong Y, et al. Nobiletin, a citrus flavonoid, suppresses invasion and migration involving FAK/PI3K/Akt and small GTPase signals in human gastric adenocarcinoma AGS cells. Molecular and Cellular Biochemistry 2011;347(1-2):103-15. 19. Ihara H, Yamamoto H, Ida T, Tsutsuki H, Sakamoto T, Fujita T, et al. Inhibition of nitric oxide production and inducible nitric oxide synthase expression by a polymethoxyflavone from young fruits of Citrus unshiu in rat primary astrocytes. Bioscience, Biotechnology, and Biochemistry 2012:120215. 20. Miyata Y, Tanaka H, Shimada A, Sato T, Ito A, Yamanouchi T, et al. Regulation of adipocytokine secretion and adipocyte hypertrophy by polymethoxyflavonoids, nobiletin and tangeretin. Life Sciences 2011;88(13-14):613-8. 21. Tominari T, Hirata M, Matsumoto C, Inada M, Miyaura C. Polymethoxy flavonoids, nobiletin and tangeretin, prevent lipopolysaccharide-induced inflammatory bone loss in an experimental model for periodontitis. Journal of Pharmacological Sciences 2012:11188SC. 22. Li W, Wang X, Niu X, Zhang H, He Z, Wang Y, et al. Protective effects of nobiletin against endotoxic shock in mice through inhibiting TNF-α, IL-6, and HMGB1 and regulating NF-κB pathway. Inflammation 2016;39(2):786-97. 23. Parkar N, Bhatt L, Addepalli V. Efficacy of nobiletin, a citrus flavonoid, in the treatment of the cardiovascular dysfunction of diabetes in rats. Food & Function 2016;7(7):3121-9. 24. Zhang L, Zhang X, Zhang C, Bai X, Zhang J, Zhao X, et al. Nobiletin promotes antioxidant and anti-inflammatory responses and elicits protection against ischemic stroke in vivo. Brain Research 2016;1636:130-41. 25. Zhang L, Zhao H, Zhang X, Chen L, Zhao X, Bai X, et al. Nobiletin protects against cerebral ischemia via activating the p-Akt, p-CREB, BDNF and Bcl-2 pathway and ameliorating BBB permeability in rat. Brain Research Bulletin 2013;96:45-53. 26. Jeong KH, Jeon M-T, Kim HD, Jung UJ, Jang MC, Chu JW, et al. Nobiletin protects dopaminergic neurons in the 1-methyl-4-phenylpyridinium-treated rat model of Parkinson's disease. Journal of Medicinal Food 2015;18(4):409-14. 27. Yabuki Y, Ohizumi Y, Yokosuka A, Mimaki Y, Fukunaga K. Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice. Neuroscience 2014;259:126-41. 28. Bi J, Zhang H, Lu J, Lei W. Nobiletin ameliorates isoflurane-induced cognitive impairment via antioxidant, anti-inflammatory and anti-apoptotic effects in aging rats. Molecular Medicine Reports 2016;14(6):5408-14. 29. Liu L, Wu Xw. Nobiletin protects human retinal pigment epithelial cells from hydrogen peroxide–induced oxidative damage. Journal of Biochemical and Molecular Toxicology 2018;32(5):e22052. 30. Qu Y, Liu Y, Chen L, Zhu Y, Xiao X, Wang D, et al. Nobiletin prevents cadmium-induced neuronal apoptosis by inhibiting reactive oxygen species and modulating JNK/ERK1/2 and Akt/mTOR networks in rats. Neurological Research 2018;40(3):211-20. 31. Malik S, Bhatia J, Suchal K, Gamad N, Dinda AK, Gupta YK, et al. Nobiletin ameliorates cisplatin-induced acute kidney injury due to its anti-oxidant, anti-inflammatory and anti-apoptotic effects. Experimental and Toxicologic Pathology 2015;67(7-8):427-33.