臺灣博碩士論文加值系統

當缺血腦部遭受再灌流刺激時將導致神經組織產生變化，有一部份組織因細胞迅速壞死而產生所謂的「缺血核心區」，在核心區周圍的「缺血緩衝區」，因可獲得部份側枝血流循環供應養分，使得此區域的神經細胞可賴以生存數天至數週之久。本實驗的動物中風模式，是以顱內微注射血管內皮素-1 (400 pmol溶於20 μl的生理食鹽水中)至中腦動脈周圍，並輔以單側頸總動脈結紮以製造一個局部腦缺血的情況。而實驗結果也確實造成腦血流降低至基礎值的20%～25%，並於再灌流後24小時產生穩定的腦部梗塞範圍。我們使用此動物模式探討，藉由中藥黃芩有效成分wogonin (10 mg/kg,15 mg/kg)的投與，是否能改善腦缺血/再灌流對腦部造成的損傷以及運動行為功能的缺失。發現於腦缺血/再灌流後20分鐘投與wogonin (15 mg/kg)治療，能改善24小時後腦部梗塞體積以及降低缺血緩衝區中神經細胞退化情形，而wogonin的投與也可以降低缺血緩衝區中促細胞凋亡基因Bax的mRNA表現量。在我們使用擺動測試評估 (EBST)以及神經學缺失分數評估 (mNSS)進行的運動行為功能的測試中也發現，wogonin可以改善因為缺血/再灌流所導致的大鼠運動行為功能缺失。藉由以上實驗結果初步判斷，wogonin具有降低神經細胞死亡及神經保護的作用。因此在腦缺血/再灌流之後的不同時間點將老鼠犧牲，以期對wogonin的神經保護機制作進一步探討。我們發現在腦脊髓液(CSF)中發炎性細胞激素 (TNF-a, IL-1b, IL-6) 的濃度，於wogonin (15 mg/kg)投與後有明顯降低的情況。因此更進一步使用聚合酶鏈反應實驗研究發炎性細胞激素 (TNF-a,IL-1b, IL-6, IL-18) 於缺血緩衝區中的mRNA表現，發現這些細胞激素的mRNA表現量在6小時大量增加，而藉由wogonin的投與可顯著降低因腦缺血/再灌流所導致的發炎性細胞激素表現量增加。另外在發炎性酵素 (iNOS, COX-2)方面，於腦缺血/再灌流後缺血緩衝區中mRNA表現量在6小時達到最高，而此大量表現的iNOS, COX-2，也可藉由wogonin的投與明顯被抑制。這些結果更進一步證實wogonin具有降低缺血/再灌流後所引起的發炎反應。我們再以自由基冷光測定大鼠腦組織超氧化自由基產生情形發現，wogonin也可明顯的降低腦缺血/再灌流後30至60分鐘超氧化自由基的產生。綜合以上結果證實，於缺血/再灌流後投與wogonin作治療，可降低腦部梗塞體積、神經細胞化情形以及改善缺血/再灌流所造成之運動功能缺失，而其原因可能為降低發炎性細胞激素 (TNF-a, IL-1b, IL-6, IL-18)、發炎相關酵素 (iNOS, COX-2)以及自由基 (free radical)的產生。因此推論wogonin之神經保護作用機轉，可能源自於對腦缺血/再灌流腦組織的抗發炎、抗氧化以及降低細胞凋亡反應所造成。

Focal cerebral ischemia-reperfusion (I/R) results in characteristic histopathological changes that manifest as a “necrotic core” in which cells die rapidly, and a surrounding “penumbra” region of variable size in which neurons die over an extended time period of days to weeks. In this thesis, I used a rat model of focal cerebral I/R by microinjection of endothelin-1 (400 pmol in 20 μl saline) to middle cerebral artery and unilateral ligation of common carotid artery. Cerebral ischemia, as evidenced by the decrease of the regional cerebral blood flow to 20~25% of the control, followed by 24 hr reperfusion (I/R24) produced stable and reproducible infarcts. Using this animal model we examined the effect of wogonin, which is an active component isolated from Scutellaria baicalensis, on I/R-induced tissue injury and behavioral deficit. Our results indicated that wogonin at the dose of 15 mg/kg (administered 20 min after I/R, i.p.), but not 10 mg/kg, significantly reduced the infarct volume following I/R 24 as well as the number of Fluoro-Jade B positive degenerating neurons in penumbra. Levels of mRNA encoding for Bax, a pro-apoptotic protein (Bax) in penumbra tissue increased gradually following I/R but was attenuated by wogonin treatment. Motor asymmetry, evaluated by swing test and modified neurological severity score (mNSS), resulted from I/R24 was also significantly improved by wogonin. The potential mechanism underlying this neuroprotective effect of wogonin was further studied. Animals were subjected to I/R for various time intervals, and sacrificed after functional evaluations. Wogonin attenuated the increase of cytokine levels in cerebrospinal fluid including TNF-a, IL-1b and IL-6 at I/R 6. Time course of mRNA expression for TNF-a , IL-1b,IL-6 and IL-18 indicated that the maximal levels of cytokine mRNA expression were after I/R 6. Wogonin reduced levels of mRNA encoding for pro-inflammatory cytokines (TNF-, IL-1, IL-6 and IL-18) after I/R 6 . Wogonin also dose-dependenly supressed I/R-induced elevation on levels of mRNA encoding enzyme synthesizing inflammatory mediators (iNOS,COX-2). Wogonin also significantly reduced in vivo superoxide production as early as I/R30min to I/R60min. Taken together, post-treatment of wogonin improved functional deficit and reduced extent of brain damage, with a concomitant reduced mRNA expression of pro-inflammatory proteins and pro-apoptotic protein in ischemic penumbra and reduced levels of pro-inflammatory cytokines in CSF. Wogonin also significantly reduced superoxide production in vivo. These data suggest the neuroprotective effects of wogonin in ischemic injury might be attributed to its anti-inflammatory, antioxidant, and anti-apoptotic mechanisms.

目錄Ⅰ
中文摘要Ⅱ
英文摘要Ⅳ
縮寫表Ⅵ
第一章 緒論1
第二章 材料與方法19
第三章 結果31
第四章 討論45
第五章 結論54
圖次55
參考文獻72
附表83

Abbott, N.J. (2000) Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol 20(2), 131-47.
Abbott, N.J. (2002) Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat 200(6), 629-38.
Adams, H.P., Jr., Brott, T.G., Furlan, A.J., Gomez, C.R., Grotta, J., Helgason, C.M., Kwiatkowski, T., Lyden, P.D., Marler, J.R., Torner, J., Feinberg, W., Mayberg, M. and Thies, W. (1996) Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Circulation 94(5), 1167-74.
Adkins, D.L., Voorhies, A.C. and Jones, T.A. (2004) Behavioral and neuroplastic effects of focal endothelin-1 induced sensorimotor cortex lesions. Neuroscience 128(3), 473-86.
Albers, G.W., Atkinson, R.P., Kelley, R.E. and Rosenbaum, D.M. (1995) Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group. Stroke 26(2), 254-8.
Allan, S.M., Parker, L.C., Collins, B., Davies, R., Luheshi, G.N. and Rothwell, N.J. (2000) Cortical cell death induced by IL-1 is mediated via actions in the hypothalamus of the rat. Proc Natl Acad Sci U S A 97(10), 5580-5.
Astrup, J., Siesjo, B.K. and Symon, L. (1981) Thresholds in cerebral ischemia - the ischemic penumbra. Stroke 12(6), 723-5.
Au, A.M., Chan, P.H. and Fishman, R.A. (1985) Stimulation of phospholipase A2 activity by oxygen-derived free radicals in isolated brain capillaries. J Cell Biochem 27(4), 449-53.
Barone, F.C., Arvin, B., White, R.F., Miller, A., Webb, C.L., Willette, R.N., Lysko, P.G. and Feuerstein, G.Z. (1997) Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke 28(6), 1233-44.
Bederson, J.B., Pitts, L.H., Germano, S.M., Nishimura, M.C., Davis, R.L. and Bartkowski, H.M. (1986) Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke 17(6), 1304-8.
Berti, R., Williams, A.J., Moffett, J.R., Hale, S.L., Velarde, L.C., Elliott, P.J., Yao, C., Dave, J.R. and Tortella, F.C. (2002) Quantitative real-time RT-PCR analysis of inflammatory gene expression associated with ischemia-reperfusion brain injury. J Cereb Blood Flow Metab 22(9), 1068-79.
Bogaert, L., Scheller, D., Moonen, J., Sarre, S., Smolders, I., Ebinger, G. and Michotte, Y. (2000) Neurochemical changes and laser Doppler flowmetry in the endothelin-1 rat model for focal cerebral ischemia. Brain Res 887(2), 266-75.
Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P. and Lipton, S.A. (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A 92(16), 7162-6.
Brett, F.M., Mizisin, A.P., Powell, H.C. and Campbell, I.L. (1995) Evolution of neuropathologic abnormalities associated with blood-brain barrier breakdown in transgenic mice expressing interleukin-6 in astrocytes. J Neuropathol Exp Neurol 54(6), 766-75.
Buttini, M., Sauter, A. and Boddeke, H.W. (1994) Induction of interleukin-1 beta mRNA after focal cerebral ischaemia in the rat. Brain Res Mol Brain Res 23(1-2), 126-34.
Callaway, J.K., Lawrence, A.J. and Jarrott, B. (2003) AM-36, a novel neuroprotective agent, profoundly reduces reactive oxygen species formation and dopamine release in the striatum of conscious rats after endothelin-1-induced middle cerebral artery occlusion. Neuropharmacology 44(6), 787-800.
Campbell, I.L., Abraham, C.R., Masliah, E., Kemper, P., Inglis, J.D., Oldstone, M.B. and Mucke, L. (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci U S A 90(21), 10061-5.
Chang, W.S., Lee, Y.J., Lu, F.J. and Chiang, H.C. (1993) Inhibitory effects of flavonoids on xanthine oxidase. Anticancer Res 13(6A), 2165-70.
Chi, Y.S., Cheon, B.S. and Kim, H.P. (2001) Effect of wogonin, a plant flavone from Scutellaria radix, on the suppression of cyclooxygenase-2 and the induction of inducible nitric oxide synthase in lipopolysaccharide-treated RAW 264.7 cells. Biochem Pharmacol 61(10), 1195-203.
Cho, J. and Lee, H.K. (2004) Wogonin inhibits excitotoxic and oxidative neuronal damage in primary cultured rat cortical cells. Eur J Pharmacol 485(1-3), 105-10.
Church, J., Zeman, S. and Lodge, D. (1988) The neuroprotective action of ketamine and MK-801 after transient cerebral ischemia in rats. Anesthesiology 69(5), 702-9.
Clark, W.M., Warach, S.J., Pettigrew, L.C., Gammans, R.E. and Sabounjian, L.A. (1997) A randomized dose-response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Neurology 49(3), 671-8.
Clemens, J.A., Stephenson, D.T., Dixon, E.P., Smalstig, E.B., Mincy, R.E., Rash, K.S. and Little, S.P. (1997) Global cerebral ischemia activates nuclear factor-kappa B prior to evidence of DNA fragmentation. Brain Res Mol Brain Res 48(2), 187-96.
Conroy, B.P., Black, D., Lin, C.Y., Jenkins, L.W., Crumrine, R.C., DeWitt, D.S. and Johnston, W.E. (1999) Lamotrigine attenuates cortical glutamate release during global cerebral ischemia in pigs on cardiopulmonary bypass. Anesthesiology 90(3), 844-54.
Dawson, T.M., Dawson, V.L. and Snyder, S.H. (1992) A novel neuronal messenger molecule in brain: the free radical, nitric oxide. Ann Neurol 32(3), 297-311.
del Zoppo, G.J., Schmid-Schonbein, G.W., Mori, E., Copeland, B.R. and Chang, C.M. (1991) Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22(10), 1276-83.
Dok-Go, H., Lee, K.H., Kim, H.J., Lee, E.H., Lee, J., Song, Y.S., Lee, Y.H., Jin, C., Lee, Y.S. and Cho, J. (2003) Neuroprotective effects of antioxidative flavonoids, quercetin, (+)-dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. saboten. Brain Res 965(1-2), 130-6.
Eldadah, B.A. and Faden, A.I. (2000) Caspase pathways, neuronal apoptosis, and CNS injury. J Neurotrauma 17(10), 811-29.
Gao, Z., Huang, K. and Xu, H. (2001) Protective effects of flavonoids in the roots of Scutellaria baicalensis Georgi against hydrogen peroxide-induced oxidative stress in HS-SY5Y cells. Pharmacol Res 43(2), 173-8.
Gao, Z., Huang, K., Yang, X. and Xu, H. (1999) Free radical scavenging and antioxidant activities of flavonoids extracted from the radix of Scutellaria baicalensis Georgi. Biochim Biophys Acta 1472(3), 643-50.
Graham, D.I. (1988) Focal cerebral infarction. J Cereb Blood Flow Metab 8(6), 769-73.
Gramsbergen, J.B., Skjoth-Rasmussen, J., Rasmussen, C. and Lambertsen, K.L. (2004) On-line monitoring of striatum glucose and lactate in the endothelin-1 rat model of transient focal cerebral ischemia using microdialysis and flow-injection analysis with biosensors. J Neurosci Methods 140(1-2), 93-101.
Heasuk Lee, Young Ok Kim and Suk, K. (2003) Flavonoid wogonin from medicinal herb is neuroprotective by inhibiting inflammatory activation of microglia. The FASEB Journal 10, 1096/fj.03-0057fje.
Hickenbottom, S.L. and Grotta, J. (1998) Neuroprotective therapy. Semin Neurol 18(4), 485-92.
Huang, J., Agus, D.B., Winfree, C.J., Kiss, S., Mack, W.J., McTaggart, R.A., Choudhri, T.F., Kim, L.J., Mocco, J., Pinsky, D.J., Fox, W.D., Israel, R.J., Boyd, T.A., Golde, D.W. and Connolly, E.S., Jr. (2001) Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke. Proc Natl Acad Sci U S A 98(20), 11720-4.
Hung LM, L.S., Chen JK, Huang SS, Su MJ. (2001) Thaliporphine protects ischemia and ischemia-reperfused rat hearts via NO-dependent mechanism. Drug Dev Res 52, 446-453.
Iadecola, C. and Alexander, M. (2001) Cerebral ischemia and inflammation. Curr Opin Neurol 14(1), 89-94.
Iadecola, C. and Ross, M.E. (1997) Molecular pathology of cerebral ischemia: delayed gene expression and strategies for neuroprotection. Ann N Y Acad Sci 835, 203-17.
Iadecola, C., Zhang, F., Xu, S., Casey, R. and Ross, M.E. (1995) Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab 15(3), 378-84.
Infeld, B., Davis, S.M., Donnan, G.A., Yasaka, M., Lichtenstein, M., Mitchell, P.J. and Fitt, G.J. (1999) Nimodipine and perfusion changes after stroke. Stroke 30(7), 1417-23.
Kaufmann, A.M., Firlik, A.D., Fukui, M.B., Wechsler, L.R., Jungries, C.A. and Yonas, H. (1999) Ischemic core and penumbra in human stroke. Stroke 30(1), 93-9.
Kim, H.K., Cheon, B.S., Kim, Y.H., Kim, S.Y. and Kim, H.P. (1999) Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW 264.7 and their structure-activity relationships. Biochem Pharmacol 58(5), 759-65.
Kimuya, Y., Kubo, M., Tani, T., Arichi, S. and Okuda, H. (1981) Studies on Scutellariae Radix. IV. Effects on lipid peroxidation in rat liver. Chem Pharm Bull (Tokyo) 29(9), 2610-7.
Klijn, C.J. and Hankey, G.J. (2003) Management of acute ischaemic stroke: new guidelines from the American Stroke Association and European Stroke Initiative. Lancet Neurol 2(11), 698-701.
Kogure, T. and Kogure, K. (1997) Molecular and biochemical events within the brain subjected to cerebral ischemia (targets for therapeutical intervention). Clin Neurosci 4(4), 179-83.
Kontos, H.A. (1987) Oxygen radicals from arachidonate metabolism in abnormal vascular responses. Am Rev Respir Dis 136(2), 474-7.
Krajewski, S., Krajewska, M., Ellerby, L.M., Welsh, K., Xie, Z., Deveraux, Q.L., Salvesen, G.S., Bredesen, D.E., Rosenthal, R.E., Fiskum, G. and Reed, J.C. (1999) Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci U S A 96(10), 5752-7.
Kubo, M., Matsuda, H., Tanaka, M., Kimura, Y., Okuda, H., Higashino, M., Tani, T., Namba, K. and Arichi, S. (1984) Studies on Scutellariae radix. VII. Anti-arthritic and anti-inflammatory actions of methanolic extract and flavonoid components from Scutellariae radix. Chem Pharm Bull (Tokyo) 32(7), 2724-9.
Kubo, M., Matsuda, H., Tani, T., Arichi, S., Kimura, Y. and Okuda, H. (1985) Studies on Scutellariae radix. XII. Anti-thrombic actions of various flavonoids from Scutellariae radix. Chem Pharm Bull (Tokyo) 33(6), 2411-5.
Lapchak, P.A. (2006) 3alpha-OL-5-beta-pregnan-20-one hemisuccinate, a steroidal low-affinity NMDA receptor antagonist improves clinical rating scores in a rabbit multiple infarct ischemia model: synergism with tissue plasminogen activator. Exp Neurol 197(2), 531-7.
Lawrence, C.B., Allan, S.M. and Rothwell, N.J. (1998) Interleukin-1beta and the interleukin-1 receptor antagonist act in the striatum to modify excitotoxic brain damage in the rat. Eur J Neurosci 10(3), 1188-95.
Lee, H., Kim, Y.O., Kim, H., Kim, S.Y., Noh, H.S., Kang, S.S., Cho, G.J., Choi, W.S. and Suk, K. (2003) Flavonoid wogonin from medicinal herb is neuroprotective by inhibiting inflammatory activation of microglia. Faseb J 17(13), 1943-4.
Lee, J.M., Grabb, M.C., Zipfel, G.J. and Choi, D.W. (2000) Brain tissue responses to ischemia. J Clin Invest 106(6), 723-31.
Leker, R.R. and Shohami, E. (2002) Cerebral ischemia and trauma-different etiologies yet similar mechanisms: neuroprotective opportunities. Brain Res Brain Res Rev 39(1), 55-73.
Lipton, P. (1999) Ischemic cell death in brain neurons. Physiol Rev 79(4), 1431-568.
Liu, P.K. (2003) Ischemia-reperfusion-related repair deficit after oxidative stress: implications of faulty transcripts in neuronal sensitivity after brain injury. J Biomed Sci 10(1), 4-13.
Maffei, C.M., Mirels, L.F., Sobel, R.A., Clemons, K.V. and Stevens, D.A. (2004) Cytokine and inducible nitric oxide synthase mRNA expression during experimental murine cryptococcal meningoencephalitis. Infect Immun 72(4), 2338-49.
Matsushita, K., Matsuyama, T., Kitagawa, K., Matsumoto, M., Yanagihara, T. and Sugita, M. (1998) Alterations of Bcl-2 family proteins precede cytoskeletal proteolysis in the penumbra, but not in infarct centres following focal cerebral ischemia in mice. Neuroscience 83(2), 439-48.
Maurice, T. and Lockhart, B.P. (1997) Neuroprotective and anti-amnesic potentials of sigma (sigma) receptor ligands. Prog Neuropsychopharmacol Biol Psychiatry 21(1), 69-102.
Mayhan, W.G. (2001) Regulation of blood-brain barrier permeability. Microcirculation 8(2), 89-104.
McCord, J.M., Roy, R.S. and Schaffer, S.W. (1985) Free radicals and myocardial ischemia. The role of xanthine oxidase. Adv Myocardiol 5, 183-9.
Memezawa, H., Zhao, Q., Smith, M.L. and Siesjo, B.K. (1995) Hyperthermia nullifies the ameliorating effect of dizocilpine maleate (MK-801) in focal cerebral ischemia. Brain Res 670(1), 48-52.
Menge, T., Jander, S. and Stoll, G. (2001) Induction of the proinflammatory cytokine interleukin-18 by axonal injury. J Neurosci Res 65(4), 332-9.
Monnet, F.P. (2005) Sigma-1 receptor as regulator of neuronal intracellular Ca2+: clinical and therapeutic relevance. Biol Cell 97(12), 873-83.
Muir, K.W. (2006) Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists. Curr Opin Pharmacol 6(1), 53-60.
Murphy, S., Simmons, M.L., Agullo, L., Garcia, A., Feinstein, D.L., Galea, E., Reis, D.J., Minc-Golomb, D. and Schwartz, J.P. (1993) Synthesis of nitric oxide in CNS glial cells. Trends Neurosci 16(8), 323-8.
Nakano, M. (1998) Detection of active oxygen species in biological systems. Cell Mol Neurobiol 18(6), 565-79.
Namura, S., Zhu, J., Fink, K., Endres, M., Srinivasan, A., Tomaselli, K.J., Yuan, J. and Moskowitz, M.A. (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18(10), 3659-68.
Ogura, K., Takayasu, M. and Dacey, R.G., Jr. (1991) Differential effects of intra- and extraluminal endothelin on cerebral arterioles. Am J Physiol 261(2 Pt 2), H531-7.
Osborne, K.A., Shigeno, T., Balarsky, A.M., Ford, I., McCulloch, J., Teasdale, G.M. and Graham, D.I. (1987) Quantitative assessment of early brain damage in a rat model of focal cerebral ischaemia. J Neurol Neurosurg Psychiatry 50(4), 402-10.
Ouyang, Y.B., Tan, Y., Comb, M., Liu, C.L., Martone, M.E., Siesjo, B.K. and Hu, B.R. (1999) Survival- and death-promoting events after transient cerebral ischemia: phosphorylation of Akt, release of cytochrome C and Activation of caspase-like proteases. J Cereb Blood Flow Metab 19(10), 1126-35.
Ozyurt, E., Graham, D.I., Woodruff, G.N. and McCulloch, J. (1988) Protective effect of the glutamate antagonist, MK-801 in focal cerebral ischemia in the cat. J Cereb Blood Flow Metab 8(1), 138-43.
Piao, H.Z., Jin, S.A., Chun, H.S., Lee, J.C. and Kim, W.K. (2004) Neuroprotective effect of wogonin: potential roles of inflammatory cytokines. Arch Pharm Res 27(9), 930-6.
Planas, A.M., Soriano, M.A., Rodriguez-Farre, E. and Ferrer, I. (1995) Induction of cyclooxygenase-2 mRNA and protein following transient focal ischemia in the rat brain. Neurosci Lett 200(3), 187-90.
Prado, R., Ginsberg, M.D., Dietrich, W.D., Watson, B.D. and Busto, R. (1988) Hyperglycemia increases infarct size in collaterally perfused but not end-arterial vascular territories. J Cereb Blood Flow Metab 8(2), 186-92.
Quan, N. and Herkenham, M. (2002) Connecting cytokines and brain: a review of current issues. Histol Histopathol 17(1), 273-88.
Radi, R., Rodriguez, M., Castro, L. and Telleri, R. (1994) Inhibition of mitochondrial electron transport by peroxynitrite. Arch Biochem Biophys 308(1), 89-95.
Reimann-Philipp, U., Ovase, R., Weigel, P.H. and Grammas, P. (2001) Mechanisms of cell death in primary cortical neurons and PC12 cells. J Neurosci Res 64(6), 654-60.
Robinson, M.J., Macrae, I.M., Todd, M., Reid, J.L. and McCulloch, J. (1990) Reduction of local cerebral blood flow to pathological levels by endothelin-1 applied to the middle cerebral artery in the rat. Neurosci Lett 118(2), 269-72.
Rothwell, N.J. (1991) Functions and mechanisms of interleukin 1 in the brain. Trends Pharmacol Sci 12(11), 430-6.
Sevanian, A., Muakkassah-Kelly, S.F. and Montestruque, S. (1983) The influence of phospholipase A2 and glutathione peroxidase on the elimination of membrane lipid peroxides. Arch Biochem Biophys 223(2), 441-52.
Sharkey, J., Ritchie, I.M. and Kelly, P.A. (1993) Perivascular microapplication of endothelin-1: a new model of focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab 13(5), 865-71.
Shen, S.C., Lee, W.R., Lin, H.Y., Huang, H.C., Ko, C.H., Yang, L.L. and Chen, Y.C. (2002) In vitro and in vivo inhibitory activities of rutin, wogonin, and quercetin on lipopolysaccharide-induced nitric oxide and prostaglandin E(2) production. Eur J Pharmacol 446(1-3), 187-94.
Shieh, D.E., Liu, L.T. and Lin, C.C. (2000) Antioxidant and free radical scavenging effects of baicalein, baicalin and wogonin. Anticancer Res 20(5A), 2861-5.
Shigeno, T., Mima, T., Takakura, K., Yanagisawa, M., Saito, A., Goto, K. and Masaki, T. (1989) Endothelin-1 acts in cerebral arteries from the adventitial but not from the luminal side. J Cardiovasc Pharmacol 13 Suppl 5, S174-6.
Shigeno, T., Teasdale, G.M., McCulloch, J. and Graham, D.I. (1985) Recirculation model following MCA occlusion in rats. Cerebral blood flow, cerebrovascular permeability, and brain edema. J Neurosurg 63(2), 272-7.
Shinoura, N., Satou, R., Yoshida, Y., Asai, A., Kirino, T. and Hamada, H. (2000) Adenovirus-mediated transfer of Bcl-X(L) protects neuronal cells from Bax-induced apoptosis. Exp Cell Res 254(2), 221-31.
Shiraishi, T., DeMeester, S.R., Worrall, N.K., Ritter, J.H., Misko, T.P., Ferguson, T.B., Jr., Cooper, J.D. and Patterson, G.A. (1995) Inhibition of inducible nitric oxide synthase ameliorates rat lung allograft rejection. J Thorac Cardiovasc Surg 110(5), 1449-59; discussion 1460.
Son, D., Lee, P., Lee, J., Kim, H. and Kim, S.Y. (2004) Neuroprotective effect of wogonin in hippocampal slice culture exposed to oxygen and glucose deprivation. Eur J Pharmacol 493(1-3), 99-102.
Steiner, T. and Hacke, W. (1998) Combination therapy with neuroprotectants and thrombolytics in acute ischaemic stroke. Eur Neurol 40(1), 1-8.
Stroemer, R.P. and Rothwell, N.J. (1998) Exacerbation of ischemic brain damage by localized striatal injection of interleukin-1beta in the rat. J Cereb Blood Flow Metab 18(8), 833-9.
Sugimoto, K. and Iadecola, C. (2003) Delayed effect of administration of COX-2 inhibitor in mice with acute cerebral ischemia. Brain Res 960(1-2), 273-6.
Szelenyi, J. (2001) Cytokines and the central nervous system. Brain Res Bull 54(4), 329-38.
Takagi, S., Yamaki, M. and Inoue, K. (1981) [On the minor constituents of the roots of Scutellaria baicalensis Georgi (Wogon) (author's transl)]. Yakugaku Zasshi 101(10), 899-903.
Takehara, Y., Kanno, T., Yoshioka, T., Inoue, M. and Utsumi, K. (1995) Oxygen-dependent regulation of mitochondrial energy metabolism by nitric oxide. Arch Biochem Biophys 323(1), 27-32.
Tamura, A., Graham, D.I., McCulloch, J. and Teasdale, G.M. (1981) Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab 1(1), 53-60.
Tarozzo, G., Campanella, M., Ghiani, M., Bulfone, A. and Beltramo, M. (2002) Expression of fractalkine and its receptor, CX3CR1, in response to ischaemia-reperfusion brain injury in the rat. Eur J Neurosci 15(10), 1663-8.
Touzani, O., Boutin, H., Chuquet, J. and Rothwell, N. (1999) Potential mechanisms of interleukin-1 involvement in cerebral ischaemia. J Neuroimmunol 100(1-2), 203-15.
Van Hemelrijck, A., Vermijlen, D., Hachimi-Idrissi, S., Sarre, S., Ebinger, G. and Michotte, Y. (2003) Effect of resuscitative mild hypothermia on glutamate and dopamine release, apoptosis and ischaemic brain damage in the endothelin-1 rat model for focal cerebral ischaemia. J Neurochem 87(1), 66-75.
van Leyen, K., Kim, H.Y., Lee, S.R., Jin, G., Arai, K. and Lo, E.H. (2006) Baicalein and 12/15-lipoxygenase in the ischemic brain. Stroke 37(12), 3014-8.
Wahlgren, N.G., Ranasinha, K.W., Rosolacci, T., Franke, C.L., van Erven, P.M., Ashwood, T. and Claesson, L. (1999) Clomethiazole acute stroke study (CLASS): results of a randomized, controlled trial of clomethiazole versus placebo in 1360 acute stroke patients. Stroke 30(1), 21-8.
Wakabayashi, I. (1999) Inhibitory effects of baicalein and wogonin on lipopolysaccharide-induced nitric oxide production in macrophages. Pharmacol Toxicol 84(6), 288-91.
Wen, L.L., Chiu, C.T., Huang, Y.N., Chang, C.F. and Wang, J.Y. (2007) Rapid glia expression and release of proinflammatory cytokines in experimental Klebsiella pneumoniae meningoencephalitis. Exp Neurol 205(1), 270-8.
Wong, D. and Dorovini-Zis, K. (1992) Upregulation of intercellular adhesion molecule-1 (ICAM-1) expression in primary cultures of human brain microvessel endothelial cells by cytokines and lipopolysaccharide. J Neuroimmunol 39(1-2), 11-21.
Woo, A.Y., Cheng, C.H. and Waye, M.M. (2005) Baicalein protects rat cardiomyocytes from hypoxia/reoxygenation damage via a prooxidant mechanism. Cardiovasc Res 65(1), 244-53.
Yamasaki, Y., Matsuura, N., Shozuhara, H., Onodera, H., Itoyama, Y. and Kogure, K. (1995) Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats. Stroke 26(4), 676-80; discussion 681.
Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., Yazaki, Y., Goto, K. and Masaki, T. (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332(6163), 411-5.
Yanagisawa, M. and Masaki, T. (1989) Molecular biology and biochemistry of the endothelins. Trends Pharmacol Sci 10(9), 374-8.
Zhang, Y., Marcillat, O., Giulivi, C., Ernster, L. and Davies, K.J. (1990) The oxidative inactivation of mitochondrial electron transport chain components and ATPase. J Biol Chem 265(27), 16330-6.
Zhao, X., Bausano, B., Pike, B.R., Newcomb-Fernandez, J.K., Wang, K.K., Shohami, E., Ringger, N.C., DeFord, S.M., Anderson, D.K. and Hayes, R.L. (2001) TNF-alpha stimulates caspase-3 activation and apoptotic cell death in primary septo-hippocampal cultures. J Neurosci Res 64(2), 121-31.
Zhuang, H., Pin, S., Li, X. and Dore, S. (2003) Regulation of heme oxygenase expression by cyclopentenone prostaglandins. Exp Biol Med (Maywood) 228(5), 499-505.