請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28190
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林君榮(Chun-Jung Lin) | |
dc.contributor.author | Yu-Chia Chang | en |
dc.contributor.author | 張祐嘉 | zh_TW |
dc.date.accessioned | 2021-06-13T00:02:25Z | - |
dc.date.available | 2012-08-08 | |
dc.date.copyright | 2007-08-08 | |
dc.date.issued | 2007 | |
dc.date.submitted | 2007-07-30 | |
dc.identifier.citation | [1] K. Abe, T. Saitoh, Y. Horiguchi, I. Utsunomiya, K. Taguchi, Synthesis and neurotoxicity of tetrahydroisoquinoline derivatives for studying Parkinson's disease, Biol. Pharm. Bull. 28 (2005) 1355-1362.
[2] E.D. Abercrombie, J.M. Finaly (Eds.), Monitoring extracellular norepinephrine in brain using in vivo microdialysis and HPLC-CE., In: Robinson, T.E., Justice, Jr J.B. , Microdialysis in the neuroscience, Elsevier, Amsterdam, 1991, 253-274 pp. [3] L. Antkiewicz-Michaluk, A. Krygowska-Wajs, A. Szczudlik, I. Romanska, J. Vetulani, Increase in salsolinol level in the cerebrospinal fluid of parkinsonian patients is related to dementia: advantage of a new high-performance liquid chromatography methodology, Biol. Psychiatry 42 (1997) 514-518. [4] S.P. Bagchi, Trace dosages of the neurotoxins MPTP and MPP+ may affect brain dopamine in vivo, Life Sci. 51 (1992) 389-396. [5] N.L. Benowitz, P. Jacob, 3rd, Daily intake of nicotine during cigarette smoking, Clin. Pharmacol. Ther. 35 (1984) 499-504. [6] T.P. Brown, P.C. Rumsby, A.C. Capleton, L. Rushton, L.S. Levy, Pesticides and Parkinson's disease--is there a link?, Environ. Health Perspect. 114 (2006) 156-164. [7] L.A. Carr, J.K. Basham, Effects of tobacco smoke constituents on MPTP-induced toxicity and monoamine oxidase activity in the mouse brain, Life Sci. 48 (1991) 1173-1177. [8] Y.L. Chang, P.L. Tsai, Y.C. Chou, J.H. Tien, T.H. Tsai, Simultaneous determination of nicotine and its metabolite, cotinine, in rat blood and brain tissue using microdialysis coupled with liquid chromatography: pharmacokinetic application, J. Chromatogr. A 1088 (2005) 152-157. [9] A. Cormier, C. Morin, R. Zini, J.P. Tillement, G. Lagrue, Nicotine protects rat brain mitochondria against experimental injuries, Neuropharmacology 44 (2003) 642-652. [10] T.M. Dawson, V.L. Dawson, Molecular pathways of neurodegeneration in Parkinson's disease, Science (New York, N.Y 302) (2003) 819-822. [11] E.C. de Lange, M. Danhof, A.G. de Boer, D.D. Breimer, Critical factors of intracerebral microdialysis as a technique to determine the pharmacokinetics of drugs in rat brain, Brain Res. 666 (1994) 1-8. [12] E.C. de Lange, M. Danhof, A.G. de Boer, D.D. Breimer, Methodological considerations of intracerebral microdialysis in pharmacokinetic studies on drug transport across the blood-brain barrier, Brain Res Brain Res Rev. 25 (1997) 27-49. [13] L. Fleming, J.B. Mann, J. Bean, T. Briggle, J.R. Sanchez-Ramos, Parkinson's disease and brain levels of organochlorine pesticides, Ann. Neurol. 36 (1994) 100-103. [14] T.E. Freyaldenhoven, J.L. Cadet, S.F. Ali, The dopamine-depleting effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in CD-1 mice are gender-dependent, Brain Res. 735 (1996) 232-238. [15] R.W. Fuller, S.K. Hemrick-Luecke, Tissue concentrations of MPTP and MPP+ after administration of lethal and sublethal doses of MPTP to mice, Toxicol. Lett. 54 (1990) 253-262. [16] R.P. Grelak, R. Clark, J.M. Stump, V.G. Vernier, Amantadine-dopamine interaction: possible mode of action in Parkinsonism, Science (New York, N.Y 169) (1970) 203-204. [17] P. Grieb, R.E. Forster, D. Strome, C.W. Goodwin, P.C. Pape, O2 exchange between blood and brain tissues studied with 18O2 indicator-dilution technique, J. Appl. Physiol. 58 (1985) 1929-1941. [18] H. Haber, A. Winkler, I. Putscher, P. Henklein, I. Baeger, M. Georgi, M.F. Melzig, Plasma and urine salsolinol in humans: effect of acute ethanol intake on the enantiomeric composition of salsolinol, Alcohol Clin Exp Res 20 (1996) 87-92. [19] H. Hallman, L. Olson, G. Jonsson, Neurotoxicity of the meperidine analogue N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on brain catecholamine neurons in the mouse, Eur. J. Pharmacol. 97 (1984) 133-136. [20] R.F. Haseloff, I.E. Blasig, H.C. Bauer, H. Bauer, In search of the astrocytic factor(s) modulating blood-brain barrier functions in brain capillary endothelial cells in vitro, Cell. Mol. Neurobiol. 25 (2005) 25-39. [21] R.E. Heikkila, A. Hess, R.C. Duvoisin, Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice, Science (New York, N.Y 224) (1984) 1451-1453. [22] M.A. Hernan, B. Takkouche, F. Caamano-Isorna, J.J. Gestal-Otero, A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease, Ann. Neurol. 52 (2002) 276-284. [23] L.A. Howard, S. Miksys, E. Hoffmann, D. Mash, R.F. Tyndale, Brain CYP2E1 is induced by nicotine and ethanol in rat and is higher in smokers and alcoholics, Br. J. Pharmacol. 138 (2003) 1376-1386. [24] J. Hukkanen, P. Jacob, 3rd, N.L. Benowitz, Metabolism and disposition kinetics of nicotine, Pharmacol. Rev. 57 (2005) 79-115. [25] I. Irwin, L.E. DeLanney, D. Di Monte, J.W. Langston, The biodisposition of MPP+ in mouse brain, Neurosci. Lett. 101 (1989) 83-88. [26] K. Ishiwata, Y. Koyanagi, K. Abe, K. Kawamura, K. Taguchi, T. Saitoh, J. Toda, T. Sano, No reduction of dopamine transporter binding sites in mice following treatment with the TIQ analogue 1-benzyl-1,2,3,4-tetrahydroisoquinoline, Brain Res. 960 (2003) 282-285. [27] J.A. Javitch, R.J. D'Amato, S.M. Strittmatter, S.H. Snyder, Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity, Proc. Natl. Acad. Sci. U. S. A. 82 (1985) 2173-2177. [28] V.A. Kashkin, P. De Witte, Nicotine increases microdialysate brain amino acid concentrations and induces conditioned place preference, Eur. Neuropsychopharmacol. 15 (2005) 625-632. [29] S.N. Kelada, P. Costa-Mallen, L.G. Costa, T. Smith-Weller, G.M. Franklin, P.D. Swanson, W.T. Longstreth, Jr., H. Checkoway, Gender difference in the interaction of smoking and monoamine oxidase B intron 13 genotype in Parkinson's disease, Neurotoxicology 23 (2002) 515-519. [30] K. Kikuchi, Y. Nagatsu, Y. Makino, T. Mashino, S. Ohta, M. Hirobe, Metabolism and penetration through blood-brain barrier of parkinsonism-related compounds. 1,2,3,4-Tetrahydroisoquinoline and 1-methyl-1,2,3,4-tetrahydroisoquinoline, Drug Metab Dispos.: the biological fate of chemicals 19 (1991) 257-262. [31] Y. Kotake, [Tetrahydroisoquinoline derivatives as possible Parkinson's disease-inducing substances], Yakugaku Zasshi-J. Pharm. Soc. Jpn. 122 (2002) 975-982. [32] Y. Kotake, S. Ohta, I. Kanazawa, M. Sakurai, Neurotoxicity of an endogenous brain amine, 1-benzyl-1,2,3,4-tetrahydroisoquinoline, in organotypic slice co-culture of mesencephalon and striatum, Neuroscience 117 (2003) 63-70. [33] Y. Kotake, Y. Tasaki, Y. Makino, S. Ohta, M. Hirobe, 1-Benzyl-1,2,3,4-tetrahydroisoquinoline as a parkinsonism-inducing agent: a novel endogenous amine in mouse brain and parkinsonian CSF, J. Neurochem. 65 (1995) 2633-2638. [34] A.E. Lang, A.M. Lozano, Parkinson's disease. First of two parts, N. Engl. J. Med. 339 (1998) 1044-1053. [35] J.W. Langston, P. Ballard, J.W. Tetrud, I. Irwin, Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis, Science (New York, N.Y 219) (1983) 979-980. [36] J.W. Langston, P.A. Ballard, Jr., Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, N. Engl. J. Med. 309 (1983) 310. [37] J.E. Levine, K.D. Powell, Microdialysis for measurement of neuroendocrine peptides, Methods Enzymol. 168 (1989) 166-181. [38] P.R. Lockman, G. McAfee, W.J. Geldenhuys, C.J. Van der Schyf, T.J. Abbruscato, D.D. Allen, Brain uptake kinetics of nicotine and cotinine after chronic nicotine exposure, J. Pharmacol. Exp. Ther. 314 (2005) 636-642. [39] E. Lorenc-Koci, J. Wojcikowski, M. Kot, A. Haduch, J. Boksa, W.A. Daniel, Disposition of 1,2,3,4,-tetrahydroisoquinoline in the brain of male Wistar and Dark Agouti rats, Brain Res. 996 (2004) 168-179. [40] R. Maggio, M. Riva, F. Vaglini, F. Fornai, R. Molteni, M. Armogida, G. Racagni, G.U. Corsini, Nicotine prevents experimental parkinsonism in rodents and induces striatal increase of neurotrophic factors, J. Neurochem. 71 (1998) 2439-2446. [41] Y. Makino, S. Ohta, O. Tachikawa, M. Hirobe, Presence of tetrahydroisoquinoline and 1-methyl-tetrahydro-isoquinoline in foods: compounds related to Parkinson's disease, Life Sci. 43 (1988) 373-378. [42] L.C. Murrin, J.R. Ferrer, W.Y. Zeng, N.J. Haley, Nicotine administration to rats: methodological considerations, Life Sci. 40 (1987) 1699-1708. [43] T. Nagatsu, Isoquinoline neurotoxins in the brain and Parkinson's disease, Neurosci. Res. 29 (1997) 99-111. [44] T. Niwa, H. Yoshizumi, A. Tatematsu, S. Matsuura, T. Nagatsu, Presence of tetrahydroisoquinoline, a parkinsonism-related compound, in foods, J. Chromatogr. 493 (1989) 347-352. [45] S. Ohta, O. Tachikawa, Y. Makino, Y. Tasaki, M. Hirobe, Metabolism and brain accumulation of tetrahydroisoquinoline (TIQ) a possible parkinsonism inducing substance, in an animal model of a poor debrisoquine metabolizer, Life Sci. 46 (1990) 599-605. [46] K. Parain, C. Hapdey, E. Rousselet, V. Marchand, B. Dumery, E.C. Hirsch, Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin, Brain Res. 984 (2003) 224-232. [47] K. Parain, V. Marchand, B. Dumery, E. Hirsch, Nicotine, but not cotinine, partially protects dopaminergic neurons against MPTP-induced degeneration in mice, Brain Res. 890 (2001) 347-350. [48] W.M. Pardridge, Blood-brain barrier drug targeting: the future of brain drug development, Mol. Interv. 3 (2003) 90-105, 151. [49] W.M. Pardridge, J. Eisenberg, J. Yang, Human blood-brain barrier insulin receptor, J. Neurochem. 44 (1985) 1771-1778. [50] J. Parkinson, An essay on the shaking palsy. 1817, J. Neuropsychiatr. Clin. Neurosci. 14 (2002) 223-236; discussion 222. [51] G. Paxinos, C. Watson (Eds.), The rat brain in stereotaxic coordinates, fifth ed. Elsevier, Academic Press, Sydney, 2005. [52] H. Payami, S. Zareparsi, Genetic epidemiology of Parkinson's disease, J. Geriatr. Psychiatry Neurol. 11 (1998) 98-106. [53] M. Quik, D.A. Di Monte, Nicotine administration reduces striatal MPP+ levels in mice, Brain Res. 917 (2001) 219-224. [54] M. Quik, N. Parameswaran, S.E. McCallum, T. Bordia, S. Bao, A. McCormack, A. Kim, R.F. Tyndale, J.W. Langston, D.A. Di Monte, Chronic oral nicotine treatment protects against striatal degeneration in MPTP-treated primates, J. Neurochem. 98 (2006) 1866-1875. [55] N.J. Riachi, W.D. Dietrich, S.I. Harik, Effects of internal carotid administration of MPTP on rat brain and blood-brain barrier, Brain Res. 533 (1990) 6-14. [56] N.G. Schneider, R.E. Olmstead, M.A. Franzon, E. Lunell, The nicotine inhaler: clinical pharmacokinetics and comparison with other nicotine treatments, Clin. Pharmacokinet. 40 (2001) 661-684. [57] G.P. Sechi, V. Agnetti, M. Piredda, M. Canu, F. Deserra, H.A. Omar, G. Rosati, Acute and persistent parkinsonism after use of diquat, Neurology 42 (1992) 261-263. [58] K. Shimizu, K. Ohtaki, K. Matsubara, K. Aoyama, T. Uezono, O. Saito, M. Suno, K. Ogawa, N. Hayase, K. Kimura, H. Shiono, Carrier-mediated processes in blood--brain barrier penetration and neural uptake of paraquat, Brain Res. 906 (2001) 135-142. [59] T. Shinka, N. Castagnoli, Jr., E.Y. Wu, M.K. Hoag, A.J. Trevor, Cation-exchange high-performance liquid chromatography assay for the nigrostriatal toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its monoamine oxidase B generated metabolites in brain tissues, J. Chromatogr. 398 (1987) 279-287. [60] M. Shoaib, I.P. Stolerman, Plasma nicotine and cotinine levels following intravenous nicotine self-administration in rats, Psychopharmacology 143 (1999) 318-321. [61] R.J. Smeyne, V. Jackson-Lewis, The MPTP model of Parkinson's disease, Brain Res Mol Brain Res. 134 (2005) 57-66. [62] Y. Song, Y. Feng, M.H. Leblanc, N. Castagloni, Jr., Y.M. Liu, 1-Benzyl-1,2,3,4-tetrahydroisoquinoline passes through the blood-brain barrier of rat brain: an in vivo microdialysis study, Neurosci. Lett. 395 (2006) 63-66. [63] R. Soto-Otero, E. Mendez-Alvarez, A. Hermida-Ameijeiras, A.M. Lopez-Real, J.L. Labandeira-Garcia, Effects of (-)-nicotine and (-)-cotinine on 6-hydroxydopamine-induced oxidative stress and neurotoxicity: relevance for Parkinson's disease, Biochem. Pharmacol. 64 (2002) 125-135. [64] R.G. Staal, J.M. Yang, W.N. Hait, P.K. Sonsalla, Interactions of 1-methyl-4-phenylpyridinium and other compounds with P-glycoprotein: relevance to toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Brain Res. 910 (2001) 116-125. [65] E.K. Tan, C. Tan, S.M. Fook-Chong, S.Y. Lum, A. Chai, H. Chung, H. Shen, Y. Zhao, M.L. Teoh, Y. Yih, R. Pavanni, V.R. Chandran, M.C. Wong, Dose-dependent protective effect of coffee, tea, and smoking in Parkinson's disease: a study in ethnic Chinese, J. Neurol. Sci. 216 (2003) 163-167. [66] R. Tao, S. Hjorth, Differences in the in vitro and in vivo 5-hydroxytryptamine extraction performance among three common microdialysis membranes, J. Neurochem. 59 (1992) 1778-1785. [67] Y. Tasaki, Y. Makino, S. Ohta, M. Hirobe, 1-Methyl-1,2,3,4-tetrahydroisoquinoline, decreasing in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse, prevents parkinsonism-like behavior abnormalities, J. Neurochem. 57 (1991) 1940-1943. [68] T.H. Tsai, Assaying protein unbound drugs using microdialysis techniques, J. Chromatogr. B:Analytical Technologies in the Biomedical and Life Sciences 797 (2003) 161-173. [69] F. Vaglini, C. Pardini, C. Viaggi, C. Bartoli, D. Dinucci, G.U. Corsini, Involvement of cytochrome P450 2E1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease, J. Neurochem. 91 (2004) 285-298. [70] M. Vila, S. Przedborski, Targeting programmed cell death in neurodegenerative diseases, Nature Rev. 4 (2003) 365-375. [71] I.Q. Whishaw, J.D. Cioe, N. Previsich, B. Kolb, The variability of the interaural line vs the stability of bregma in rat stereotaxic surgery, Physiol. Behav. 19 (1977) 719-722. [72] T. Yamakawa, Y. Kotake, M. Fujitani, H. Shintani, Y. Makino, S. Ohta, Regional distribution of parkinsonism-preventing endogenous tetrahydroisoquinoline derivatives and an endogenous parkinsonism-preventing substance-synthesizing enzyme in monkey brain, Neurosci. Lett. 276 (1999) 68-70. [73] M.Y. Zhang, C.E. Beyer, Measurement of neurotransmitters from extracellular fluid in brain by in vivo microdialysis and chromatography-mass spectrometry, J. Pharm. Biomed. Anal. 40 (2006) 492-499. [74] Y. Zhang, W.M. Pardridge, Rapid transferrin efflux from brain to blood across the blood-brain barrier, J. Neurochem. 76 (2001) 1597-1600 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28190 | - |
dc.description.abstract | 巴金森氏症是一種與年齡有關係的黑質紋狀體神經退化疾病,它會導致病人產生行動遲緩、靜止型顫抖、姿勢障礙和肌肉僵硬。一種具有選擇性在多巴胺神經產生毒性的物質MPTP,在給予之後會造成類似巴金森氏症的症狀。往後,MPTP就被用來建立各種適合的動物模式來進一步研究巴金森氏症相關的神經死亡以及神經保護作用。
流行病學的研究顯示出吸煙者與罹患巴金森氏症具有負相關性。為了探討香煙中主要成分尼古丁對於血腦障壁運送引起巴金森氏症的物質的影響,我們使用大腦微透析技術收集大鼠腦紋狀體的透析液進行研究。先將雄性Wistar大鼠分成2大組。一組腹腔注射生理食鹽水,另一組則是在注射MPTP前30分鐘給予單一劑量的尼古丁(0.3, 0.6, 2.0 and 4.0 mg/ kg)。然後在腹腔注射生理食鹽水或是尼古丁30分鐘後由股靜脈給予MPTP (10 mg/ kg)輸注。透析液以輸注MPTP後開始收集,每30分鐘一管共收取150分鐘。MPTP與MPP+的濃度以高效能液相層析系統進行定量,此系統使用C18層析管柱以及紫外光與螢光光譜偵測儀。結果顯示,在尼古丁的作用下,第0~30分鐘腦細胞外液中的MPTP量有明顯地減少(666.31±65.53 ng/ mL, 561.50±12.11 ng/ mL, 493.23±35.46 ng/ mL, 375.94±76.24 ng/ mL 以及 329.35±55.14 ng/ mL分別代表控制組與用0.3, 0.6, 2.0, 4.0 mg/ kg尼古丁前給予的組別)。此時我們也監測給予0.6 mg/ kg尼古丁的腦中以及血中濃度,結果顯示尼古丁在第30~60分鐘(相當於收集MPTP的第0~30分鐘)是濃度達到最高的時段(136.8±16.6 ng/mL, 233.1±9.2 ng/mL)。另外我們以上述建立的系統,也進一步探討投予次數與性別是否會影響尼古丁的作用。結果顯示,在多次劑量尼古丁的給予下,MPTP量的確有比控制組少,但是其改變量與單一劑量尼古丁比較,並沒有因投予尼古丁次數增加而有明顯地減少。在性別上,控制組與各劑量尼古丁的MPTP量,有明顯減少,但是尼古丁的作用並沒有因性別差異而在效力上有明顯的不同。另外,Tetrahydroisoquinoline (TIQ)是一個與MPTP結構類似且會引起巴金森氏症的物質。我們同樣也研究了尼古丁對於血腦障壁運送TIQ的影響。結果顯示,腦細胞外液中的TIQ並沒有因為事先給予尼古丁(0.6, 2.0 mg/kg)而有明顯減少。 總結本實驗的結果,我們發現尼古丁確實可以減少MPTP被運送過血腦障壁至腦中,但是與MPTP結構相似的TIQ,尼古丁無法有效減少它被運送過血腦障壁。有關為何抽煙有較低巴金森氏症發生率的詳細機轉可能還需要進一步確認。 | zh_TW |
dc.description.abstract | Parkinson’s disease (PD) is an age-related neurodegeneration disorder resulting in bradykinesia, resting tremor, postural instability and muscle rigidity. Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective dopaminergic neurotoxin, causes a Parkinson-like syndrome. In this regard, MPTP is used to establish suitable animal models to study neurodegenerative and neuroprotective processes in PD.
Epidemiological researches have shown a negative association between cigarette smoking and incidences of PD. In order to investigate the effect of nicotine, one of major cigarette constituents, on blood-brain barrier (BBB) transfer of PD-induced agents, a brain microdialysis technique was used to collect dialysates in the striatum of male Wistar rats treated by MPTP with or without nicotine pretreatment. Saline or single dose of nicotine (0.3, 0.6, 2.0 and 4.0 mg/ kg) was given to rats by intraperitoneal injection 30 min prior to the femoral administration of MPTP (10 mg/ kg, i.v.). Dialysates were collected in a 30-min interval for 150 min. Concentrations of MPTP and MPP+ were quantified by a HPLC method using an ODS-column coupled with a UV-Vis and a fluorescence detector. The results showed that MPTP in 0~30 min interval in brain extracellular fluid can be significantly reduced by nicotine (666.31±65.53 ng/ mL, 561.50±12.11 ng/ mL, 493.23±35.46 ng/ mL, 375.94±76.24 ng/ mL and 329.35±55.14 ng/ mL for control and 0.3, 0.6, 2.0, 4.0 mg/ kg nicotine-pretreatment group, respectively). We also monitored nicotine concentrations in the brain and blood of nicotine at a concentration of 0.6 mg/ kg. The results showed that nicotine concentration in the brain and blood dialysates were 136.8±16.6 ng/ mL and 233.1±9.2 ng/ mL, respectively, in 30~60 min interval. There was no significant difference between a single-dose nicotine treatment and a multi-dose nicotine treatment. In addition, we also investigated whether the inhibitory effects of nicotine on MPTP is gender dependant. As the result, we found that the effect of nicotine showed no significant difference between male and female. Given that tetrahydroisoquinoline (TIQ) is a MPTP-like substance, we also investigated the effect of nicotine on BBB transfer of TIQ. The result indicated TIQ in brain extracellular fluid can not be significantly reduced by nicotine (0.6 and 2.0 mg/ kg). In conclusion, these data indicate that nicotine can reduce the transfer of MPTP into the brain. However, nicotine can not reduce the transfer of TIQ across BBB. The mechanism of lower incidence of PD associated with smoking needs to be confirmed in the future. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T00:02:25Z (GMT). No. of bitstreams: 1 ntu-96-R93423023-1.pdf: 1230952 bytes, checksum: 13509a34a901334b3cf6f099c47fdbad (MD5) Previous issue date: 2007 | en |
dc.description.tableofcontents | 致謝 vi
英文摘要 vii 中文摘要 ix 第一章 緒論 (Introductions) 1 1.1帕金森氏症 (Parkinson’s disease,PD) 1 1.2 MPTP和MPP+ 2 1.3異喹啉 (Isoquinolines) 4 1.4尼古丁 (Nicotine) 5 1.5血腦屏障 (Blood-brain barrier,BBB) 6 1.6微透析系統 (Microdialysis system) 7 第二章 實驗目的 (Objectives) 14 第三章 實驗材料 (Materials) 16 3.1藥品 16 3.1.1 ECF buffer 16 3.1.2 ACD buffer 16 3.1.3 MPTP & MPP+移動相 16 3.1.4尼古丁、可丁尼移動相 17 3.1.5 TIQs移動相 17 3.1.6實驗動物用藥 17 3.1.7分析物標準品 18 3.2儀器設備 18 3.2.1高效能液相層析系統 18 3.2.2動物實驗 19 3.2.3腦微透析探針之製作 20 3.3實驗動物 20 3.4緩衝液及藥品溶液之配製 20 第四章 實驗方法 (Methods) 22 4.1腦微透析探針之製作 22 4.2探針回收率之測定 (Recovery) 23 4.3 MPTP/ MPP+,TIQs,Nicotine/ Cotinine定量方法 25 4.4大鼠股靜脈插管手術 26 4.5大鼠頸靜脈埋血液型微透析探針手術 27 4.6大鼠立體定位手術與埋大腦微透析探針手術 28 4.7大鼠微透析系統探討MPTP與不同劑量模式Nicotine之研究 29 4.8大鼠微透析系統探討在性別上MPTP與不同劑量Nicotine之研究 31 4.9大鼠微透析系統探討MPTP類似物-TIQ與Nicotine之研究 31 4.10高效能液相層析法及紫外光/可見光與螢光偵測法 32 4.11數據分析 33 第五章 實驗結果 (Results) 36 5.1藥物標準品及檢品定量試驗 36 5.2給予一次性不同劑量之尼古丁後,腦中MPTP/ MPP+濃度之探討 37 5.3給予單次0.6 mg/ kg尼古丁後,腦中與血中濃度之探討 38 5.4給予多次性不同劑量之尼古丁後,腦中MPTP/ MPP+濃度之探討 38 5.5給予一次性不同劑量尼古丁後,腦中MPTP/ MPP+濃度在性別上之探討 39 5.6給予一次性不同劑量之尼古丁後,腦中與血中TIQ濃度之探討 39 第六章 結果討論 (Discussion) 58 6.1探針回收率的影響 58 6.2 MPTP系列通透血腦屏障之研究 59 6.2.1不同劑量之尼古丁與MPTP之探討 59 6.2.2尼古丁腦中及血中濃度監測試驗之探討 61 6.2.3性別因素對於尼古丁與MPTP之關係探討 62 6.3尼古丁與MPTP類似物-TIQ關係之研究 63 第七章 結 論 (Conclusion) 66 第八章 參考文獻 (References) 67 附錄 73 原始數據 76 圖1-1 巴金森氏症患者外觀圖 9 圖1-2 MPTP進入腦中之示意圖 9 圖1-3 TIQ毒性之假想機轉示意圖 10 圖1-4 腦部微血管以及週邊微血管組成示意圖 10 圖1-5 微透析系統示意圖 11 圖1-6 本章節有提及之化學結構式 12 圖4-1 自製腦部微透析探針示意圖 34 圖4-2 大鼠微透析實驗概略圖 34 圖4-3 大鼠腦部微透析埋針示意圖 35 圖4-4 大鼠靜脈血管分佈示意圖 35 圖5-1 ECF空白液之HPLC圖譜 (紫外光部分) 41 圖5-2 ECF空白液之HPLC圖譜 (螢光部分) 41 圖5-3 含最低定量濃度MPTP之ECF透析液之HPLC圖譜 (紫外光部分) 42 圖5-4 含最低定量濃度MPP+之ECF透析液之HPLC圖譜 (螢光部分) 42 圖5-5 ECF空白液之HPLC圖譜 (紫外光部分) 43 圖5-6 含最低定量濃度TIQ之ECF透析液之HPLC圖譜 (紫外光部分) 43 圖5-7 ACD空白液之HPLC圖譜 (紫外光部分) 44 圖5-8 含最低定量濃度Nicotine & Cotinine之ACD透析液之HPLC圖譜 (紫外光部分) 44 圖5-9 在大鼠腦微透析實驗中腦細胞外液之MPTP量對於時間的關係圖 45 圖5-10 在大鼠腦微透析實驗中腦細胞外液之MPP+量對於時間的關係圖 46 圖5-11 大鼠微透析實驗中血中與腦中之尼古丁與可丁尼對於時間的關係圖 48 圖5-12 在大鼠腦微透析實驗中腦細胞外液之MPTP量對於時間的關係圖 49 圖5-13 在大鼠腦微透析實驗中腦細胞外液之MPP+量對於時間的關係圖 50 圖5-14 在大鼠腦微透析實驗中腦細胞外液之MPTP量對於時間的關係圖 52 圖5-15 在大鼠腦微透析實驗中腦細胞外液之MPP+量對於時間的關係圖 53 圖5-16在大鼠腦微透析實驗中腦細胞外液之TIQ量對於時間的關係圖 55 圖5-17在大鼠腦微透析實驗中血液中之TIQ量對於時間的關係圖 56 表5-1 在大鼠腦微透析實驗中腦細胞外液之MPTP/ MPP+於各時段之平均濃度(單次劑量) 47 表5-2 在大鼠腦微透析實驗中腦細胞外液之MPTP/ MPP+於各時段之平均濃度(多次劑量) 51 表5-3 在大鼠腦微透析實驗中腦細胞外液之MPTP/ MPP+於各時段之平均濃度(性別) 54 表5-4 在大鼠腦微透析實驗中腦細胞外液之TIQ於各時段之平均濃度 57 表6-1 MPTP (MPP+)與TIQs (IQ+s)性質之比較表 65 | |
dc.language.iso | zh-TW | |
dc.title | 以大鼠大腦微透析模式探討尼古丁對MPTP/TIQ通過血腦屏障(BBB)影響之研究 | zh_TW |
dc.title | Effects of nicotine on Blood-Brain Barrier (BBB) transfer of MPTP/ TIQ-an in vivo brain microdialysis study | en |
dc.type | Thesis | |
dc.date.schoolyear | 95-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林文貞(Wen-Jen Lin),郭錦樺(Ching-Hua Kuo) | |
dc.subject.keyword | 微透析,尼古丁,血腦屏障, | zh_TW |
dc.subject.keyword | microdialysis,nicotine,MPTP, | en |
dc.relation.page | 86 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2007-07-31 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-96-1.pdf 目前未授權公開取用 | 1.2 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。