摘要
在全世界腦中風是導致死亡重要的原因。常因缺乏有效的及時治療，引發短暫性局部大腦缺血的狀況，是由於興奮毒素神經傳導物質的釋放、鈣離子內流入神經元、自由基的產生和脂質過氧化，可因而產生不可逆的細胞損傷及神經行為不良，最終將導致細胞的壞死或細胞程式死亡的情形。
在研究中為採用之研究藥物MA-1-PS，是為MA-1的衍生物，而MA-1由菲律賓樟樹（Cinnamomum philippinense）萃取而來，MA-1 本為高脂溶性的化合物，由過去的研究已證實脂溶性MA-1為一抗氧化物及自由基清道夫，且可抑制血小板聚集，易通過血腦障壁治療急性缺血性腦中風，並發現強而有效的神經保護作用。但是當病患中風昏迷時，無法口服藥物，於是將MA-1進行化學結構修飾而產生的MA-1-PS，為水溶性，同時也增加溶解度，以致更易應用與達到提供靜脈注射的目的。
為證實MA-1-PS是否對神經元有相同之保護效果，研究中利用初代神經元培養 （primary neural culture）及海馬迴組織培養，並且利用缺氧及葡萄糖的實驗模式，模擬體內組織局部缺血而造成腦部損害的實驗。另外，進一步探討藥物是否可經由抑制脂質過氧化與清除自由基來達到保護神經的作用。

Abstract
Cerebral stroke is a leading cause of death worldwide. Because of the lack of efficient therapeutic alternatives, induced to transient focal cerebral ischemia that occurs during cerebrovascular surgery may result in irreversible cell damage and neurobehavioral dysfunction due to the release of excitotoxic neurotransmitters, influx of calcium ions into neurons, free radical generation, lipid peroxidation, and protein degradation. They eventually lead to necrotic and/or apoptotic cell death.
MA-1-PS is a derivative of MA-1. MA-1, a natural compound isolated from Cinnamomum philippinense. The agent is highly lipophilic. In the past researches have been demonstrated MA-1 was a strong natural antioxidant and free radical scavenger, had the potential to cross the blood-brain barrier to the brain and had neuroprotective properties. But when a serious patient is in a stupor, can not to oral drug by himself, so to modify MA-1, the product is MA-1-PS, is water soluble, moreover improve the solubility, can be easy to supply intravenous injection for therapy.
To confirm MA-1-PS whether has the same efficiency of neuroprotection. In experiment model, we use primary neural culture and organotypic hippocampal slice cultures, combined with oxygen-glucose deprivation ( OGD ), to mimic ischemia closely the situation in vivo result in brain disease. Further, to demonstrated that MA-1-PS have neuroprotection of ability via inhibiting lipidperoxidation and scavenging free radical.

參考文獻
1.Kristian P. Doyle, Roger P. Simon, Mary P. Stenzel-Poore. Mechanisms of Ischemic Brain Damage . Review Article. Neuropharmacology.2008
2.Newman M.F, Grocott H.P, Mathew J.P. Report of the substudy assessing the impact of neurocognitive function on quality of life 5 years after cardiac surgery. Stroke. 2001;32:2874-2881
3.蔡宜殷. 以Melatonin 治療暫時性局部腦缺血白鼠有助其電生理及神經行為之改善.國立成功大學醫學工程研究所碩士論文.2003
4.http://stroke.tw/page/2-5-2.html
5.http://baike.baidu.com/view/9706.htm
6.http://life.nthu.edu.tw/~g864264/Neuroscience/neuron/cell.htm
7.http://content.edu.tw/junior/bio/tc_wc/textbook/ch05/text-ch05-2.htm
8.http://commons.wikimedia.org/wiki/File:Complete_neuron_cell_diagram_zh-tw.svg
9.朱復禮 (民81)‧臨床神經醫學‧臺北：合記。
10.吳進安 (民81)‧基礎神經學‧臺北：合記。
11.Heart Center Online (HCO)；http://heart.healthcentersonline.com/stroke/tia.cfm
12.http://webanatomy.net/anatomy/circulatory_notes.htm
13.陳俐璇（民93）‧以鎂離子治療暫時性局部腦缺血白鼠之電生理及神經行為之研究‧國立成功大學醫學工程研究所碩士論文
14.Durukan A, Tatlisumak T. Acute ischemia stroke：Overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacology Biochemistry and Behavior 2007；87；179-197
15.Seok Joon Won, Doo Yeon Kim, Byoung Joo Gwag. Cellular and Molecular Pathways of Ischemic Neuronal Death. Journal of Biochemistry and Molecular Biology 2002；35；67-86
16.Siesjo B.K., Katsura K., Kristina T. Acidosis-related damage. Adv Neurol 1996；71；209-33；discussion 234-6
17.廖佩斐 (民96) ‧代謝性麩胺酸第五型作用調節劑NMDA 結抗劑對NMDA受體的抑制反應‧慈濟大學藥理暨毒理學研究所碩士論文
18.Dirnagl U., Iadecola C., Moskowitz M.A. Pathobiology of ischemic stroke：an integrate view. Trends Neurosci 1999；22；391-7
19.Takano K., Latour L.L., Farmato J.E., Carano R.A., Helamer K.G., Hasegawa Y., Sotak C.H., Fisher M. The role of spreading in focal ischemia evaluated by diffusion mapping. Ann Neurol 1996；39；308-18
20.Mergenthaler P., Dirnagl U., Meisel A. Pathophysiology of stroke：lessons from animal models. Metab Brain Dis 2004；19；151-67
21.Alexandra Loidl, Eva Sevcsik, et al. Oxidized phospholipids in mmLDL induce apoptotic signaling via activation of acid sphingomyelinase in arterial smooth muscle cells. J. Biol. Chem 2003；10；1074
22.Emerich D.F., Dean R.L., 3rd & Bartus R.T. The role of leukocyte following cerebral ischemia：pathogenic variable or bystander reaction to emerging infarct？ Exp Neurol 2002；173；168-81
23.Love S. Apoptosis and brain ischaemia. Prog Neuropsychopharmacol Biol Psychiatry 2003；27；267-82
24.Blaine C. White, Jonathon M. Sullivan, Donald J. DeGracia, Brian J. O’Neil, Robert W. Neumar, Lawrence I. Grossman, Jose´ A. Rafols, Gary S. Krause. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. Journal of the Neurological Sciences 2000；179；1–33
25.http://www.psycheducation.org/emotion/hippocampus.htm
26.Lipski J, Wan CK, Bai JZ, Pi R, Li D, Donnelly D. Neuroprotective potential of ceftriaxone in in vitro models of stroke. Neuroscience 2007；146：617-629
27.http://scienceblogs.com/purepedantry/2007/04/stress_precedes_volume_reducti.php
28.http://www.bristol.ac.uk/synaptic/info/pathway/hippocampal.htm
29.Laura M.D, Crystal L.M, Dale R.C, Frederick C. Post-ischemia diazepam does not reduce hippocampal CA1 injury and does not improve hypothermic neuroprotection after forebrain ischemia in gerbils. Brain Research 2004；1013：223-229
30.George Hsiao, Che-Ming Teng, Joen-Rong Sheu, Yu-Wen Cheng, Kwok-Keung Lam, Yen-Mei Lee, Tian-Shung Wu, Mao-Hsiung Yen. Cinnamophilin as a novel antiperoxidative cytoprotectant and free radical scavenger. Biochimica et Biophysica Acta 2001；1525；77-88
31.Sheu-Meei Yu, Tian-Shung Wu, Che-Ming Teng. Pharmacological characterization of cinnamophilin, a novel dual inhibitor of thromboxane synthase and thromboxane A2 receptor. Br. J. Pharmacol 1994；111；906-912
32.E.-Jian Lee, Hung-Yi Chena, Ming-Yang Lee, Tsung-Ying Chena, Yun-Shang Hsu, Yu-Ling Hu, Guan-Liang Chang, Tian-Shung Wu. Cinnamophilin reduces oxidative damage and protects against transient focal cerebral ischemia in mice. Free Radical Biology & Medicine 2005；39；495 – 510
33.余舒晴. MA-1對離體神經元保護:治療窗口與抗神經興奮毒性，抗氧化及清除自由基能力之探討.國立成功大學生物科技研究所碩士論文.2007
34.Pringle AK, Iannotti F, Wilde GJC, et al. Neuroprotection by both NMDA and non-NMDA receptor antagonists in in vitro ischemia. Brain Research 1997；755：36-46
35.Wang JP, Ho TF, Chang LC et al. J Pharm Pharmacol 1995；47：857-860
36.Anna R, Tobias C, Fredrik A, Sailasree N, Tadeusz W. Mouse Hippocampal Organotypic Tissue Cultures Exposed to In Vitro “Ischemia ”Show Selective and Delayed CA1 Damage That Is Aggravated by Glucose. J Cerebral Blood Flow &Metabolism 2003；23；(1):23-33
37.Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, TraugerJW. Antioxidant properties of minocycline: Neuroprotection in an oxidative stress Assay and direct radical-scavenging activity. J Neurochem 2005；94：819-827
38.Takayuki Negishi, Yoshiyuki Ishii, Shigeru Kyuwa, Yoichiro Kuroda, Yasuhiro Yoshikawa. Primary culture of cortical neurons, type-1 astrocytes, and microglial cells from cynomolgus monkey (Macaca fascicularis) fetuses. Journal of Neuroscience Methods 2003；131；133–140
39.G. Fotakis, J.A. Timbrell. In vitro cytotoxicity assays: Comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicology Letters 2006；160；171–177
40.http://en.wikipedia.org/wiki/File:Mttscheme.png
41.Gruol DL, Yu N, Parsons KL, Billaud JN, Elder JH, Phillips TR. Neurotoxic effects of feline immunodeficiency virus, FIV-PPR. J Neurovirol 1998；4；415-25
42.Matsumoto Y, Yamamoto S, Suzuki Y, Tsuboi T, Terakawa S, Ohashi N, Umemura K. Na+/H+ exchanger inhibitor, SM-20220, is protective against excitotoxicity in cultured cortical neurons. Stroke 2004；35；185-190
43.Johnson EM, Greenlund LJS, Akins PT, Hsu CY. Neuronal apoptosis：Current understanding of molecular mechanisms and potential role in ischemia brain injury. J.Neurotrama 1995；12；843-852
44.Lawrence EJ, Dentcheva E, Curtis KM, et al. Neuroprotection with delayed initiation of prolonged hypothermia after in vitro transient global ischemia. Resuscitation 2005；64；383-388
45.Lipski J, Wan CK, Bai JZ, Pi R, Li D, Donnelly D. Neuroprotective potential of ceftriaxone in in vitro models of stroke. Neuroscience 2007；146；617-629
46.Stoppini L, Parisi L, Oropesa C, Muller D. Sprouting and functional recovery in co-cultures between old and young hippocampal organotypic slices. Neuroscience 1997；80；1127-1136
47.Strasser U, Fischer G. Quantitative measurement of neuronal degeneration in organotypic hippocampal cultures after combined oxygen/glucose deprivation. J Neurosci Methods 1995；57；177-186
48.Laake JH, Haug FM, Wieloch T, Ottersen OP. A simple in vitro model of ischemic based on hippocampal slice cultures and propidium iodide fluorescence. Brain Res Protocols 1999；4；173-184
49.Arai K, Nishiyama N, Matsuki N, Ikegaya Y. Neuroprotective effects of lipoxygenase inhibitors against ischemic injury in rat hippocampal slice cultures.Brain Res 2001；904；167-172
50.ROBERT E. CHILDS and WILLIAM G. BARDSLEY. The Steady-State Kinetics of Peroxidase with 2,2'-Azino-di-(3-ethylbenzthiazoline-6-sulphonic acid) as Chromogen. Biochem. J. 1975；145；93-103
51.Yamaguchi T, Takamura H, Matoba T, Terao J. Hplc method for evaluation of the free radical-scavenging activity of foods by using 1,1-diphenyl-2-picrylhydrazyl. Biosci Biotechnol Biochem 1998；62；1201-1204
52.Mir C, Clotet J, Aledo R, Durany N, Argemi J, Lozano R, Cervos-Navarro J, Casals N. Cdp-choline prevents glutamate-mediated cell death in cerebellar granule neurons. J Mol Neurosci. 2003；20；53-60
53.Won SJ, Kim DY, Gwag BJ. Cellular and molecular pathways of ischemic neuronal death. J Biochem Mol Biol. 2002；35；67-86
54.Buck J, Derguini F, Levi E, Nakanishi K, Hammerling U. Intracellular signaling by 14-hydroxy-4,14-retro-retinol. Science. 1991；254；1654-1656
55.Mosbacher J, Schoepfer R, Monyer H, Burnashev N, Seeburg PH, Ruppersberg JP. A molecular determinant for submillisecond desensitization in glutamate receptors. Science 1994；266；1059-1062
56.Tamura, H., & Shibamoto T, "Antioxidantive activity measurement and 4-hydroxy nonenal.", J. Am. Oil Chem. Soc. 1991；68；941–943