Filiz KAZAK, Metin ÇENESİZ, Murat YARIM, Gül Fatma YARIM, Sena ÇENESİZ

Nöroprotektif Etkili Bir Flavonoid: Nobiletin

Nörodejeneratif hastalıkların tedavisinde flavonoidlerin kullanımı yeni umutlar vaad etmektedir. Nobiletin, narenciye kabuklarında bulunan bir polimetoksi flavonoiddir. Nobiletinin nöroprotektif etkiye sahip olduğu pek çok in vivo ve in vitro araştırma ile ortaya konulmuştur. Nobiletin, öğrenme ve hafıza ile ilişkili sinyalizasyon kaskadlarını etkilemekte, enflamasyon mediyatörlerini modüle ederek nörodejenerasyonu hafifletmekte, dopamin salınımını artırarak motor ve bilişsel işlev bozukluğunu engellemekte, duygusal ve yenilikleri tanıma belleğini geliştirmektedir. Güncel çalışmalar, nobiletinin nörodejeneratif hastalıkların tedavisi için yeni bir ilaç olma potansiyeline sahip olduğunu desteklemektedir. Bu derlemede, nobiletinin nöroprotektif etkileri üzerinde durularak, literatürden elde edilen sonuçlar özetlenmiştir.

Anahtar Kelimeler:

Flavonoid, Nobiletin, Nöroprotektif

A Flavonoid has Neuroprotective Effect: Nobiletin

The use of flavonoids promises new approach for the treatment of neurodegenerative diseases. Nobiletine is a polymethoxy flavonoid found in the citrus peel. The neuroprotective effect of nobiletin has been demonstrated in vivo and in vitro. Nobiletine affects the signaling cascades associated with learning and memory, alleviates neurodegeneration by modulating inflammatory mediators, inhibits motor and cognitive dysfunction by increasing dopamine release and enhances memory and recognition of emotions and innovations. Recent studies suggest that nobiletine has the potential to be a new drug for the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of nobiletin was emphasized and the results obtained from the literature were summarized.

Keywords:

Flavonoid, Nobiletin, Neuroprotective,

PDF

___

Bi J, Zhang H, Lu J, Lei W, 2016: Nobiletin ameliorates isoflurane-induced cognitive impairment via antioxidant, anti-inflammatory and anti-apoptotic effects in aging rats. Mol Med Rep, 14, 6, 5408-5414.
Cho HW, Jung SY, Lee GH, Cho JH, Choi IY, 2015: Neuroprotective effect of Citrus unshiu immature peel and nobiletin inhibiting hydrogen peroxide-induced oxidative stress in HT22 murine hippocampal neuronal cells. Pharmacogn Mag, 11, Suppl 2, 284-289.
Choi SY, Ko HC, Ko SY, Hwang JH, Park JG, Kang SH, Han SH, Yun SH, Kim SJ, 2007: Correlation between flavonoid content and the NO production inhibitory activity of peel extracts from various citrus fruits. Biol Pharm Bull, 30, 4, 772-778.
Choi SM, Kim BC, Cho YH, Choi KH, Chang J, Park MS, Kim MK, Cho KH, Kim JK, 2014: Effects of flavonoid compounds on β-amyloid-peptide-induced neuronal death in cultured mouse cortical neurons. Chonnam Med J, 50, 2, 45-51.
Cui Y, Wu J, Jung SC, Park DB, Maeng YH, Hong JY, Kim SJ, Lee SR, Kim SJ, Kim SJ, Eun SY, 2010: Anti-neuroinflammatory activity of nobiletin on suppression of microglial activation. Biol Pharm Bull, 33, 11, 1814-1821.
Cui QJ, Wang LY, Wei ZX, Qu WS, 2014: Continual naringin treatment benefits the recovery of traumatic brain injury in rats through reducing oxidative and inflammatory alterations. Neurochem Res, 39, 7, 1254-1262.
Hiraiwa M, Taylor EM, Campana WM, Darin SJ, O'Brien JS, 1997: Cell death prevention, mitogen-activated protein kinase stimulation, and increased sulfatide concentrations in Schwann cells and oligodendrocytes by prosaposin and prosaptides. Proc Natl Acad Sci USA, 94, 9, 4778-4781.
Ho SC, Kuo CT, 2014: Hesperidin, nobiletin, and tangeretin are collectively responsible for the anti-neuroinflammatory capacity of tangerine peel (Citri reticulatae pericarpium). Food Chem Toxicol, 71, 176-182.
Horowitz RM, Gentilli B, 1977: Flavonoid constituents of citrus. In: Nagy S, Shaw PE, Veldhuis MK, editors. CT: Avi Publishing Company Inc., Citrus Science and Technology, Westport.
Huang H, Li L, Shi W, Liu H, Yang J, Yuan X, Wu L, 2016: The Multifunctional Effects of Nobiletin and Its Metabolites In Vivo and In Vitro. Evid Based Complement Alternat Med, 2016, 2918796.
Jeong KH, Jeon MT, Kim HD, Jung UJ, Jang MC, Chu JW, Yang SJ, Choi IY, Choi MS, Kim SR, 2015: Nobiletin protects dopaminergic neurons in the 1-methyl-4-phenylpyridinium-treated rat model of Parkinson's disease. J Med Food, 18, 4, 409-414.
Jung UJ, Jeon MT, Choi MS, Kim SR, 2014: Silibinin attenuates MPP⁺-induced neurotoxicity in the substantia nigra in vivo. J Med Food, 17, 5, 599-605.
Kang J, Shin JW, Kim YR, Swanberg KM, Kim Y, Bae JR, Kim YK, Lee J, Kim SY, Sohn NW, Maeng S, 2016: Nobiletin improves emotional and novelty recognition memory but not spatial referential memory. J Nat Med, 71, 1, 181-189.
Kawahata I, Yoshida M, Sun W, Nakajima A, Lai Y, Osaka N, Matsuzaki K, Yokosuka A, Mimaki Y, Naganuma A, Tomioka Y, Yamakuni T, 2013: Potent activity of nobiletin-rich Citrus reticulata peel extract to facilitate cAMP/PKA/ERK/CREB signaling associated with learning and memory in cultured hippocampal neurons: identification of the substances responsible for the pharmacological action. J Neural Transm (Vienna), 120, 10, 1397-1409.
Kim HG, Ju MS, Ha SK, Lee H, Lee H, Kim SY, Oh MS, 2012: Acacetin protects dopaminergic cells against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neuroinflammation in vitro and in vivo. Biol Pharm Bull, 35, 8, 1287-1294.
Kim HD, Jeong KH, Jung UJ, Kim SR, 2016: Myricitrin ameliorates 6-hydroxydopamine-induced dopaminergic neuronal loss in the substantia nigra of mouse brain. J Med Food, 19, 4, 374-382.
Lee E, Park HR, Ji ST, Lee Y, Lee J, 2014: Baicalein attenuates astroglial activation in the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine-induced Parkinson's disease model by downregulating the activations of nuclear factor-κB, ERK, and JNK. J Neurosci Res, 92, 1, 130-139.
Leem E, Nam JH, Jeon MT, Shin WH, Won SY, Park SJ, Choi MS, Jin BK, Jung UJ, Kim SR, 2014: Naringin protects the nigrostriatal dopaminergic projection through induction of GDNF in a neurotoxin model of Parkinson's disease. J Nutr Biochem, 25, 7, 801-806.
Li S, Yu H, Ho CT, 2006: Nobiletin: efficient and large quantity isolation from orange peel extract. Biomed Chromatogr, 20, 1, 133-138.
Li R, Liang T, Xu L, Zheng N, Zhang K, Duan X, 2013: Puerarin attenuates neuronal degeneration in the substantia nigra of 6-OHDA-lesioned rats through regulating BDNF expression and activating the Nrf2/ARE signaling pathway. Brain Res. 1523, 1-9.
Lu YH, Su MY, Huang HY, Lin-Li, Yuan CG, 2010: Protective effects of the citrus flavanones to PC12 cells against cytotoxicity induced by hydrogen peroxide. Neurosci Lett, 484, 1, 6-11.
Matsuzaki K, Yamakuni T, Hashimoto M, Haque AM, Shido O, Mimaki Y, Sashida Y, Ohizumi Y, 2006: Nobiletin restoring beta-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer's disease model rats. Neurosci Lett, 400, 3, 230-234.
Matsuzaki K, Miyazaki K, Sakai S, Yawo H, Nakata N, Moriguchi S, Fukunaga K, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y, 2008: Nobiletin, a citrus flavonoid with neurotrophic action, augments protein kinase A-mediated phosphorylation of the AMPA receptor subunit, GluR1, and the postsynaptic receptor response to glutamate in murine hippocampus. Eur J Pharmacol, 578, 194-200.
Moosavi F, Hosseini R, Saso L, Firuzi O, 2015: Modulation of neurotrophic signaling pathways by polyphenols. Drug Des Devel Ther, 10, 23-42. Nagase H, Yamakuni T, Matsuzaki K, Maruyama Y, Kasahara J, Hinohara Y, Kondo S, Mimaki Y, Sashida Y, Tank AW, Fukunaga K, Ohizumi Y, 2005: Mechanism of neurotrophic action of nobiletin in PC12D cells. Biochemistry, 44, 42, 13683-13691.
Nakajima A, Yamakuni T, Matsuzaki K, Nakata N, Onozuka H, Yokosuka A, Sashida Y, Mimaki Y, Ohizumi Y, 2007: Nobiletin, a citrus flavonoid, reverses learning impairment associated with N-methyl-D-aspartate receptor antagonism by activation of extracellular signal-regulated kinase signaling. J Pharmacol Exp Ther, 321, 2, 784-790.
Nakajima A, Aoyama Y, Nguyen TT, Shin EJ, Kim HC, Yamada S, Nakai T, Nagai T, Yokosuka A, Mimaki Y, Ohizumi Y, Yamada K, 2013: Nobiletin, a citrus flavonoid, ameliorates cognitive impairment, oxidative burden, and hyperphosphorylation of tau in senescence-accelerated mouse. Behav Brain Res, 250, 351-360.
Nakajima A, Aoyama Y, Shin EJ, Nam Y, Kim HC, Nagai T, Yokosuka A, Mimaki Y, Yokoi T, Ohizumi Y, Yamada K, 2015a: Nobiletin, a citrus flavonoid, improves cognitive impairment and reduces soluble Aβ levels in a triple transgenic mouse model of Alzheimer's disease (3XTg-AD). Behav Brain Res, 289, 69-77. Nakajima M, Shimizu R, Furuta K, Sugino M, Watanabe T, Aoki R, Okuyama S, Furukawa Y, 2015b: Nobiletin induces oligodendrocyte lineage precursor cells in a cuprizone-administered demyelination animal model. J Mult Scler (Foster City), 2 4, 1-6.
Nogata Y, Sakamoto K, Shiratsuchi H, Ishii T, Yano M, Ohta H, 2006: Flavonoid composition of fruit tissues of citrus species. Biosci Biotechnol Biochem, 70, 1, 178-192.
Onozuka H, Nakajima A, Matsuzaki K, Shin RW, Ogino K, Saigusa D, Tetsu N, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y, 2008: Nobiletin, a citrus flavonoid, improves memory impairment and Abeta pathology in a transgenic mouse model of Alzheimer's disease. J Pharmacol Exp Ther, 326, 3, 739-744.
Schroeter H, Spencer JP, Rice-Evans C, Williams RJ, 2001: Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. Biochem J, 358 (Pt 3), 547-557.
Singh SP, Wahajuddin, Tewari D, Patel K, Jain GK, 2011: Permeability determination and pharmacokinetic study of nobiletin in rat plasma and brain by validated high-performance liquid chromatography method. Fitoterapia, 82, 8, 1206-1214. Vafeiadou K, Vauzour D, Lee HY, Rodriguez-Mateos A, Williams RJ, Spencer JP, 2009: The citrus flavanone naringenin inhibits inflammatory signalling in glial cells and protects against neuroinflammatory injury. Arch Biochem Biophys, 484, 1, 100-109.
Vauzour D, Vafeiadou K, Rodriguez-Mateos A, Rendeiro C, Spencer JP, 2008: The neuroprotective potential of flavonoids: a multiplicity of effects. Genes Nutr, 3 (3-4), 115-126.
Vemuri GS, McMorris FA, 1996: Oligodendrocytes and their precursors require phosphatidylinositol 3-kinase signaling for survival. Development, 122, 8, 2529-2537.
Yabuki Y, Ohizumi Y, Yokosuka A, Mimaki Y, Fukunaga K, 2014: Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice. Neuroscience, 259, 126-141.