研究生: |
柯孟昌 Meng-Chang Ko |
---|---|
論文名稱: |
周邊發炎反應誘發MPTP對小白鼠神經毒害之加成作用 Systemic Inflammation Induce Synergistic Neurotoxicity of the MPTP in the Mice |
指導教授: |
黃基礎
Hwang, Ji-Chuu 呂國棟 Lu, Kwok-Tung |
學位類別: |
碩士 Master |
系所名稱: |
生命科學系 Department of Life Science |
論文出版年: | 2005 |
畢業學年度: | 93 |
語文別: | 中文 |
論文頁數: | 68 |
中文關鍵詞: | 巴金森氏症 、周邊發炎反應 、氧化壓力 、白藜蘆醇 |
論文種類: | 學術論文 |
相關次數: | 點閱:388 下載:8 |
分享至: |
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報 |
壹、中文摘要
巴金森氏症是常見的漸進性神經退化性疾病,最近的相關研究認為巴金森氏症成因可能是多項致病因素綜合的結果,包含暴露於環境中有害毒物,以及中樞神經發炎反應皆可能增加致病的風險。在離體實驗中,以內毒素(lipopolysaccharide ; LPS)預先誘發的發炎反應會增加神經毒素rotenone的毒害效果。在本實驗中,同時給予內毒素與神經毒素1-甲基4-酚基-1,2,3,6-四氫嘌呤(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;MPTP)處理的老鼠在運動功能測試儀(rota-rod)行為表現能力有顯著的下降,而在抓力測試(grasp strengthen)的結果也發現抓力有顯著的增強,組織切片染色亦發現黑質緻密區(pars compacta of substantia nigra)神經細胞數降低、多巴胺神經細胞減少的現象。顯示發炎反應是會加重病情的進展。實驗中發現,若合併投予抗氧化藥物白藜蘆醇(resveratrol),則發炎所引起的MPTP毒性加成效果大為減緩。利用微透析技術(microdialysis)與高效液相層析法(high performance liquid chromatography),亦發現resveratrol可減緩小白鼠黑質部位的氧化壓力。顯示發炎反應所引發的自由基增加,對於MPTP在黑質紋狀體路徑毒害效果具有重要的影響性,而resveratrol抗氧化的功能可減緩自由基對神經細胞的毒害,達到保護效果。
貳、英文摘要
Parkinson’s disease (PD) is a common progressive neurodegenerative disease. Recent results suggest that PD may represent the final outcome of complicated interactions, including exposure to environmental toxins and the occurrence of inflammation in the brain. In vitro test , the combination of rotenone with lipopolysaccharide (LPS) could enhance the neurotoxic effect of rotenone. Our present results showed that mice receiving a co-treatment of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with LPS reduced the rota-rod activities but strengthened the grasp ability and reduced the survival ratio of dopaminergic neuron in the pars compacta of substantia nigra (SNpc). Furthermore, pretreatment of resveratrol, an antioxidation drug, could reduce the neurotoxic effect of LPS. Using microdialysis and high performance liquid chromatography, we demonstrated that oxidative stress in SNpc was reduced by resveratrol. These results suggest that systemic inflammation may play an important role in selective destruction of nigrostriatal dopaminergic neurons by MPTP and resveratrol could decrease oxidative stress and protect dopaminergic neurons.
柒、參考文獻
Adams JD, Chang ML, Klaidman L (2001) Parkinson’s disease-redox mechanisms. Curr. Med. Chem. 8: 809-814.
Alarcon de la Lastra C, Villegas I (2005) Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications. Mol. Nutr. Food Res. 49: 405-430.
Arimoto T, Bing G (2003) Up-regulation of inducible nitric oxide synthase in the substantia nigra by lipopolysaccharide causes microglial activation and neurodegeneration. Neurobiol. Dis. 12: 35-45.
Barbosa ER, Limongi JCP, Cummings JL (1997) Parkinson’s disease. Psych. Clin. North. Am. 20: 769-790.
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3: 1301-1306.
Clement MV, Hirpara JL, Chawdhury SH, Pervaiz S (1998) Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood 92: 996-1002.
Di-Monte DA, Lavasani M, Manning-Bog AB (2002) Environmental factors in Parkinson’s disease. Neurotoxicology 23: 487–502.
Fremont L (2000) Biological effects of resveratrol. Life Sci. 66: 663-673.
Fremont L, Belguendouz L, Delpal S (1999) Antioxidant activity of resveratrol and alcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fatty acids. Life Sci. 64: 2511-2521.
Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B (2002) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease. J. Neurochem. 81: 1285-1297.
Gao HM, Jau SH, Zhang WQ, Liu B (2003a) Synergistic dopaminergic neurotoxicity of the pesticide rotenone and inflammogen lipopolysaccharide: relevance to the etiology of parkinson’s disease. J. Neurosci. 23: 1228-1236.
Gao HM, Liu B, Zhang W, Hong JS (2003b) Novel anti-inflammatory therapy for Parkinson's disease. Trends Pharmacol. Sci. 24: 395-401.
Gelinas S, Martinoli MG (2002) Neuroprotective effect of estradiol and phytoestrogens on MPP+-induced cytotoxicity in neuronal PC12 cells. J. Neurosci. Res. 70: 90-96.
Goralski KB, Renton KW (2003) Brain inflammation enhances 1-methyl-4-phenylpyridinium-evoked neurotoxicity in rats. Toxicol. Appl. Pharmacol. 196: 381-389.
Hantraye P, Brouillet E, Ferrante R, Palfi S, Dolan R, Matthews RT, Beal MF (1996) Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat. Med. 2: 1017-1021.
Herrera AJ, Castano A, Venero JL, Cano J, Machado A (2000) The single intranigral injection of LPS as a new model for studying the selective effects of inflammatory reactions on dopaminergic system. Neurobiol. Dis. 7: 429-447.
Hows ME, Ashmeade TE, Billinton A, Perren MJ, Austin AA, Virley DJ, Organ AJ, Shah AJ (2004) High-performance liquid chromatography/tandem mass spectrometry assay for the determination of 1-methyl-4-phenyl pyridinium (MPP+) in brain tissue homogenates. J. Neurosci. Methods. 137: 221-226.
Hsieh TC, Burfeind P, Laud K, Backer JM, Traganos F, Darzynkiewicz Z, Wu JM (1999) Cell cycle effects and control of gene expression by resveratrol in human breast carcinoma cell lines with different metastatic potentials. Int. J. Oncol. 15: 245-252.
Hung LM, Chen JK, Huang SS, Lee RS, Su MJ (2000) Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc. Res. 47: 549-555.
Iravani MM, Kashefi K, Mander P, Rose S, Jenner P (2002) Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration. Neurosci. 110: 49-58.
Kim WG, Mohney RP, Wilson B, Jeohn GH, Liu B, Hong JS (2000) Regional difference in susceptibility to lipopolysaccharide- induced neurotoxicity in the rat brain: role of microglia. J. Neurosci. 20: 6309-6316.
Konsman JP, Parnet P, Dantzer R (2002) Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci. 25: 154-159.
Kruger R, Vieira-Saecker AM, Kuhn W, Berg D, Muller T, Kuhnl N, Fuchs GA, Storch A, Hungs M, Woitalla D, Przuntek H, Epplen JT, Schols L, Riess O (1999) Increased susceptibility to sporadic Parkinson's disease by a certain combined alpha-synuclein /apolipoprotein E genotype. Ann. Neurol. 45: 611-617.
Kurkowska-Jastrzebska I, Babiuch M, Joniec I, Przybylkowski A, Czlonkowski A, Czlonkowska A (2002) Indomethacin protects against neurodegeneration caused by MPTP intoxication in mice. International Immunopharmacol. 2: 1213-1218.
Kurkowska-Jastrzebska I, Litwin T, Joniec I, Ciesielska A, Przybylkowski A, Czlonkowski A, Czlonkowska A (2004) Dexamethasone protects against dopaminergic neurons damage in a mouse model of Parkinson's disease. Int. Immunopharmacol. 4: 1307-1318.
Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219: 979–980.
Langston JW, Irwin I, Langston EB, Forno LS (1984) 1-Methyl-4-phenylpyridinium ion (MPP+): identification of a metabolite of MPTP, a toxin selective to the substantia nigra. Neurosci. Lett. 48: 87-92.
Lee EJ, Min HY, Joo Park H, Chung HJ, Kim S, Nam Han Y, Lee SK (2004) G2/M cell cycle arrest and induction of apoptosis by a stilbenoid, 3,4,5-trimethoxy-4'-bromo-cis-stilbene, in human lung cancer cells. Life Sci. 75: 2829-2839.
Li XJ, Gu J, Lu SD, Sun FY (2002) Melatonin attenuates MPTP-induced dopaminergic neuronal injury associated with scavenging hydroxyl radical. J. Pineal Res. 32: 47-52.
Lu X, Bing G, Hagg T (2000) Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats. Neuroscience 97: 285-291.
Martin ER, Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC, Lyons K, Pahwa R, Stern MB, Colcher A, Hiner BC, Jankovic J, Ondo WG, Allen FH Jr, Goetz CG, Small GW, Masterman D, Mastaglia F, Laing NG, Stajich JM, Ribble RC, Booze MW, Rogala A, Hauser MA, Zhang F, Gibson RA, Middleton LT, Roses AD, Haines JL, Scott BL, Pericak-Vance MA, Vance JM (2001) Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease. JAMA. 286: 2245-2250.
McGeer PL, McGeer EG (2002) Local neuroinflammation and the progression of Alzheimer's disease. J. Neurovirol. 8: 529-538.
Mutoh M, Takahashi M, Fukuda K, Matsushima-Hibiya Y, Mutoh H, Sugimura T, Wakabayashi K (2000) Suppression of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells by chemopreventive agents with a resorcin-type structure. Carcinogenesis 21: 959-963.
Pan W, Kastin AJ (1999) Penetration of neurotrophins and cytokines across the blood-brain/blood-spinal cord barrier. Adv Drug Deliv Rev. 36: 291-298.
Pavlov VA, Tracey KJ (2005) The cholinergic anti-inflammatory pathway. Brain Behav. Immun. 25: Epub ahead of print.
Perry VH (2004) The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav. Immun. 18: 407-413
Pervaiz S (2003) Resveratrol: from grapevines to mammalian biology. FASEB J. 17: 1975-1985.
Przedborski S, Ischiropoulos H (2005) Reactive oxygen and nitrogen species: weapons of neuronal destruction in models of Parkinson's disease. Antioxid Redox Signal 7: 685-693.
Przedborski S, Kostic V, Jackson-Lewis V, Naini AB, Simonetti S, Fahn S, Carlson E, Epstein CJ, Cadet JL (1992) Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- induced neurotoxicity. J. Neurosci. 12: 1658-1667.
Przedborski S, Vila M (2001) MPTP: a review of its mechanisms of neurotoxicity. Clin. Neurosci. 3: 81-88.
Rimando AM, Nagmani R, Feller DR, Yokoyama W (2005) Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters. J. Agric Food Chem. 53: 3403-3407.
Sairam K, Saravanan KS, Banerjee R, Mohanakumar KP (2003) Non-steroidal anti-inflammatory drug sodium salicylate, but not diclofenac or celecoxib, protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats. Brain Res. 966: 245-252.
Schulte T, Schols L, Muller T, Woitalla D, Berger K, Kruger R, (2002) Polymorphisms in the interleukin-1 alpha and beta genes and the risk for Parkinson’s disease. Neurosci. Lett. 326: 70-72.
Schulz JB, Matthews RT, Jenkins BG, Ferrante RJ, Siwek D, Henshaw DR, Cipolloni PB, Mecocci P, Kowall NW, Rosen BR (1995) Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo. J. Neurosci. 15: 8419-8429.
Shigematsu S, Ishida S, Hara M, Takahashi N, Yoshimatsu H, Sakata T, Korthuis RJ (2003) Resveratrol, a red wine constituent polyphenol, prevents superoxide-dependent inflammatory responses induced by ischemia/reperfusion, platelet-activating factor, or oxidants. Free Radic Biol. Med. 34: 810-817.
Sinha K, Chaudhary G, Gupta YK (2002) Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats. Life Sci. 71: 655-665.
Stojanovic S, Sprinz H, Brede O (2001) Efficiency and mechanism of the antioxidant action of trans-resveratrol and its analogues in the radical liposome oxidation. Arch. Biochem. Biophys. 391: 79-89.
Streit WJ, Walter SA, Pennell NA (1999) Reactive microgliosis. Prog. Neurobiol. 57: 563-581.
Subbaramaiah K, Michalurat P, Chung WJ, Tanabe T, Telang N, Dannenberg AJ (1998) Resveratrol inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Ann. N.Y. Acad. Sci. 899: 214-223.
Teismann P, Schwaninger M, Weih F, Ferger B (2001) Nuclear factor-kappaB activation is not involved in a MPTP model of Parkinson's disease. Neuroreport. 12: 1049-1053.
Thiffault C, Aumont N, Quirion R, Poirier J (1995) Effect of MPTP and L-deprenyl on antioxidant enzymes and lipid peroxidation levels in mouse brain. J. Neurochem. 65: 2725-2733.
Tillerson JL, Caudle WM, Reveron ME, Miller GW (2002) Detection of behavioral impairments correlated to neurochemical deficits in mice treated with moderate doses of 1-methyl-4-phenyl-1,2,3,6-Tetrahydropyridine. Exp. Neurol. 178: 80-90.
Tillerson JL, Miller GW (2003) Grid performance test to measure behavioral impairment in the MPTP-treated-mouse model of parkinsonism. J. Neurosci. 123: 189-200.
Tomas-Camardiel M, Rite I, Herrera AJ, de Pablos RM, Cano J, Machado A, Venero JL (2004) Minocycline reduces the lipopolysaccharide-induced inflammatory reaction, peroxynitrite- mediated nitration of proteins, disruption of the blood-brain barrier, and damage in the nigral dopaminergic system. Neurobiol. Dis. 16: 190-201.
Wallenstein S, Zucker CL, Fleiss JL (1980) Some statistical methods useful in circulation research. Circ. Res. 47: 1-9
Wu DC, Teismann P, Tieu K, Vila M, Jackson-Lewis V, Ischiropoulos H, Przedborski S (2003) NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. Proc. Natl. Acad Sci. 100: 6145-6150.
Xaio H, Banks WA, Niehoff ML, Morley JE (2001) Effect of LPS on the permeability of the blood-brain barrier to insulin. Brain Res. 896: 36-42.
Zhou HF, Liu XY, Niu DB, Li FQ, He QH, Wang XM (2005) Triptolide protects dopaminergic neurons from inflammation-mediated damage induced by lipopolysaccharide intranigral injection. Neurobiol. Dis. 18: 441-449.