脑缺血/再灌注PDGF-BB和TGF-β1表达的实验研究
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摘要
目的 血小板衍生生长因子BB(PDGF-BB)在缺血再灌注中的功能及其与转化生长因子β1(TGF-β1)的表达关系。
方法 选取尸解人脑标本，分为脑梗死组及对照组；制备大鼠脑缺血再灌注(MCAO／R)模型，分为：a假手术组；b缺血再灌注组，缺血2h后依照再灌注时间的不同分为0h、6h、12h、24h、48h、3d及7d共6组；c组为MCAO2h／R24h尼莫通药物干预组；d组为TTC染色组测量缺血灶体积。a、b、c组各时相点取材，免疫组化显示脑PDGF-BB及TGF-β1的表达变化并进行定量分析。
结果 人脑标本：脑梗死组较对照组PDGF-BB和TGF-β1免疫阳性表达均增高。动物实验：缺血灶体积MCAO2h组最小，再灌注后增加，第3d时达到高峰，第7d时有所减小。药物干预组较无干预组缺血灶体积减小。PDGF-BB在对照组、MCAO2h组阳性表达无差异。随再灌注时间延长表达增加，7d后达高峰，药物干预组与无干预组相比阳性表达增多。TGF-β1在MCAO2h组较对照组阳性表达减低，再灌注6h后表达开始增多，48h达高峰，并持续至7d。药物干预组与无干预组相比阳性表达增加。
结论 脑缺血／再灌注损伤可以诱导PDGF-BB和TGF-β1表达，二者有自我保护、自我调节作用，促进缺血灶周围血管再生以及损伤修复；TGF-β1可能通过上调PDGF-BB起到神经保护作用；尼莫通可以增加这两个生长因子的表达，起到神经保护作用。
Purpose The study aims at the function of platelet-derived growth factor BB (PDGF-BB) and the relation of PDGF-BB and TGF- ?1 in brain ischemia/reperfusion.
Method Remove brain tissues from fatal cases with cerebral infarct and cases with non-cerebrovascular diseases. Rat model of ischemic reperfusion of cerebral middle artery was established. Rats were randomly divided into sham operation group, ischemia/reperfusion group, medicine treated group and TTC staining ischemia/reperfusion group. The ischemia/reperfusion group is divided into six subgroups according to reperfusion time difference such as Oh> 6h 12h. 24h. 3d and Id. MACO2h/R24h group was treated with Nimodipine. Using immunohistochemical staining method and color image analysis, the expression of PDGF-BB and TGF- ?1 in cerebral hippocampi were measured. The infarct volume was measured by TTC staining.
Results Compared with control group, the expression of PDGF-BB and TGF- P 1 in infarct group in brain tissues from fatal cases increase. The ischemia volume (IV) in MCAO2h group is the smallest and the IV in MCAO2h/R3d group is the biggest. The IV in medicine treated group is smaller than the corresponding group without medicine. Expression of PDGF-BB in MCAO2h group remains the same as control group and increases after reperfusion with the peak value in 7d group. Expression of PDGF-BB in medicine treated group is higher than the expression in the group without medicine. Expression of TGF- P 1 decreases in MCAO2h group and increases after reperfusion with the climax in 48h until 7d. Expression of TGF- P 1 in medicine treated group is higher than the expression in the group without medicine.
Conclusions Ischemia and reperfusion can induce expression of PDGF-BB and TGF-P 1. The two factors can protect and regulate themselves and promote blood vessels proliferation surrounding ischemic zone and help damage recovery. TGF- P 1 acts as a neuroprotection factor by the way of upregulation of PDGF-BB. Nimodipine can relieve cerebral tissue damage and increase expression of the two proteins and protect cells from damage.
方法 选取尸解人脑标本，分为脑梗死组及对照组；制备大鼠脑缺血再灌注(MCAO／R)模型，分为：a假手术组；b缺血再灌注组，缺血2h后依照再灌注时间的不同分为0h、6h、12h、24h、48h、3d及7d共6组；c组为MCAO2h／R24h尼莫通药物干预组；d组为TTC染色组测量缺血灶体积。a、b、c组各时相点取材，免疫组化显示脑PDGF-BB及TGF-β1的表达变化并进行定量分析。
结果 人脑标本：脑梗死组较对照组PDGF-BB和TGF-β1免疫阳性表达均增高。动物实验：缺血灶体积MCAO2h组最小，再灌注后增加，第3d时达到高峰，第7d时有所减小。药物干预组较无干预组缺血灶体积减小。PDGF-BB在对照组、MCAO2h组阳性表达无差异。随再灌注时间延长表达增加，7d后达高峰，药物干预组与无干预组相比阳性表达增多。TGF-β1在MCAO2h组较对照组阳性表达减低，再灌注6h后表达开始增多，48h达高峰，并持续至7d。药物干预组与无干预组相比阳性表达增加。
结论 脑缺血／再灌注损伤可以诱导PDGF-BB和TGF-β1表达，二者有自我保护、自我调节作用，促进缺血灶周围血管再生以及损伤修复；TGF-β1可能通过上调PDGF-BB起到神经保护作用；尼莫通可以增加这两个生长因子的表达，起到神经保护作用。
Purpose The study aims at the function of platelet-derived growth factor BB (PDGF-BB) and the relation of PDGF-BB and TGF- ?1 in brain ischemia/reperfusion.
Method Remove brain tissues from fatal cases with cerebral infarct and cases with non-cerebrovascular diseases. Rat model of ischemic reperfusion of cerebral middle artery was established. Rats were randomly divided into sham operation group, ischemia/reperfusion group, medicine treated group and TTC staining ischemia/reperfusion group. The ischemia/reperfusion group is divided into six subgroups according to reperfusion time difference such as Oh> 6h 12h. 24h. 3d and Id. MACO2h/R24h group was treated with Nimodipine. Using immunohistochemical staining method and color image analysis, the expression of PDGF-BB and TGF- ?1 in cerebral hippocampi were measured. The infarct volume was measured by TTC staining.
Results Compared with control group, the expression of PDGF-BB and TGF- P 1 in infarct group in brain tissues from fatal cases increase. The ischemia volume (IV) in MCAO2h group is the smallest and the IV in MCAO2h/R3d group is the biggest. The IV in medicine treated group is smaller than the corresponding group without medicine. Expression of PDGF-BB in MCAO2h group remains the same as control group and increases after reperfusion with the peak value in 7d group. Expression of PDGF-BB in medicine treated group is higher than the expression in the group without medicine. Expression of TGF- P 1 decreases in MCAO2h group and increases after reperfusion with the climax in 48h until 7d. Expression of TGF- P 1 in medicine treated group is higher than the expression in the group without medicine.
Conclusions Ischemia and reperfusion can induce expression of PDGF-BB and TGF-P 1. The two factors can protect and regulate themselves and promote blood vessels proliferation surrounding ischemic zone and help damage recovery. TGF- P 1 acts as a neuroprotection factor by the way of upregulation of PDGF-BB. Nimodipine can relieve cerebral tissue damage and increase expression of the two proteins and protect cells from damage.
引文
1. Marks AR. Intracellular calcium-release channels: a regulator of cell life and death. Am J Physiol, 1997;272:H597.
2. Hagstad E, Berg J, Langmoen IA. Failure of all opurinol to protect against cerebral injury when given after the start of hypixia. Acta Neurol Scand, 1991 ;83:286.
3. Clark WM, Madden KP, Rothlein R, et al. Reduction of central nervous system ischemic injury in rabbits using leukocyte adhesion antibody treatment. Stroke, 1991 ;22: 877.
4. Wang PY, Kao CH, Mui MY, et al. Leukocyte infiltration in acute hemispheric ischemic stroke. Stroke, 1993;24:236.
5. Hallenbeck JM, Dutka AJ. Background review and current concepts of reperfusion injury. Arch Neurol, 1990;47:1245.
6. Dennis WC. Calcium-mediate neurotoxicity: relationship to specific channel type sand role in ischemic damage. TINS,1988;11:465.
7. Fisher M, Levine PH, Cohen RA. A21-amino steroid reduces hydrogen peroxide generation by and chemilumi-nescence of stimulated human leukocytes. Stroke, 1990;21:1435.
8. Bozzo L, Fantozzi LM, Bastianello S. Early collateral blood supply and late parenchymal brain damage in patient with middle cerebral artery occlusion. Stroke, 1989;20:735.
9. Ilan Y, Roy Chowdhury N, Prakash R, et al. Massive repopulation of rat liver by transplantation of hepatocytes into specific lobes of liver and ligation of portal vein branches to other lobes[J]. Transplantation,1997;64(1):8.
10. Hayashi A, Ito H, Shomori K, et al. Frequent occurrence of hepatocytic apoptosis in acute rejection of the grafted rat liver[J]. Pathol Int, 1997;47(8):518.
11. Nedergard M. Mechanisms of brain damage in focal cere-bralischemia. Acta Neurol Scand, 1988;77:8121
12. Brain M. Excitatory amino-acid neurotoxicity and neurodegenerative disease. TINS, 1990;13:379.
13. Minamisawa H, Terashi A, Katayana Y, etal. Braine-icosanoid levels in spontaneously hypertensive rats after ischemia with reperfusion: leukotriene C4 as a possible cause of cerebral edema. Stroke,1988;19:372.
14．潘力雄，姚志彬，陈以慈．c-fos蛋白在大鼠脑缺血再灌流海马中的表达及其与黄莲素抗脑缺血的关系．中华实验外科杂志，1996；13：57．
15. Landschulz WH, Johnson PF, Mcknight SL. The leucinezipper: a hypothelical structure common to a new class of DNA binding proteins. Science, 1988;240(4860): 1759.
16. Morgan I, Curran T. Role of onflux in the control of cfos expression. Nature, 1986;322(6079):552.
17. Jorgensen MB. Delayed cfos protooncogene expression in the rat hippocampus induced by transient global cerebral ischemia: an insitu hybridization study. Brain Res, 1989;484(2):393.
18. Lefter AM. Role of the beta2-integrins and immunoglobulin superfamily members in myocardial ischemia-reperfusion. Ann Thorac Surg, 1999,68(5): 1920-3.
19. Majno G, Joris I. Apoptosis, oncosis and necrosis. An overview of cell death [J]. Am J Pathol,1995;146(1):3.
20. Rodriguez I, Matsuura K, Khatib K, et al. Abel 2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti Fas antibody injection. [J]. J Exp Med, 1996;183(3):1031.
21. Zarnzami N, Brenner C, Marzo I, et al. Subcellular and submit to chondrial mode of action of bcl 2 like oncoproteins. [J]. Oncogene, 1998; 16(17):2265.
22. Cai JY, Jones DP. Superoxide in apoptosis: mitochondrial generation triggered by cytochrome C loss. [J]. J Biol Chem, 1998;273(19):11401.
23. Kaplan B, Brint S, Tanabe J, et al. Temporal thresholds for Neocortical infarction in rats subjected to reversible focal cerebral ischemia. Stroke 1991;22:1032.
24. Hajime Memezawa, Maj-lis Smith, Siesjo BoK. Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke 1992;23:552.
25. Ross R. Platelet-derived growth factor. Lancet, 1989;27:1179-89.
26. Ohno M, Sasahara M, Narumiya S, Tanaka N, Yamano T, Shimada M, Hazama F. Expression of platelet-derived growth factor B-chain and beta-receptor in hypoxic/ischemic encephalopathy of neonatal rats. Neuroscience 1999 May;90(2):643-51.
27. Jerzy Krupinski, Razao Issa, et al. A putative role for platelet-derived growth factor in angiogenesis and neuroprotection after ischemic stroke in humans. Stroke. 1997;28:564-73.
28. Renner O, Tsimpas A, Kostin S, et al. Time- and cell type-specific induction of platelet-derived growth factor receptor-beta during cerebral ischemia. Brain Res Mol Brain Res 2003 May 12;113(1-2):44-51.
29. Sakata M, Yanamoto H, Hashimoto N, Iihara K, Tsukahara T, Taniguchi T, Kikuchi H. Induction of infarct tolerance by platelet-derived growth factor against reversible focal ischemia. Brain Res 1998 Feb 16;784(1-2):250-5.
30. Iihara K, Hashimoto N, Tsukahara T, Sakata M, Yanamoto H, Taniguchi T. Platelet-derived growth factor-BB, but not -AA, prevents delayed neuronal death after forebrain ischemia in rats. J Cereb Blood Flow Metab 1997 Oct;17(10):1097-106.
31. Othberg A, Odin P, Ballagi A, (?)hgren A, Funa K, Lindvall O. Specific effects of platelet derived growth factor (PDGF) on fetal rat and human dopaminergic neurons in vitro. Exp. Brain Res. 1995;105:111-22.
32. Zhang FX, Hutchins JB. Protein phosphorylation in response to PDGF stimulation in cultured neurons and astrocytes. Brain Res Dev Brain Res 1997 Apr
18;99(2):216-25.
33. Satoh T et al. Platelet-derived growth factor receptor mediates activation of ras through different signaling pathways in different cell types. Mol Cell Biol, 1993;13:3706-13.
34. Crosby JR, Seifert RA, Soriano P, Bowen-Pope D. F. Chimaeric analysis reveals role of PDGF receptors in all muscle lineages. Nature Genet. 1998;18:385-8.
35. Dernck R, Jarrett JA, Chen EY, et al. Human transforming growth factor beta cDNA sequence and expression in normal and transformed cells. Nature, 1985;316(6030): 701-5.
36. Sporn MB, Robert AB, Wakefield LM, et al. Transforming growth factor beta: biological function and chemical structure. Science,1986;233(4763):532-4.
37. Heldin CH, Miyazono K, ten Dijke P.TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997 Dec 4;390(6659):465-71.
38. Whitman M.Smads and early developmental signaling by the TGFbeta superfamily. Genes Dev. 1998 Aug 15;12(16):2445-62.
39. Massague J.TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753-91.
40. Knuckey NW, Finch P, Palm DE, et al. Differential neuronal and astrocytic expression of transforming growth factor beta isoforms in rat hippocampus following transient forebrain ischemia [J]. Brain Res Mol Brain Res,1996,40(1):1-14.
41. Lehrmann E, Kiefer R, Finsen B, et al. Cytokines in cerebral ischemia: expression of transforming growth factor beta 1(TGF beta 1)mRNA in the post ischemic adult rat hippocampus [J]. Esp Neurol, 1995,131 (1): 114-23.
42. Wang X, Yue TL, White RF, et al. Transforming growth factor beta 1 exhibits delayed gene expression following focal cerebral ischemia [J]. Brain Res Bull, 1995,36(6):607-9.
43. Lehrmann E, Kiefer R, Christensen T, et al. Microglia and macrophages are major sources of locally produced transforming growth factor beta 1 after transient middle cerebral artery occlusion in rats [J]. Glia, 1998,24(4):437-48.
44. Jerzy Krupinski, Pat Kumar, Shant Kumar, FRC Path, Jozef Kaluza. Increased expression of TGF-1 in brain tissue after ischemic stroke in humans. Stroke. 1996;27:852-7.
45. Logan A, Baird A, Berry M. Decorin attenuates gliotic scar formation in the rat cerebral hemisphere. Exp Neurol, 1999;159(2):504-10.
46. Roussel S, Mackenzie ET, Vivien D, et al. A transforming growth factor beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury [J]. J Cereb Blood Flow Metab,1999,19(12): 1345-53.
47. Armstead WM, Mirro R, Zuckerman SL, et al. Transforming growth factor beta attenuates ischemia induce alterations in cerebrovascular responses [J]. Am J Physiol, 1993, 264(2Pt2): H381-5.
48. Yoshida Y. Pharmacology of cerebral ischemia [M]. Stuttgart Germany: Medpharm Scientific Publishers, 1994.329.
49. Durante W, Liao L, Reynas V, et al. Transforming growth factor-β1 stimulates L-Arginine Transport and Metabolism in vascular smooth Muscle cells: Role in polyamine and collagen synthesis. Circulation,2001,103(8): 1121-7.
50. Henrich Noack P, Prehn JH, Krieglstein J. Neuroprotective effects of TGF beta 1 [J]. J Neural Transm Suppl, 1994,43:33-45.
51. Mc Neill H, Williams C, Guan J, et al. Neuronal rescue with transforming growth factor beta after hypoxic isehemic brain injury [J]. Neuro report, 1994,5(8):901-4.
52. Yuan Zhu, Guo-Yuan Yang, Barbara Ahlemeyer, Li Pang, Xiao-Ming Che, Carsten Culmsee, Susanne Klumpp, and Josef Krieglstein. Transforming growth factor-β1 increases Bad phosphorylation and protects neurons against damage. J Neurosci, May 15, 2002, 22(10):3898-909.
53. Henrich Noack P, Prehn JH, Krieglstein J.TGF beta 1 protects hippocampal neurons against degeneration caused by transient global ischemia. Dose response relationship and potential neuroprotective mechanisms [J]. Stroke, 1996,27(9): 1609-15.
54. Krupinski J, Vodovotz Y, Li C, et al. Inducible nitric oxide production and expression of transforming growth factor betal in serum and CSF after cerebral ischemic stroke in man [J]. Nitric Oxide,1998,2(6):442-53.
55．胡治平．转化生长因子β与缺血性脑损伤(综述)[J]国外医学神经病学神经外科学分册，2000，27(2)：9799。
56. Klaus Unsicker, Jens Strelau. Functions of transforming growth factor-β isoforms in the nervous system. Cues based on localization and experimental in vitro and in vivo evidence. Eur. J. Biochem. 2000:267;6972-5.
57. Smith GM, Hale JH. Macrophage/microglia regulation of astrocytic tenascin: synergistic action of Transforming growth factor-beta and basic fibroblast growth factor. J Neurosci, 1997; 17(24):9624-33.
58. Anders JJ, Hurlock JA. Transplanted glial scar impedes olfactory bulb rein nervation. Exp Neurol, 1996; 142:144-50.
59. Yagi T, Jikihara I, Fukumuia M, et al. Rescue ofischemic brain injury by adenoviral gene transfer of glial cell line-derived neurotrophic factor after transient global ischemia in gerbils [J]. Brain Res,2000,885(2):273-82.
60. Chao CC, Hu S, Sheng WS, et al. Tumor Necrosis Factor-α mediates the release of bioactive transforming growth factor-β1 in murine microglial cell culture. Clinical Immunology and Immunopathology,1995;77(3):358-65.
61. Logan A, Frautschy SA, Gonzalez AM, et al. Enhanced expression of transforming growth factor-β1 in the rat brain after a localized cerebral injury. Brain Res, 1992;587(2):216-25.
62. Docagne F, Nicole O, Marti HH, et al. Transforming growth factor beta 1 as a regulator of the serpins/tPA axis in cerebral ischemia[J].FASEB
J,1999,13(11):1315-24.
63. Buisson A, Lesne S, Docagne F, Ali C, Nicole O, MacKenzie ET, Vivien D. Transforming growth factor-beta and ischemic brain injury. Cell Mol Neurobiol. 2003 Oct;23(4-5):539-50.
64. McDonald NQ, Hendrickson WA A structural superfamily of growth factors containing a cystine knot motif.. Cell. 1993 May 7;73(3):421-4.
65．冯亦璞．缺血性脑卒中的病理生理及药物治疗现状[J]．药学学报，1999，34(1)：72
66．刘永坚，严徽瑾．大鼠全脑缺血再灌流对脑内钙调蛋白的影响及Nimodipine的作用．中华神经外科杂志，1990；6(增刊)：33-5．
67. Heffez DS, Dienal GA. Effect of nimodipine on cerebral metabolism during ischemia and recirculation in the mongolian gerbil. J CBF Metab, 1985;5:525-6.
68．张晓彪，王建伟，胡卫星等．插线法制作大鼠大脑中动脉闭塞局灶性脑缺血再灌注模型．南京医科大学学报，2001；21(1)：32-7．
69．辛世萌，刘远洪，聂志余．栓线长度、直径及大鼠体重与栓线法大鼠局灶性脑缺血模型关系的研究．大连医科大学学报，2000；22(2)：105-7．
70. Anna Eriandsson, Maria Enarsson, Karin Forsberg-Nilsson. Immature neurons from CNS stem cells proliferate in response to platelet-derived growth factor. J Neurosci, 2001 ,May 15;21 (10):3483-91.
2. Hagstad E, Berg J, Langmoen IA. Failure of all opurinol to protect against cerebral injury when given after the start of hypixia. Acta Neurol Scand, 1991 ;83:286.
3. Clark WM, Madden KP, Rothlein R, et al. Reduction of central nervous system ischemic injury in rabbits using leukocyte adhesion antibody treatment. Stroke, 1991 ;22: 877.
4. Wang PY, Kao CH, Mui MY, et al. Leukocyte infiltration in acute hemispheric ischemic stroke. Stroke, 1993;24:236.
5. Hallenbeck JM, Dutka AJ. Background review and current concepts of reperfusion injury. Arch Neurol, 1990;47:1245.
6. Dennis WC. Calcium-mediate neurotoxicity: relationship to specific channel type sand role in ischemic damage. TINS,1988;11:465.
7. Fisher M, Levine PH, Cohen RA. A21-amino steroid reduces hydrogen peroxide generation by and chemilumi-nescence of stimulated human leukocytes. Stroke, 1990;21:1435.
8. Bozzo L, Fantozzi LM, Bastianello S. Early collateral blood supply and late parenchymal brain damage in patient with middle cerebral artery occlusion. Stroke, 1989;20:735.
9. Ilan Y, Roy Chowdhury N, Prakash R, et al. Massive repopulation of rat liver by transplantation of hepatocytes into specific lobes of liver and ligation of portal vein branches to other lobes[J]. Transplantation,1997;64(1):8.
10. Hayashi A, Ito H, Shomori K, et al. Frequent occurrence of hepatocytic apoptosis in acute rejection of the grafted rat liver[J]. Pathol Int, 1997;47(8):518.
11. Nedergard M. Mechanisms of brain damage in focal cere-bralischemia. Acta Neurol Scand, 1988;77:8121
12. Brain M. Excitatory amino-acid neurotoxicity and neurodegenerative disease. TINS, 1990;13:379.
13. Minamisawa H, Terashi A, Katayana Y, etal. Braine-icosanoid levels in spontaneously hypertensive rats after ischemia with reperfusion: leukotriene C4 as a possible cause of cerebral edema. Stroke,1988;19:372.
14．潘力雄，姚志彬，陈以慈．c-fos蛋白在大鼠脑缺血再灌流海马中的表达及其与黄莲素抗脑缺血的关系．中华实验外科杂志，1996；13：57．
15. Landschulz WH, Johnson PF, Mcknight SL. The leucinezipper: a hypothelical structure common to a new class of DNA binding proteins. Science, 1988;240(4860): 1759.
16. Morgan I, Curran T. Role of onflux in the control of cfos expression. Nature, 1986;322(6079):552.
17. Jorgensen MB. Delayed cfos protooncogene expression in the rat hippocampus induced by transient global cerebral ischemia: an insitu hybridization study. Brain Res, 1989;484(2):393.
18. Lefter AM. Role of the beta2-integrins and immunoglobulin superfamily members in myocardial ischemia-reperfusion. Ann Thorac Surg, 1999,68(5): 1920-3.
19. Majno G, Joris I. Apoptosis, oncosis and necrosis. An overview of cell death [J]. Am J Pathol,1995;146(1):3.
20. Rodriguez I, Matsuura K, Khatib K, et al. Abel 2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti Fas antibody injection. [J]. J Exp Med, 1996;183(3):1031.
21. Zarnzami N, Brenner C, Marzo I, et al. Subcellular and submit to chondrial mode of action of bcl 2 like oncoproteins. [J]. Oncogene, 1998; 16(17):2265.
22. Cai JY, Jones DP. Superoxide in apoptosis: mitochondrial generation triggered by cytochrome C loss. [J]. J Biol Chem, 1998;273(19):11401.
23. Kaplan B, Brint S, Tanabe J, et al. Temporal thresholds for Neocortical infarction in rats subjected to reversible focal cerebral ischemia. Stroke 1991;22:1032.
24. Hajime Memezawa, Maj-lis Smith, Siesjo BoK. Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke 1992;23:552.
25. Ross R. Platelet-derived growth factor. Lancet, 1989;27:1179-89.
26. Ohno M, Sasahara M, Narumiya S, Tanaka N, Yamano T, Shimada M, Hazama F. Expression of platelet-derived growth factor B-chain and beta-receptor in hypoxic/ischemic encephalopathy of neonatal rats. Neuroscience 1999 May;90(2):643-51.
27. Jerzy Krupinski, Razao Issa, et al. A putative role for platelet-derived growth factor in angiogenesis and neuroprotection after ischemic stroke in humans. Stroke. 1997;28:564-73.
28. Renner O, Tsimpas A, Kostin S, et al. Time- and cell type-specific induction of platelet-derived growth factor receptor-beta during cerebral ischemia. Brain Res Mol Brain Res 2003 May 12;113(1-2):44-51.
29. Sakata M, Yanamoto H, Hashimoto N, Iihara K, Tsukahara T, Taniguchi T, Kikuchi H. Induction of infarct tolerance by platelet-derived growth factor against reversible focal ischemia. Brain Res 1998 Feb 16;784(1-2):250-5.
30. Iihara K, Hashimoto N, Tsukahara T, Sakata M, Yanamoto H, Taniguchi T. Platelet-derived growth factor-BB, but not -AA, prevents delayed neuronal death after forebrain ischemia in rats. J Cereb Blood Flow Metab 1997 Oct;17(10):1097-106.
31. Othberg A, Odin P, Ballagi A, (?)hgren A, Funa K, Lindvall O. Specific effects of platelet derived growth factor (PDGF) on fetal rat and human dopaminergic neurons in vitro. Exp. Brain Res. 1995;105:111-22.
32. Zhang FX, Hutchins JB. Protein phosphorylation in response to PDGF stimulation in cultured neurons and astrocytes. Brain Res Dev Brain Res 1997 Apr
18;99(2):216-25.
33. Satoh T et al. Platelet-derived growth factor receptor mediates activation of ras through different signaling pathways in different cell types. Mol Cell Biol, 1993;13:3706-13.
34. Crosby JR, Seifert RA, Soriano P, Bowen-Pope D. F. Chimaeric analysis reveals role of PDGF receptors in all muscle lineages. Nature Genet. 1998;18:385-8.
35. Dernck R, Jarrett JA, Chen EY, et al. Human transforming growth factor beta cDNA sequence and expression in normal and transformed cells. Nature, 1985;316(6030): 701-5.
36. Sporn MB, Robert AB, Wakefield LM, et al. Transforming growth factor beta: biological function and chemical structure. Science,1986;233(4763):532-4.
37. Heldin CH, Miyazono K, ten Dijke P.TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997 Dec 4;390(6659):465-71.
38. Whitman M.Smads and early developmental signaling by the TGFbeta superfamily. Genes Dev. 1998 Aug 15;12(16):2445-62.
39. Massague J.TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753-91.
40. Knuckey NW, Finch P, Palm DE, et al. Differential neuronal and astrocytic expression of transforming growth factor beta isoforms in rat hippocampus following transient forebrain ischemia [J]. Brain Res Mol Brain Res,1996,40(1):1-14.
41. Lehrmann E, Kiefer R, Finsen B, et al. Cytokines in cerebral ischemia: expression of transforming growth factor beta 1(TGF beta 1)mRNA in the post ischemic adult rat hippocampus [J]. Esp Neurol, 1995,131 (1): 114-23.
42. Wang X, Yue TL, White RF, et al. Transforming growth factor beta 1 exhibits delayed gene expression following focal cerebral ischemia [J]. Brain Res Bull, 1995,36(6):607-9.
43. Lehrmann E, Kiefer R, Christensen T, et al. Microglia and macrophages are major sources of locally produced transforming growth factor beta 1 after transient middle cerebral artery occlusion in rats [J]. Glia, 1998,24(4):437-48.
44. Jerzy Krupinski, Pat Kumar, Shant Kumar, FRC Path, Jozef Kaluza. Increased expression of TGF-1 in brain tissue after ischemic stroke in humans. Stroke. 1996;27:852-7.
45. Logan A, Baird A, Berry M. Decorin attenuates gliotic scar formation in the rat cerebral hemisphere. Exp Neurol, 1999;159(2):504-10.
46. Roussel S, Mackenzie ET, Vivien D, et al. A transforming growth factor beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury [J]. J Cereb Blood Flow Metab,1999,19(12): 1345-53.
47. Armstead WM, Mirro R, Zuckerman SL, et al. Transforming growth factor beta attenuates ischemia induce alterations in cerebrovascular responses [J]. Am J Physiol, 1993, 264(2Pt2): H381-5.
48. Yoshida Y. Pharmacology of cerebral ischemia [M]. Stuttgart Germany: Medpharm Scientific Publishers, 1994.329.
49. Durante W, Liao L, Reynas V, et al. Transforming growth factor-β1 stimulates L-Arginine Transport and Metabolism in vascular smooth Muscle cells: Role in polyamine and collagen synthesis. Circulation,2001,103(8): 1121-7.
50. Henrich Noack P, Prehn JH, Krieglstein J. Neuroprotective effects of TGF beta 1 [J]. J Neural Transm Suppl, 1994,43:33-45.
51. Mc Neill H, Williams C, Guan J, et al. Neuronal rescue with transforming growth factor beta after hypoxic isehemic brain injury [J]. Neuro report, 1994,5(8):901-4.
52. Yuan Zhu, Guo-Yuan Yang, Barbara Ahlemeyer, Li Pang, Xiao-Ming Che, Carsten Culmsee, Susanne Klumpp, and Josef Krieglstein. Transforming growth factor-β1 increases Bad phosphorylation and protects neurons against damage. J Neurosci, May 15, 2002, 22(10):3898-909.
53. Henrich Noack P, Prehn JH, Krieglstein J.TGF beta 1 protects hippocampal neurons against degeneration caused by transient global ischemia. Dose response relationship and potential neuroprotective mechanisms [J]. Stroke, 1996,27(9): 1609-15.
54. Krupinski J, Vodovotz Y, Li C, et al. Inducible nitric oxide production and expression of transforming growth factor betal in serum and CSF after cerebral ischemic stroke in man [J]. Nitric Oxide,1998,2(6):442-53.
55．胡治平．转化生长因子β与缺血性脑损伤(综述)[J]国外医学神经病学神经外科学分册，2000，27(2)：9799。
56. Klaus Unsicker, Jens Strelau. Functions of transforming growth factor-β isoforms in the nervous system. Cues based on localization and experimental in vitro and in vivo evidence. Eur. J. Biochem. 2000:267;6972-5.
57. Smith GM, Hale JH. Macrophage/microglia regulation of astrocytic tenascin: synergistic action of Transforming growth factor-beta and basic fibroblast growth factor. J Neurosci, 1997; 17(24):9624-33.
58. Anders JJ, Hurlock JA. Transplanted glial scar impedes olfactory bulb rein nervation. Exp Neurol, 1996; 142:144-50.
59. Yagi T, Jikihara I, Fukumuia M, et al. Rescue ofischemic brain injury by adenoviral gene transfer of glial cell line-derived neurotrophic factor after transient global ischemia in gerbils [J]. Brain Res,2000,885(2):273-82.
60. Chao CC, Hu S, Sheng WS, et al. Tumor Necrosis Factor-α mediates the release of bioactive transforming growth factor-β1 in murine microglial cell culture. Clinical Immunology and Immunopathology,1995;77(3):358-65.
61. Logan A, Frautschy SA, Gonzalez AM, et al. Enhanced expression of transforming growth factor-β1 in the rat brain after a localized cerebral injury. Brain Res, 1992;587(2):216-25.
62. Docagne F, Nicole O, Marti HH, et al. Transforming growth factor beta 1 as a regulator of the serpins/tPA axis in cerebral ischemia[J].FASEB
J,1999,13(11):1315-24.
63. Buisson A, Lesne S, Docagne F, Ali C, Nicole O, MacKenzie ET, Vivien D. Transforming growth factor-beta and ischemic brain injury. Cell Mol Neurobiol. 2003 Oct;23(4-5):539-50.
64. McDonald NQ, Hendrickson WA A structural superfamily of growth factors containing a cystine knot motif.. Cell. 1993 May 7;73(3):421-4.
65．冯亦璞．缺血性脑卒中的病理生理及药物治疗现状[J]．药学学报，1999，34(1)：72
66．刘永坚，严徽瑾．大鼠全脑缺血再灌流对脑内钙调蛋白的影响及Nimodipine的作用．中华神经外科杂志，1990；6(增刊)：33-5．
67. Heffez DS, Dienal GA. Effect of nimodipine on cerebral metabolism during ischemia and recirculation in the mongolian gerbil. J CBF Metab, 1985;5:525-6.
68．张晓彪，王建伟，胡卫星等．插线法制作大鼠大脑中动脉闭塞局灶性脑缺血再灌注模型．南京医科大学学报，2001；21(1)：32-7．
69．辛世萌，刘远洪，聂志余．栓线长度、直径及大鼠体重与栓线法大鼠局灶性脑缺血模型关系的研究．大连医科大学学报，2000；22(2)：105-7．
70. Anna Eriandsson, Maria Enarsson, Karin Forsberg-Nilsson. Immature neurons from CNS stem cells proliferate in response to platelet-derived growth factor. J Neurosci, 2001 ,May 15;21 (10):3483-91.