依达拉奉和万珂对大鼠脑缺血再灌注损伤保护作用机制的研究
|
摘要
本研究旨在动态观察反映脑缺血再灌注损伤的各项指标,寻找其高峰时间点,并在此时单独及联合应用依达拉奉和万珂,通过HE、TTC染色;化学比色法、免疫组化法、Western-blot法和TUNEL法测MDA、SOD、Cyt C、Caspase-3、NF-κBp65、IL-1β和细胞凋亡,观察二者对脑缺血再灌注损伤的作用,探讨其脑保护机制。结果发现:1.脑缺血再灌注后炎症反应、自由基增加、线粒体损伤和细胞凋亡等呈动态改变;2.依达拉奉和万珂均可减轻线粒体损伤,减少细胞凋亡,缩小脑梗死体积,有脑保护作用;3.两药联合应用疗效优于单独用药。本实验创新点:1.国内首次将万珂用于治疗脑缺血再灌注损伤,国内外首次证实蛋白酶体抑制剂的脑保护作用机制可能主要通过抑制线粒体凋亡途径而减轻脑损伤;2.依达拉奉除抗脂质过氧化外还有抑制后续炎症反应的作用,可能主要通过抑制线粒体凋亡途径发挥脑保护作用,尚未有学者提出此观点;3.国内外首次证实早期联合应用蛋白酶体抑制剂和自由基清除剂的“鸡尾酒疗法”治疗脑缺血再灌注损伤效果明显,二者可能共同抑制线粒体凋亡途径实现脑保护作用。
Background and purpose Many factors are involved in cerebral ischemia-reperfusion injury, among them inflammatory reaction and free radicals play an important role in early stage. Edaravone, a kind of free radical scavenger, has been used to treat cerebral infarction and verified effective, while the precise mechanisms are unclear. At present, there is no an effective medicine on restrain inflammatory reaction. The proteasome inhibitors can induce apoptosis on proliferating tumor cells and are permitted to use for the multiple myeloma. Recent research shows that the proteasome inhibitors can control inflammatory reaction on transcriptional level and are used in treating cerebral infarction. Now the mechanism is unclear.
The study plans to apply the animal model of cerebral ischemia-reperfusion to observe the changes of inflammatory reaction, free radicals, mitochondria and cell apoptosis, and to treat with Edaravone and Velcade on the proper time. Comparing the changes pre- and post–treatment and observing the effects on the cerebral ischemia-reperfusion injury, the aims is to explore the protective mechanisms of Edaravone and Velcade on cerebral reperfusion inury.
Methods
1. Experimental animal and group 175 Wistar rats were randomly divided into the normal group(5), the sham operation group and cerebral ischemical reperfusion group (55 in each group), the physiological saline control group, Edaravone treatment group, Velcade treatment group and combined treatment group (15 in each group). The transient middle cerebral artery occlusion models were applied and reperfused after 2 hours. All the groups were divided into 5 subgroups according to different reperfusion time points, 0h, 6h, 12h, 24h, 48h (10 in each group). The others were used to measure infarct volume with TTC stain.
2. Decapitation and detection methods Edaravone was given instantly and on 12h (3mg/kg), and Velcade was given instantly too (0.2mg/kg) after reperfusion via vena caudalis injection. Combined treatment method was given according to the above all. The physiological saline was used in control group. After 24h 5 rats were infused , decapitated and fixed with 4% paraformaldehyde after reperfusion 24h, alcoholic dehydration, dimethyl benzene transparence, paraffin imbedding and sect serial sections. Immunohistochemistry was used to detect the expression of Cyt C, Caspase-3, NF-κBp65 and IL-1βprotein, while cell apoptosis was detected by TUNEL. At the same time, the expression of Cyt C and Caspase-3 protein were detected by Western-blot. Another 5 rats were decapitated on ice plate immediately. The 2/3 brain tissue was used to make brain homogenate for detecting MDA and SOD, the others were preserved in -70℃refrigerator for Western-blot. After TTC stain, the images were measured and the cerebral infarct volume were calculated with Motic Images Advanced 3.2 image analysis system.
Results
1. Histological changes: The chromatospherites was clear, endochylema was profuse in normal group and sham operation group, while in reperfusion group karyopyknosis,工团chromoplasm condense. The interspace between cells became wide. brain tissue became loose. These changes were gradually obvious with time .
2. There were seldom immune reaction positive cells and apoptosis cells in normal group and sham operation group. The difference between MDA and SOD was not significant (p>0.05) in them. MDA increased gradually after reperfusion and peaked at 12h, while SOD decreased obviously at that time. Compared with the physiological saline control group , the combined treatment group and single treatment groups MDA decreased and SOD activity restored, the differences were significant (p<0.05). There were lots of NF-κBp65, IL-1β, CytC and Caspase-3 positive cells in all the intervention groups. All kinds of positive cells increased gradually until 24h, compared with all the subgroups of the sham operation group, the differences were significant (p<0.05). Compared the single treatment group with the physiological saline control group and combined treatment group with all the other groups, NF-κBp65, IL-1β, CytC and Caspase-3 positive cells and apoptosis cells decreased obviously, the differences were significant (p<0.05). The expression of Cyt C, Caspase-3 by Western-blot in different time points and pre-and post-treatment were consistent with the results of immunohistochemistry methods.
3. Cerebral infarct was found in all the operation groups except the sham operated group, and the infarct volumes with TTC stain in treatment group became smaller than the physiological saline group (p<0.05).
Conclusion
1. The change of inflammatory reaction, free radicals and mitochondria damage involved in cerebral ischemical reperfusion injury were dynamic . Cell apoptosis was coincident to the above changes.
2. Edaravone can inhibit lipid peroxidation, scavenge free radicals, restrain inflammatory reaction, protect mitochondria and reduce cells apoptosis. So Edaravone maybe mitigate cerebral ischemical reperfusion injury through blocking mitochondria apoptosis pathway. On the other hand, Velcade can restrain inflammatory reaction and free radicals following that which can protect mitochondria and reduce cells apoptosis. So we assumed that Velcade mitigate cerebral ischemical reperfusion injury by blocking mitochondria apoptosis pathway too.
3. Edaravone can scavenge free radicals and Velcade can inhibit inflammatory reaction. Combined treatment of them may deduce synergistic inhibition to mitochondria apoptosis pathway. The protection will be more effectively than single treatment.
Background and purpose Many factors are involved in cerebral ischemia-reperfusion injury, among them inflammatory reaction and free radicals play an important role in early stage. Edaravone, a kind of free radical scavenger, has been used to treat cerebral infarction and verified effective, while the precise mechanisms are unclear. At present, there is no an effective medicine on restrain inflammatory reaction. The proteasome inhibitors can induce apoptosis on proliferating tumor cells and are permitted to use for the multiple myeloma. Recent research shows that the proteasome inhibitors can control inflammatory reaction on transcriptional level and are used in treating cerebral infarction. Now the mechanism is unclear.
The study plans to apply the animal model of cerebral ischemia-reperfusion to observe the changes of inflammatory reaction, free radicals, mitochondria and cell apoptosis, and to treat with Edaravone and Velcade on the proper time. Comparing the changes pre- and post–treatment and observing the effects on the cerebral ischemia-reperfusion injury, the aims is to explore the protective mechanisms of Edaravone and Velcade on cerebral reperfusion inury.
Methods
1. Experimental animal and group 175 Wistar rats were randomly divided into the normal group(5), the sham operation group and cerebral ischemical reperfusion group (55 in each group), the physiological saline control group, Edaravone treatment group, Velcade treatment group and combined treatment group (15 in each group). The transient middle cerebral artery occlusion models were applied and reperfused after 2 hours. All the groups were divided into 5 subgroups according to different reperfusion time points, 0h, 6h, 12h, 24h, 48h (10 in each group). The others were used to measure infarct volume with TTC stain.
2. Decapitation and detection methods Edaravone was given instantly and on 12h (3mg/kg), and Velcade was given instantly too (0.2mg/kg) after reperfusion via vena caudalis injection. Combined treatment method was given according to the above all. The physiological saline was used in control group. After 24h 5 rats were infused , decapitated and fixed with 4% paraformaldehyde after reperfusion 24h, alcoholic dehydration, dimethyl benzene transparence, paraffin imbedding and sect serial sections. Immunohistochemistry was used to detect the expression of Cyt C, Caspase-3, NF-κBp65 and IL-1βprotein, while cell apoptosis was detected by TUNEL. At the same time, the expression of Cyt C and Caspase-3 protein were detected by Western-blot. Another 5 rats were decapitated on ice plate immediately. The 2/3 brain tissue was used to make brain homogenate for detecting MDA and SOD, the others were preserved in -70℃refrigerator for Western-blot. After TTC stain, the images were measured and the cerebral infarct volume were calculated with Motic Images Advanced 3.2 image analysis system.
Results
1. Histological changes: The chromatospherites was clear, endochylema was profuse in normal group and sham operation group, while in reperfusion group karyopyknosis,工团chromoplasm condense. The interspace between cells became wide. brain tissue became loose. These changes were gradually obvious with time .
2. There were seldom immune reaction positive cells and apoptosis cells in normal group and sham operation group. The difference between MDA and SOD was not significant (p>0.05) in them. MDA increased gradually after reperfusion and peaked at 12h, while SOD decreased obviously at that time. Compared with the physiological saline control group , the combined treatment group and single treatment groups MDA decreased and SOD activity restored, the differences were significant (p<0.05). There were lots of NF-κBp65, IL-1β, CytC and Caspase-3 positive cells in all the intervention groups. All kinds of positive cells increased gradually until 24h, compared with all the subgroups of the sham operation group, the differences were significant (p<0.05). Compared the single treatment group with the physiological saline control group and combined treatment group with all the other groups, NF-κBp65, IL-1β, CytC and Caspase-3 positive cells and apoptosis cells decreased obviously, the differences were significant (p<0.05). The expression of Cyt C, Caspase-3 by Western-blot in different time points and pre-and post-treatment were consistent with the results of immunohistochemistry methods.
3. Cerebral infarct was found in all the operation groups except the sham operated group, and the infarct volumes with TTC stain in treatment group became smaller than the physiological saline group (p<0.05).
Conclusion
1. The change of inflammatory reaction, free radicals and mitochondria damage involved in cerebral ischemical reperfusion injury were dynamic . Cell apoptosis was coincident to the above changes.
2. Edaravone can inhibit lipid peroxidation, scavenge free radicals, restrain inflammatory reaction, protect mitochondria and reduce cells apoptosis. So Edaravone maybe mitigate cerebral ischemical reperfusion injury through blocking mitochondria apoptosis pathway. On the other hand, Velcade can restrain inflammatory reaction and free radicals following that which can protect mitochondria and reduce cells apoptosis. So we assumed that Velcade mitigate cerebral ischemical reperfusion injury by blocking mitochondria apoptosis pathway too.
3. Edaravone can scavenge free radicals and Velcade can inhibit inflammatory reaction. Combined treatment of them may deduce synergistic inhibition to mitochondria apoptosis pathway. The protection will be more effectively than single treatment.
引文
[1] Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischemic stroke: an integrated view[J]. Trends Neurosci, 1999,22(9):391-397.
[2] Liao SL, Chen WY, Raung SL, et al. Association of immune responses and ischemic brain infarction in rat [J]. Neuroreport, 2001,12(9):1943-1947.
[3] Iadecola C, Alexander M. Cerebral ischemia and inflammation[J]. Curr Opin Neurol, 2001,14(1):89-94.
[4] Huie RE, Padmaja S. The reaction of NO with superoxide[J]. Free Radic Res Commun, 1993,18(4):195-199.
[5] Barone FC, Schmidt DB, Hillegass LM, et al. Reperfusion increases neutrophilis and leukotriene B4 receptor binding in rat focal ischemia[J]. Stroke, 1992, 23(9):1337-1347.
[6] De Grada TJ. The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy[J]. Neurology, 1998,51(3Suppl3):S62-68.
[7] Aggarwal BB. Nuclear factor-kappa B: the enemy within[J]. Cancer Cell, 2004,6 (3):203-208.
[8] Toledo-Pereyra LH, Toledo AH, Walsh J, et al. Molecular signaling pathways in ischemia / reperfusion[J]. Exp Clin Transplant, 2004,2(1):174-177.
[9] Berti R, Williams AJ, Moffett JR, et al. Quantitative real-time RT-PCR analysis of inflammatory gene expression associated with ischemia-reperfusion brain injury[J]. J Cereb Blood Flow Metab, 2002,22(9):1068-1079.
[10] Tran K, Merika M, Thanos D. Distinct functional properties of Ikappa B alpha and Ikappa B beta[J]. Mol cell Biol, 1997,17(9):5386-5399.
[11] Whiteside ST, Isra?l A. Ikappa B protein: structure, function and regulation[J]. Semin Cancer Biol, 1997,8(2):75-82.
[12] FlohéL, Brigelius FlohéR, Saliou C, et al. Pedox regulation of NF-kappa B activation[J]. Free Radic Biol Med, 1997:22(6):1115-1126.
[13] May MJ, Ghosh S. Signal transduction through NF-kappa B[J]. Immunol Today, 1998,19(2):80-88.
[14] HanY, Weinman S, Boldogh I, et al. Tumor necrosis factor-alpha -inducible I kappa B alpha proteolysis medited by cytosolic m-calpain. A mechanism parallel to the ubiquitin-Proteasome pathway for nuclear factor-kappB activation[J]. J Biol Chem, 1999,274(2):787-794.
[15] Sacht G M?rten A, Deiters U, et al. Activation of nuclear factor-kappa B in macrophages by mycoplasmal lipopeptides[J]. Eur J Immunol, 1998,28(12): 4207-4212.
[16] Glasgow JN, Wood T, Perez-Polo JR. Identification and characterization of nuclear factor kappaB binding sites in the murine bcl-x promoter[J]. J Neurochem, 2000,75(4):1377-1389
[17] Wojcik C, Di Napoli M. Ubiquitin-proteasome system and proteasome inhibition: New strategies in stroke therapy [J]. Stroke, 2004,35(6):1506-1518.
[18] Orlowski R, Baldwin AS Jr. NF-κB as a therapeutic target in cancer[J]. 2002, 2002,8(8):385-389.
[19] Wang C, Deng L, Hong M, et al. TAK1 is a ubiquitin-dependent kinase Of MKK and IKK [J]. Nature, 2001,412(6844):346-351.
[20] Mercurio F, Zhu H, Murray BW, et al. IKK-1and IKK-2: cytokine-activated Ikappa B kinases essential for NF–kappa B activation [J]. Science, 1997,278 (5339):860-866.
[21] Kaloqeris TJ, Kevil CG, Laroux FS, et al. Differential monocyte adhesion and adhesion molecule expression in venous and arterial endothelial cells [J]. Am J Physiol, 1999,276(1 Pt 1):L9-L19.
[22] Williams AJ, Hale SL, Moffett JR, et al. Delayed treatment with MLN519 reduces infarction and associated neurologic deficit caused by focal ischemic brain injury in rats via anti-inflammatory mechanisms involving nuclear factor-kappaB activation, gliosis, and leukocyte infiltration[J]. J Cereb Blood Flow Metab, 2003:23(l):75-87.
[23] Williams AJ, Dave JR, Tortella FC. Neuroprotection with the proteasome inhibitor MLN519 in focal ischemic brain injury: Relation to nuclear factor kappaB (NF-kappaB), inflammatory gene expression, and leukocyte infiltration [J]. Neurochem Int, 2006,49(2):106-112.
[24] Elliott PJ, Zollner TM, Boehncke WH. Proteasome inhibition: a new anti-inflammatory strategy[J]. J Mol Med, 2003,81(4):235-245.
[25] Qiu JH, Asai A, Chi S, et al. Proteasome inhibitors induce cytochrome c Caspase- 3-like protease-mediated apoptosis in cultured cortical neurons[J]. J Neurosci, 2000,20(1): 259-265.
[26] Morris DC, Zhang L, Zhang ZG, et al. Extension of the therapeutic window for recombinant tissue plasminogen activator with argatroban in a rat model of embolic stroke[J]. Stroke, 2001,32(11):2635-2640.
[27] Rajkumar SV, Richardson PG, Hideshima T, et al. Proteasome inhibition as a novel therapeutic target in human cancer[J]. J Clin Oncol, 2005,23(3):630-639.
[28] Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma[J]. N Engl J Med, 2003,348(26):2609-26.
[29] Sinn DI, Lee ST, Chu K, et al. Proteasomal inhibition in intracerebral hemorrhage: neuroprotective and anti-inflammatory effects of bortezomib[J]. Neurosci Res, 2007,58(1):12-18.
[30] Yamamoto T, Maruyama W, Kato Y, et al. Selective nitration of mitochondrial complex I by peroxynitrite: involvement in mitochondria dysfunction and cell death of dopaminergic SH-SY5Y cells[J]. J Neural Transm, 2002,109(1):1-13.
[31] Gamen S, Anel A, Pérez-Galán P, et al. Doxorubicin treatment activates a Z-VAD-Sensitive caspase, which causes deltapsim loss, caspase-9 Activity, and apoptosis in Jurkat cells[J]. Exp Cell Res, 2000,258(1):223-235.
[32] Budd SL, Tenneti L, Lishnak T, et al. Mitochondrial and extramitochondral apoptotic signaling pathways in cerebrocortical neurons[J]. Proc Natl Acad Sci USA, 2000,97(11):6161-6166.
[33] Graham SH, Chen J. Programmed cell death in cerebral ischemia[J]. J Cereb Blood Flow Metab, 2001,21(2):99-109.
[34] Fiskum G. Mitochondrial participation in ischemic and traumatic neural cell death[J]. J Neurotrauma, 2000,17(10):843-855.
[35] Ow YP, Green DR, Hao Z, et al. Cytochrome c: function beyond respiration[J]. Nat Rev Mol Cell Biol, 2008,9(7):532-542.
[36] Adrain C, Martin SJ. The mitochondrial apoptosome: a killer Unleashed by thecytochromeseas[J]. Trends Biochem Sci, 2001,26(6):390-397.
[37] Daniel PT. Dissecting the pathways to death[J]. Leukemia, 2000,14(12):2035 -2044.
[38] Goonesinghe A, Mundy E, Smith M, et al. Pro-apoptotic Bid induces membrane perturbation by inserting selected lysolipids into the bilayer[J]. Biochem J, 2005, 387(1):109-118.
[39] McConkey DJ, Nutt LK. Calcium flux measurements in apoptosis[J]. Methods Cell Biol, 2001,66(2):229-246.
[40] Herrmann J, Ciechanover A, Lerman LO, et al. The ubiquitin-proteasome system in cardiovascular diseases-a hypothesis extended[J]. Cardiovasc Res, 2004,61(1): 11-21.
[41] Raasi S, Wolf DH. Ubiquitin receptors and ERAD: A network of pathways to the proteasome [J]. Sem in Cell Dev Biol, 2007,18(6):78-91.
[42] Ferrari S, Smeland S, Mercuri M. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups [J]. J Clin Oncol, 2005,23(34):8845-8852.
[43] McNaught KS, Olanow CW, Halliwell B, et al. Failure of the ubiquitin proteasome system in Parkinson’s disease[J]. Nat Rev Neurosci, 2001, 2(8): 589-594.
[44] O’Connell BC, Harper JW. Ubiquitin proteasome system (UPS): what can chromatin do for you [J] ? Curr Opin Cell Biol, 2007,19(2):206-214.
[45] Glickman MH, Maytal V. Regulating the 26S proteasome[J]. Curr Top Microbiol Immunol, 2002,268(2):43-72.
[46] Aguilar RC, Wendland B. Ubiquitin: not just for proteasomes anymore[J]. Curr Opin Cell Bio, 2003,15(2):184-190.
[47] Rohde JR, Breitkreutz A, Chenal A, et al. Type III secretion effectors of the IpaH Family are E3 ubiquitin Ligases [J]. Cell Host Microbe, 2007,1(1):77-83.
[48] Koegl M, Hoppe T, Schlenker S, et al. A novel ubiquitination factor E4 is involved in multiubiquitin chain assembly[J]. Cell, 1999,96(5):635-644.
[49] Roqers GC, Rusan NM, Roberts, DM, et al. The SCF Slimb ubiquitin ligase regulates Plk4/Sak levels to block centriole reduplication[J]. J Cell Biol, 2009, 184(2):225-239.
[50] Kim H T, Kim K P, Ledias F, et al. Certain pairs of ubiquitin-conjugating enzymes(E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages [J]. J Biol Chem, 2007,282(24): 17375-17386.
[51] Ciechanover A, Orian A, Schwartz AL. The ubiquitin-mediated proteolytic pathway: mode of action and clinical implications[J]. J Cell Biochem, 2000,34 (Suppl):40-51.
[52] Yeh ET, Gong L, Kamitani T. Ubiquitin-like proteins: new wines in new bottles[J]. Gene, 2000,248(1-2):1-14.
[53] Kisselev AF, Apoian TN, Woo KM, et al. The sizes of peptides Generated from protein by mammalian 26S and 20S proteasome[J]. J Biol Chem, 1999,274 (6): 3363-3371.
[54] Li M, Chen D, Shiloh A, et a1. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization[J]. Nature, 2002,416(6881):648-653.
[55] Meiners S, Ludwig A, Stangl V, et al. Proteasome inhibitors: Poisons and remedies[J]. Med Res Rev, 2008,28(2):309-327.
[56] Burger AM, Seth AK. The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications[J]. Eur J Cancer, 2004,40(15):2217-2229.
[57] Verhoef LG, Heinen C, Selivanova A, et al. Minimal length requirement for proteasomal degradation of ubiquitin-dependent substrates[J]. FASEB J, 2009, 23(1):123-133.
[58] Price SR, Du J, Bailey JL, et al. Molecular mechanisms regulating protein turnover in muscle[J]. Am J Kidney Dis, 2001,37(1suppl2):S112-114.
[59] Strickland E, Hakala K, Thomas PJ, et al. Recognition of misfolding proteins by PA700, the regulatory subcomplex of the 26S proteasome[J]. Biol Chem, 2000, 275(8):5565-5572.
[60] Groll M, Clausen T. Molecular shredders: how proteasome fulfill their role[J]. Curr Opin Struct Biol, 2003,13(6):665-673.
[61] Hershko A. The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle [J]. 1Cell Death Differ, 2005,12(9):1191-1197.
[62] Yano M, Kanesaki Y, Koumoto Y, et al. Chaperone activities of the 26S and 20S proteasome [J]. Curr Protein Pept Sci, 2005,6(2):197-203.
[63] Schwartz AL, Ciechanover A. The ubiquitin-proteasome pathway and pathogenesis of human diseases [J]. Annu Rev Med, 1999,50(2):57-74.
[64] Strous GJ, Govers R. The ubiquitin-proteasome system and endocytosis[J]. J Cell Sci, 1999,112(pt10):1417-1423.
[65] Knowlton JR, Jolnston SC, Whitby FG, et al. Structure of the proteasome activator REGalpha ( PA28alpha) [J]. Nature, 1997,390(6660):639-643.
[66] Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells[J]. Cancer Res, 2001,61(7):3071-3076.
[67] Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells[J]. Proc Natl Acad Sci USA, 2002, 99(22): 14374-14379.
[68] Momand J, Wu HH, Dasgupta G. MDM2-master regulator of the p53 tumor suppressor protein[J]. Gene, 2000,242(1-2):15-29.
[69] Mitsiades CS, Mitsiades N, Hideshima T, et al. Proteasome inhibition as a new therapeutic principle in hematological malignancies[J].Curr Drug Targets, 2006,7(10): 1341-1347.
[70] Jana NR, Dikshit P, Goswami A, et al. Inhibition of proteasomal function by curcumin induces apoptosis through mitochondrial pathway[J]. J Biol Chem, 2004,279(12): 11680-11685.
[71] Adams J. The development of proteasome inhibitors as anticancer drugs[J]. Cancer Cell, 2004,5(5):417-21.
[72] Lightcap ES, McCormack TA, Pien CS, et al. Proteasome inhibition measurements: clinical application [J]. Clin Chem 2000,46(5):673-683.
[73] Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer[J]. J Clin Invest, 2001,107 (2):135-142.
[74] Goldberg AL, Cascio P, Saric T, et al. The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides[J]. Mol Immunol, 2002,39(3-4):147-164.
[75] Shih SC, Sloper-Mould KE, Hicke L. Monoubiquitin carries a novel internalization sinagal that is appended to activated receptors[J]. EMBO J, 2000,19(2):187-198.
[76] Murata T, Shimotohno K. Ubiquitination and proteasome-dependent degradation of human eukaryotic translation initiation factor 4E[J]. J Biol Chem, 2006, 281(30): 20788-20800.
[77] Vinitsky A, Cardozo C, Sepp-Lorenzino L, et al. Inhibition of the proteolytic activity of the multicatalytic proteinase complex (proteasome) by substrate- related peptidyl- aldehydes[J]. J Biol Chem, 1994,269(47):29860-29866.
[78] Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. PhaseⅠtrial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies[J]. J Clin Oncol, 2002,20(22):4420-4427.
[79] Phillips JB, Williams AJ, Adams J,et al. Proteasome inhibitor PS519 reduces infarction and attenuates leukocyte infiltration in a rat model of focal cerebral ischemia[J]. Stroke, 2000,31(7):1686-1693.
[80] Liqhtcap ES, McCormack TA, Pien CS, et al. Proteasome inhibition measurements: clinical application[J]. Clin Chem, 2000,46(5):673-683.
[81] Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents[J]. Cancer Res, 1999,59(11):2615-2622.
[82] Aqhajanian C, Soiqnet S, Dizon DS, et al. A phaseⅠtrial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies [J]. Clin Cancer Res, 2002,8 (8):2505-2511.
[83] Tan C, Waldmann TA, Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemia[J]. Cancer Res, 2002,62(4):1083-1086.
[84] Zavrski I, Jakob C, Schmid P, et al. Proteasome: an emerging target for cancer therapy[J]. Anticancer Drugs, 2005,16(5):475-481.
[85] Stephenson D, Yin T, Smalstig EB, et al. Transcription factor nuclear Factor-kappa B is activated in neurons after focal cerebral ischemia [J]. J Cereb Blood Flow Metab, 2000,20(3):592-603.
[86] Schneider A, Martin-Villalba A, Weih F, et al. NF-kappaB is activated and promotes cell death in focal cerebral ischemia[J]. Nat Med, 1999,5(5):554-559.
[87] Seegers H, Grillon E, Trioullier Y, et al. Nuclear factor-kappa B activation in permanent intraluminal focal cerebral ischemia in the rat[J]. Neurosci Lett, 2000, 288(3):241-245.
[88] Imajoh-Ohmi S, Kawaquchi T, Sugiyama S, et al. Lactacystin, a specific inhibitor of the proteasome, induces apoptosis in human monoblast U937 cells[J]. Biochem Biophys Res Commun, 1995,217(3):1070-1077.
[89] Zhang XM, Lin H, Chen C, et al. Inhibition of ubiquitin-proteasome pathway activates a Caspase-3-like protease and induces Bcl-2 cleavage in human M-07e leukaemic cells [J]. Biochem J, 1999,340(Pt 1):127-133.
[90] Shinohara K, Tomioka M, Nakano H, et al. Apoptosis induction resulting from proteasome inhibition [J]. Biochem J, 1996,317(Pt 2):385-388.
[91] Meriin AB, Gabai VL, Yaqlom J, et al. Proteasome inhibitors activate stress kinases and induce Hsp72. Diverse effects on apoptosis [J]. J Biol Chem, 1998, 273(11): 6373-6379.
[92] Orlowski RZ, Zeger EL. Targeting the proteasome as a therapeutic strategy against haematological malignancies[J]. Expert Opin Invest Drugs 2006, 15(2): 117-130.
[93] Orlowski RZ, Kuhn DJ. Proteasome inhibitors in cancer therapy: lessons from the first decade [J]. Clin Cancer Res, 2008,14(6):1649-1657.
[94] Zavrski I, Kleeberg L, Kaiser M, et al. Proteasome as an emerging therapeutic target in cancer [J]. Curr Pharm Design, 2007, 13(5):471-485.
[95] Meiners S, Ludwig A, Stangl V, et al. Proteasome inhibitors: poisons and remedies [J]. Med Res Rev, 2008,28(2):309-327.
[96] Kane RC, Bross PF, Farrell AT, et al. Velcade: U. S. FDA approval for the treatment of multiple myeloma progressing on prior therapy [J]. Oncologist, 2003,8(6):508-513.
[97] Voorhees PM, Dees EC, O’Nell B, et al. The proteasome as a target for cancer therapy [J]. Clin Cancer Res, 2003,9(17):6316-6325.
[98] Xiao D, Zhu SP, Gu ZL. Quercetin induced apoptosis in human leukemia HL-60 cells[J]. Zhongguo Yao Li Xue Bao, 1997,18(3):280-283.
[99] Sadoul R, Fernandez PA, Quiquerez AL, et al. Involvement of the proteasome in the programmed cell death of NGF-deprived sympathetic neurons[J]. EMBO J, 1996,15(15):3845-3852.
[100] Grimm LM, Goldberg AL, Poirier GG, et al. Proteasomes play an essential role in thymocyte apoptosis[J]. EMBO J, 1996,15(15):3835-3844.
[101] Canu N, Barbato C, Ciotti MT, et al. Proteasome involvement and accumulation of ubiquitinated proteins in cerebellar granule neurons undergoing apoptosis[J]. J Neurosci, 2000,20(2):589-599.
[102] Sawada H, Kohno R, Kihara T, et al. Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes alpha-synuclein inclusions[J]. J Biol Chem, 2004,279(11):10710-10719.
[103] Orlowski RZ. The role of the ubiquitin-proteasome pathway in apoptosis[J]. Cell Death Differ, 1999,6(4):303-313.
[104] Masdehors P, Omura S, Merle-Béral H, et al. Increased sensitivity of CLL- derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin[J]. Br J Haematol, 1999,105(3):752-757.
[105] Fenteany G, Schreiber SL. Lactacystin, proteasome function, and cell fate[J]. J Biol Chem, 1998,273(15):8545-8548.
[106] LeBlanc R, Catley LP, Hideshima T, et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model[J]. Cancer Res, 2002,62(17):4996-5000.
[107] Adams J. Development of the Proteasome Ihibitor PS-341[J]. Oncologist, 2002,7(1):9-16.
[108] Rajkumar SV, Richardson PG, Hideshima T, et al. Proteasome inhibition as a novel therapeutic target in human cancer[J]. J Clin Oncol, 2005,23(3):630-639.
[109] Drexler HC, Risau W, Konerding MA. Inhibition of proteasome function induces programmed cell death in proliferating endothelial cells[J]. FASEB J, 2000,14(1): 65-77.
[110] Zheng Z, Yenari MA. Post-ischemic inflammation: molecular mechanisms and therapeutic implications[J]. Neurol Res, 2004,26(8):884-892.
[111] Kawamura S, Li Y, Shirasawa M, et al. Reversible middle cerebral artery occlusion in rats using an intraluminal thread technique[J]. Surg Neurol, 1994,41(5):368-373.
[112] Ludwig H, Khayat D, Giaccone G, et al. Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies[J]. Cancer, 2005,104(9): 1794-1807.
[113] Zhang L, Zhang ZG, Zhang RL, et al. Postischemic (6-h) treatment with recombinant human tissue plasminogen activator and proteasome inhibitor PS-519 reduces infarction in a rat model of embolic focal cerebral ischemia[J]. Stroke, 2001,32(12):2926-2931.
[114] Henninger N, Sicard KM, Bouley J, et al. The proteasome inhibitor VELCADE reduces infarction in rat models of focal cerebral ischemia[J]. Neurosci Lett, 2006,398(3):300-305.
[115] Schulze-Osthoff K, Ferrari D, Riehemann K, et al. Regulation of NF-kappaB activation by MAP kinase cascades[J]. Immunobiology, 1997,198(1-3):35-49.
[116] Aggarwal BB. Nuclear factor-kappa B: the enemy within[J]. Cancer Cell, 2004,6 (3):203-208.
[117] Tamatani M, Mitsuda N, Matsuzaki H,et al. A pathway of neuronal apoptosis induced by hypoxia/reoxygenation: roles of nuclear factor-kappaB and Bcl-2[J]. J Neurochem, 2000,75(2):683-93.
[118] Lam YA, Lawson TG, Velayutham M, et al. A proteasomal ATPase subunit recognizes the polyubiquitin degradation signal[J]. Nature, 2002,416(6882):763-767.
[119] Demasi M, Davies KJ. Proteasome inhibitors induce intracellular protein aggregation and cell death by an oxygen-dependent mechanism[J]. FEBS Lett, 2003,542 (1-3):89-94.
[120] Hu BR, Martone ME, Jones YZ, et al. Protein aggregation after transient cerebral ischemia[J]. J Neurosci, 2000,20(9):3191-3199.
[121] Asai A, Tanahashi N, Qiu JH, et al. Selective proteasomal dysfunction in the hippocampal CA1 region after transient forebrain ischemia[J]. J Cereb Blood Flow Metab, 2002,22(6):705-710.
[122] Youdim MB, Amit T, Falach-Yoqev M, et al. The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the Neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline[J]. Biochem Pharmacol, 2003,66(8): 1635-1641.
[123] Dimmeler S, Breitschopf K, Haendeler J, et al. Dephosphorylation targets Bcl-2 for ubiquitin-dependent degradation: a link between the apoptosome and the proteasome pathway[J]. J Exp Med, 1999,189(11):1815-1822.
[124] Rideout HJ, Wang Q, Park DS, et al. Cyclin-dependent kinase activity is required for apoptotic death but not inclusion formation in cortical neurons after proteasomal inhibition[J]. J Neurosci, 2003,23(4):1237-1245.
[125] Johnston JA, Ward CL, Kopito RR. Aggresomes: a cellular response to misfolded proteins[J]. J Cell Biol, 1998,143(7):1883-1898.
[126] Lipton P. Ischemic cell death in brain neurons[J]. Physiol Rev, 1999,79(4): 1431-1568.
[127] Zhai Q, Wang J, Kim A, et al. Involvement of the ubiquitin-proteasome system in the early stages of wallerian degeneration[J]. Neuron, 2003,39(2):217-225.
[128]曹三勇,徐胜利,陈彪.蛋白酶体抑制剂对神经细胞的双重作用[J].脑与神经疾病杂志, 2006,14(4):274-277.
[129] Bobba A, Canu N, Atlante A, et al. Proteasome inhibitors prevent cytochrome c release during apoptosis but not in excitotoxic death of cerebellar granule neurons [J]. FEBS Lett, 2002,515(1-3):8-12.
[130] Keller JN, Markesbery WR. Proteasome inhibition results in increased poly-ADP- ribosylation: implications for neuron death[J]. J Neurosci Res, 2000, 61(4): 436-442.
[131] Kollmar R, Henninger N, Bardutzky J, et al. Combination therapy of moderate hypothermia and thrombolysis in experimental thromboembolic stroke-an MRI study[J]. Exp Neurol. 2004,190(1):204-212.
[132] Toomey JR, Valocik RE, Koster PF, et al. Inhibition of factor IX(a) is protective in a rat model of thromboembolic stroke[J]. Stroke. 2002,33(2):578-585.
[133] Fujimura M, Gasche Y, Morita-Fujimura Y, et al. Early appearance of activated matrix metalloproteinase-9 and blood brain barrier disruption in mice after focal cerebral ischemia and reperfusion[J]. Brain Res, 1999,842(1):92-100.
[134] McNaught KS, Belizaire R, Isacson O, et al. Altered proteasomal function in sporadic Parkinson’s disease[J]. Exp Neurol, 2003,179(1):38-46.
[135] McNaught KS, Mytilineou C, Jnobaptiste R, et al. Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures [J]. J Neurochem, 2002,81(2):301-306.
[136] Ding Q, Bruce-Keller AJ, Chen Q, et al. Analysis of gene expression in neural cells subject to chronic proteasome inhibition[J]. Free Radic Biol Med, 2004,36(4): 445-455.
[137] Golab J, BauerTM, Daniel V, et al. Role of the ubiquitin-proteasome pathway in the diagnosis of human diseases[J]. Clin Chim Acta, 2004,340(1-2):27-40.
[138] Ardley HC, Robinson PA. The role of ubiquitin-protein ligases in neurodegenerative disease[J]. Neurodeqener Dis, 2004,1(2-3):71-87.
[139] Jnaa NR, Nukina N. Recent advances in understanding the pathogenesis of polyglutamine deseases: involvement of molecular chaperones and ubiquitin- proteasome pathway[J]. J Chem Neuroanat, 2003,26(2):95-101.
[140] Orlowski RZ, Eswara JR, Lafond-Walker A, et al. Tumor growth inhibition induced in a murine model of human Burkitt’s Lymphoma by a proteasome inhibitor[J]. Cancer Res, 1998,58(19):4342-4348.
[141] Goy A, Younes A, McLaughlin P, et al. PhaseⅡstudy of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma[J]. J Clin Oncol, 2005,23(4):667-675.
[142] Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma[J]. N Engl J Med, 2003,348(26):2609-2617.
[143] Wallace KB, Eells JT, Madeira VM, et al. Mitochondria-mediated cell injury. Sympo- i. sium overview[J]. Fundam Appl Toxicol, 1997,38(1):23-37.
[144] Green DR, Reed JC. Mitochondria and apoptois[J]. Science, 1999,281(5381): 1309- 1312.
[145] Sims NR, Anderson MF, Hobbs LM, et al. Brain mitochondrial response to postischemic reperfusion :A role for calcium and hydrogen peroxide[J]? Dev Neurosci, 2000,22(5-6):366-375.
[146] Rao AM, Hatcher JF, Dempsey RJ. Lipid alterations in transient forebrain ischemia: possible new mechanisms of CDP-choline neuroprotection[J]. J Neurochem, 2000, 75(6):2528-2535.
[147] Lemasters JJ, Nieminen AL, Qian T, et al. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy[J]. Biochim Biophys Acta, 1998,1366(1-2):177-196.
[148] Kroemer G, Zamzami N, Susin SA. Mitochondrial control of apoptosis[J]. Immunol Today, 1997,18(1):44-51.
[149] Ferrer I, Planas AM. Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra [J]. J Neuropathol Exp Neurol, 2003,62(4):329-339.
[150] Zheng Z, Zhao H, Steinberg GK, et al. Cellular and molecular events underlying ischemia-induced neuronal apoptosis[J]. Drug News Perspect, 2003,16(8): 497-503.
[151] Kroemer G, Reed JC. Mitochondrial control of cell death[J]. Nat Med, 2000,6 (5): 513-519.
[152] Haeberlein SL. Mitochondrial function in apoptotic neuronal cell death [J]. Neurochem Res, 2004,29(3):521-530.
[153] Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death[J]. Physiol Rev, 2007,87(1):99-163.
[154] Martinou JC, Desagher S, Antonsson B. Cytochrome c release from mitochondria: all or nothing[J]. Nat Cell Biol, 2000, 2(3):E41-43.
[155] Haga N, Fujita N, Tsuruo T. Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis[J]. Oncogene, 2003,22(36):5579-5585.
[156] Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade[J]. Cell, 1997,91(4):479-489.
[157] Mronga T, Stahnke T, Goldbaum O, et al. Mitochondrial pathway is involved in hydrogen-peroxide-induced apoptotic cell death of oligodendrocytes[J]. Glia, 2004,46(4): 446-455.
[158] Lauber K, Appel HA, Schlosser SF, et al. The adapter protein apoptotic protease- activating factor-1 (Apaf-1) is proteolytically processed during apoptosis [J]. J Biol Chem, 2001, 276(32):29772-29781.
[159] Fu WN, Kelsey SM, Newland AC, et al. Apaf-1 XL is an inactive isoform comparedwith Apaf-1L [J]. Biochem Biophys Res Commun, 2001,282(1): 268-272.
[160] Benedict MA, Hu Y, Inohara N, et al. Expression and functional analysis of Apaf-1 isoforms. Extra Wd-40 repeat is required for cytochrome c binding and regulated activation of procaspase-9[J]. J Biol Chem, 2000,275(12):8461-8468.
[161] Yu X, Wang L, Acehan D, et al. Three-dimensional structure of a double apoptosome formed by the Drosophila Apaf-1 related killer[J]. J Mol Biol, 2006, 355(3):577-589.
[162] Fridman JS, Lowe SW. Control of apoptosis by p53[J]. Oncogene, 2003,22(56): 9030- 9040.
[163] Stennicke HR, Salvesen GS. Properties of Caspases[J]. Biochim Biophys Acta, 1998,1387(1-2):17-31.
[164] Jia L, Srinivasula SM, Liu FT, et al. Apaf-1 protein deficiency confers resistance to cytochrome c-dependent apoptosis in human leukemic cells[J]. Blood, 2001,98(2): 414-421.
[165] Assefa Z, Vantieghem A, Garmyn M, et al. p38 mitogen-activated protein kinase regulates a novel, Caspase-independent pathway for the mitochondrial cytochrome c release in ultraviolet B radiation-induced apoptosis[J]. J Biol Chem, 2000, 275(28):21416-21421.
[166] Shibata M, Hattori H, Sasaki T, et al. Subcellular localization of a promoter and an inhibitor of apoptosis (Smac/DIABLO and XIAP) during brain ischemia/ reperfusion [J]. Neuroreport, 2002,13(15):1985-1988.
[167] Fleisher TA. Apoptosis[J]. Ann Allergy Asthma Immunol, 1997,78(3):245-249.
[168] MatéMJ, Ortiz-Lombardía M, Boitel B, et al. The crystal structure of the mouse apoptosis-inducing factor AIF[J]. Nat Struct Biol, 2002,9(6):442-446.
[169] Du C, Fang M, Li Y, et al. Smac, a mitochondrial protein that promotes cytochrome c dependent caspase activation by eliminating IAP inhibition[J]. Cell, 2000,102(1): 33-42.
[170] Wu C, Fujihara H, Yao J, et al. Different expression patterns of Bcl-2, Bcl-xl, and Bax proteins after sublethal forebrain ischemia in C57Black/Crj6 Mouse Striatum[J]. Stroke, 2003, 34(7):1803-1808.
[171] Adams JM, Cory S. Life-or-death decisions by the Bcl-2 protein family[J]. TrendsBiochem Sci, 2001,26(1):61-66.
[172] Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis[J]. Genes Dev, 1999,13(15):1899-1911.
[173] MA, Gross. Mitochondrial carries and pores: key regulators of the mitochondrial apoptotic program[J]? Apoptosis, 2007,12(5):869-876.
[174] Schwarz CS, Evert BO, Seyfried J, et al. Overexpression of bcl-2 results in reduction of cytochrome c content and inhibition of complex I activity[J]. Biochem Biophys Res Commun, 2001,280(4):1021-1027.
[175] Hsu SY, Hsueh AJ. Tissue-specific Bcl-2 protein partners in apoptosis: An ovarian paradigm[J]. Physiol Rev, 2000,80(2):593-614.
[176] Orrenius S. Mitochondrial regulation of apoptotic cell death[J]. Toxicol Lett, 2004, 149(1-3):19-23.
[177] Swanton E, Savory P, Cosulich S. Bcl-2 regulates a caspase-3/caspase-2 apoptotic cascade in cytosolic extracts[J]. Oncogene, 1999, 18(10):1781-1787.
[178] Crompton M, Barksby E, Johnson N, et al. Mitochondrial intermembrane junctional complexes and their involvement in cell death[J]. Biochimie, 2000,84(1-2):143-152.
[179] Shimizu S, Ide T, Yanagida T, et al. Electrophysiological study of a novel large pore formed by Bax and the voltage dependent anion channel that is permeable to cytochrome c[J]. J Biol Chem, 2000,275(16):12321-12325.
[180] Burlacu A. Regulation of apoptosis by Bcl-2 family proteins[J]. J Cell Mol Med, 2003,7(3):249-257.
[181] Kuwana T, Mackey MR, Perkins G, et al. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane[J]. Cell, 2002,111 (3): 331-342.
[182] Budihardjo I, Oliver H, Lutter M, et al. Biochemical pathways of caspase activation during apoptosis[J]. Annu Rev Cell Dev Biol, 1999,15(1):269-290.
[183] Endres M, Engelhardt B, Koistinaho J, et al. Improving outcome after stroke: overcoming the translational roadblock[J]. Cerebrovasc Dis, 2008,25(3):268-278.
[184] Huang Y, McNamara JO, et al. Ischemic stroke:“acidotoxicity”is a perpetrator[J]. Cell, 2004,118(6):665-666.
[185] Chan, Pak H, et al. Reactive oxygen radicals in signaling and damage in the ischemic brain[J]. J Cereb Blood Flow Metab, 2001,21(1):2-14.
[186] Liu, Hsueh-Ning L, Walter E, et al. AMPA receptor-mediated toxicity in oligodendrocyte progenitors involves free radical generation and activation of JNK, calpain and Caspase-3[J]. J Neurochem, 2002,82(2):398-409.
[187] Ali, Carine, Nicole, et al. Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitoxicity in the brain[J]. J Cerebral Blood Flow Metab, 2000,20(6):956-966.
[188] Ramachandran A, Ceaser E, Darley-Usmar VM. Chronic exposure to nitric oxide alters the free iron pool in endothelial cells: role of mitochondrial respiratory complexes and heat shock proteins[J]. Proc Natl Acad Sci USA, 2004, 101(1):384-389.
[189] Dela Monte SM, Neely TR, Cannon J, et al. Oxidative stress and hypoxia-like injury cause Alzheimer-type molecular abnormalities in central nervous system neurons [J]. Cell Mol Life Sci, 2000, 57(10):1471-1481.
[190] Huang CY, Fujimura M, Noshita N, et al. SOD1 down-regulates NF-kappaB and c-Myc expression in mice after transient focal cerebral ischemia[J]. J Cereb Blood Flow Metab, 2001,21(2):163-173.
[191] Neumar RW. Molecular mechanisma of ischemic neuronal injury. Ann Emerg Med 2000,36(5):483- 506.
[192] Paschen W, Doutheil J. Disturbance of endoplasmic reticulum functions: a key mechanism underlying cell damage[J]? Acta Neurochir Suppl, 1999,73:1-5.
[193] Bradham CA, Qian T, Streetz K, et al. The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release [J]. Mol Cell Biol, 1998,18(11):6353-6364.
[194] Kristián T, Siesj? BK. Calcium in ischemic cell death[J]. Stroke, 1998,29(3):705-718.
[195] Bosetti F, Yu G, Zucchi R, et al. Myocardial ischemic preconditioning and mitochondrial F1F0-ATPase activity[J]. Mol Cell Biochem, 2000, 215(1-2): 31-37.
[196] Yuan J, Yankner BA. Apoptosis in the nervous system[J]. Nature, 2000, 407(6805): 802-809.
[197] Kroemer G, Dallaporta B, Resche-Rigon M. The mitochondrial death/life regulator in apoptosis and necrosis[J]. Annu Rev Physiol,1998,60(1):619-642.
[198] Nakamura K, Bossy-Wetzel E, Burns K, et al. Changes in endoplasmic reticulum luminal environment affect cell sensitivity to apoptosis[J]. J Cell Biol, 2000, 150(4):731-740.
[199] Suzuki S, Higuchi M, Proske RJ, et al. Implication of mitochondria-derived reactive oxygen species, cytochrome C and Caspase-3 in N-(4-hydroxyphenyl) retinamideinduced apoptosis in cervical carcinoma cells[J]. Oncogene, 1999, 18 (46):6380-6387.
[200] Shiraishi H, Okamoto H, Yoshimura A, et al. ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1[J]. J Cell Sci, 2006,119(pt19):3958-3966.
[201] Fujimura M, Morita-Fujimura Y, Murakami K, et al. Cytosolic redistribution of cytochrome c after transient focal cerebral ischemia in rats [J]. J Cereb Blood Flow Metab, 1998,18(11):1239-1247.
[202] Fujimura M, Morita-Fujimura Y, Kawase M, et al. Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome and subsequent DNA fragment-ation after permanent focal cerebral ischemia in mice[J]. J Neurosci, 1999, 19(9):3414-3422.
[203] Green DR. Apoptotic pathway: the roads to ruin[J]. Cell,1998,94(6):695-698.
[204] Guégan C, Sola B. Early and sequential recruitment of apoptotic effectors after focal permanent ischemia in mice[J]. Brain Res, 2000,856(1-2):93-100.
[205] Ashkenazi A, Dixit VM. Death receptors: signaling and modulation[J]. Science, 1998, 281(5381):1305-1308.
[206] Breckenridge DG, Stojanovic M, Marcellus RC, et al. Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol [J]. J Cell Biol, 2003, 160 (7):1115-1127.
[207] Wang B, Nguyen M, Breckenridge DG, et al. Uncleaved BAP31 in association with A4 protein at the endoplasmic reticulum is an inhibitor of Fas-initiated release ofcytochrome c from mitochondria[J]. J Biol Chem, 2003,278 (16):14461-14468.
[208] Longa EZ, Weinstein PR, Carlson S, et al. Reversible middle cerebral artery occlusion without craniectomy in the rats[J]. Stroke, 1989,20(1):84-91.
[209] Sakamoto A, Ohnishi ST, Ohnishi T, et al. Relationship between free radical production and lipid peroxidation during ischemia-reperfusion injury in the rat brain[J]. Brain Res, 1991,554(1-2):186-192.
[210] Traystman RJ, Kirsch JR, Koehler RC. Oxygen radical mechanisms of brain injury following ischemia and reperfusion[J]. J Appl Physiol, 1991,71(4): 1185-1195
[211] Watanabe T, Yuki S, Egawa M, et al. Protective effects of MCI-186 on cerebral ischemia: possible involvement of free radical scavenging and antioxidant actions[J]. J Pharmacol Exp Ther, 1994,268(3):1597-1604.
[212] Zhai QH, Futrell N, Chen FJ. Gene expression of IL-10 in relationship to TNF-alpha, IL-1beta and IL-2 in the rat brain following middle cerebral artery occlusion [J]. J Neurol Sci, 1997,152(2):119-124.
[213] Gibson RM, Rothwell NJ, Le Feuvre RA. CNS injury: the role of the cytokine IL-1[J]. Vet J, 2004,168(3):230-237.
[214] Mercurio F, Manning AM. Multiple signals converging on NF-kappaB[J]. Curr Opin Cell Biol, 1999,11(2):226-232.
[215] DeGraba TJ. The role of inflammation after acute stroke: utility of pursing anti-adhesion molecule therapy[J]. Neurology, 1998,51(3Suppl3):S62-68.
[216] Mergenthaler P, Dirnagl U, Meisel A. Pathophysiology of stroke: Lessons from animal models[J]. Metab Brain Dis, 2004,19(3-4):151-167.
[217] Danton GH, Dietrich WD. Inflammatory mechanisms after ischemia and stroke[J]. J Neuropathol ExP Neurol, 2003,62(2):127-136.
[218] De Simoni MG, Milia P, Barba M, et al. The inflammatory response in cerebral ischemia: focus on cytokines in stroke patients[J]. Clin Exp Hypertens, 2002, 24(7-8): 535-542.
[219] Newcomb JK, Zhao X, Pike BR, et al. Temporal profile of apoptotic-like changes in neurons and astrocytes following controlled cortical impact injury in the rat[J]. Exp Neurol, 1999,158(1):76-88.
[220] Baeuerle PA, Baltimore D. NF-kappaB: ten years after[J]. Cell, 1996,87(l):13-20.
[221] Gorlich D, Kutay U. Transport between the cell nucleus and the cytoplasm [J]. Annu Rev Cell Dev Biol, 1999,15(4):607-660.
[222] Birbach A, Gold P, Binder BR, et al. Signaling molecules of the NF-kappa B pathway shuttle constitutively between cytoplasm and nucleus[J]. J Biol Chem, 2002,277(13): 10842-10851.
[223] Stennicke HR, Salvesen GS. Properties of Caspases[J]. Biochim Biophys Acta, 1998, 1387(1-2):17-31.
[224] Wang CX, Shuaib A. Neuroprotective effects of free radical scavengers in stroke[J]. Drugs Aging, 2007,24(7):537-546.
[225] Suda S, Igarashi H, Arai Y, et al. Effect of edaravone, a free radical scavenger, on ischemic cerebral edema assessed by magnetic resonance imaging[J]. Neurol Med Chir(Tokyo), 2007,47(5):197-201.
[226] Edaravone Acute Infarction Study Group. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters[J]. Cerebrovasc Dis, 2003,15(3):222-229.
[227] Yasuoka N, Nakajima W, Ishida A, et al. Neuroprotection of edaravone on hypoxic-ischemic brain injury in neonatal rats[J]. Brain Res Dev Brain Res, 2004, 151(1-2):129-139.
[228] Higashi Y. Edaravone for the treatment of acute cerebral infarction: role of endothelium-derived nitric oxide and oxidative stress[J]. Expert Opin Pharmacother, 2009,10(2):323-331.
[229] Xiao B, Bi FF, Hu YQ, et al. Edaravone neuroprotection effected by suppressing the gene expression of the Fas signal pathway following transient focal ischemia in rats[J]. Neurotox Res, 2007,12(3):155-162.
[230] Wen J, Watanabe K, Ma M, et al. Edaravone inhibits JNK-c-Jun pathway and restores anti-oxidative defense after ischemia-reperfusion injury in aged rats [J]. Biol Pharm Bull, 2006,29(4):713-718.
[231] Takizawa S, Izuhara Y, Kitao Y, et al. A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia[J].Brain Res, 2007,5(1183):124-137.
[232]冯加纯,饶明俐,张淑琴.自由基在大鼠全脑缺血再灌注损伤中的作用机理及保精增智液的保护作用[J].中风与神经疾病杂志, 1995,12(3):135-137.
[233] Tomatsuri N, Yoshida N, Takaqi T, et al. Edaravone, a newly developed radical scavenger, protects against ischemia-reperfusion injury of the small intesine in rats [J]. Int J Mol Med, 2004,13(1):105-109.
[234] Haeberlein SL. Mitochondrial function in apoptotic neuronal cell death [J]. Neurochem Res, 2004,29(3):521-530.
[235] Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death[J]. Physiol Rev, 2007,87(1):99-163.
[236] Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade[J]. Cell, 1997,91(4):479-489.
[237] Acehan D, Jiang X, Morgan DG, et al. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding and activation [J]. Mol Cell, 2002,9(2):423-432.
[238] Yoshida H, Kong YY, Yoshida R, et al. Apaf-1 is required for mitochondrial pathways of apoptosis and brain development[J]. Cell, 1998,94(6):739-750.
[239]薛晶,冯加纯.依达拉奉对中枢神经系统疾病治疗作用及机制的研究进展[J].临床荟萃, 2008,23(15):1137-1139.
[240] Huang L, Chen CH. Proteasome regulators: activators and inhibitors[J]. Curr Med Chem, 2009,16(8):931-939.
[241] Moore BS, Eustáguio AS, McGlinchey RP. Advances in and applications of proteasome inhibitors[J]. Curr Opin Chem Biol, 2008,12(4):434-440.
[242] Park JW, Kim KM, Oh kj, et al. Proteasome inhibition promotes functional recovery after peripheral nerve reperfusion injury[J]. J Trauma, 2009,66(3): 743-748.
[243] Park JW, Qi WN, Cai Y, et al. Proteasome inhibitor attenuates skeletal muscle reperfusion injury by blocking the pathway of nuclear factor-kappaB activation[J]. Plast Reconstr Surg, 2007,120(7):1808-1818.
[244] Lanzani F, Mattavelli L, Frigeni B, et al. Role of pre-existing neuropathy on thecourse of bortezomib-induced peripheral neurotoxicity[J]. J Peripher Nerv Syst, 2008,13(4):267-274.
[245] Richardson PG, Sonneveld P, Schuster MW, et al. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline[J]. Br J Haematol, 2009,144(6):895-903.
[246] Gilardini A, Marmiroli P, Cavaletti G.. Proteasome inhibition: a promoising strategy for treating cancer, but what about neurotoxicity[J]? Curr Med Chem, 2008,15(29): 3025-3035.
[2] Liao SL, Chen WY, Raung SL, et al. Association of immune responses and ischemic brain infarction in rat [J]. Neuroreport, 2001,12(9):1943-1947.
[3] Iadecola C, Alexander M. Cerebral ischemia and inflammation[J]. Curr Opin Neurol, 2001,14(1):89-94.
[4] Huie RE, Padmaja S. The reaction of NO with superoxide[J]. Free Radic Res Commun, 1993,18(4):195-199.
[5] Barone FC, Schmidt DB, Hillegass LM, et al. Reperfusion increases neutrophilis and leukotriene B4 receptor binding in rat focal ischemia[J]. Stroke, 1992, 23(9):1337-1347.
[6] De Grada TJ. The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy[J]. Neurology, 1998,51(3Suppl3):S62-68.
[7] Aggarwal BB. Nuclear factor-kappa B: the enemy within[J]. Cancer Cell, 2004,6 (3):203-208.
[8] Toledo-Pereyra LH, Toledo AH, Walsh J, et al. Molecular signaling pathways in ischemia / reperfusion[J]. Exp Clin Transplant, 2004,2(1):174-177.
[9] Berti R, Williams AJ, Moffett JR, et al. Quantitative real-time RT-PCR analysis of inflammatory gene expression associated with ischemia-reperfusion brain injury[J]. J Cereb Blood Flow Metab, 2002,22(9):1068-1079.
[10] Tran K, Merika M, Thanos D. Distinct functional properties of Ikappa B alpha and Ikappa B beta[J]. Mol cell Biol, 1997,17(9):5386-5399.
[11] Whiteside ST, Isra?l A. Ikappa B protein: structure, function and regulation[J]. Semin Cancer Biol, 1997,8(2):75-82.
[12] FlohéL, Brigelius FlohéR, Saliou C, et al. Pedox regulation of NF-kappa B activation[J]. Free Radic Biol Med, 1997:22(6):1115-1126.
[13] May MJ, Ghosh S. Signal transduction through NF-kappa B[J]. Immunol Today, 1998,19(2):80-88.
[14] HanY, Weinman S, Boldogh I, et al. Tumor necrosis factor-alpha -inducible I kappa B alpha proteolysis medited by cytosolic m-calpain. A mechanism parallel to the ubiquitin-Proteasome pathway for nuclear factor-kappB activation[J]. J Biol Chem, 1999,274(2):787-794.
[15] Sacht G M?rten A, Deiters U, et al. Activation of nuclear factor-kappa B in macrophages by mycoplasmal lipopeptides[J]. Eur J Immunol, 1998,28(12): 4207-4212.
[16] Glasgow JN, Wood T, Perez-Polo JR. Identification and characterization of nuclear factor kappaB binding sites in the murine bcl-x promoter[J]. J Neurochem, 2000,75(4):1377-1389
[17] Wojcik C, Di Napoli M. Ubiquitin-proteasome system and proteasome inhibition: New strategies in stroke therapy [J]. Stroke, 2004,35(6):1506-1518.
[18] Orlowski R, Baldwin AS Jr. NF-κB as a therapeutic target in cancer[J]. 2002, 2002,8(8):385-389.
[19] Wang C, Deng L, Hong M, et al. TAK1 is a ubiquitin-dependent kinase Of MKK and IKK [J]. Nature, 2001,412(6844):346-351.
[20] Mercurio F, Zhu H, Murray BW, et al. IKK-1and IKK-2: cytokine-activated Ikappa B kinases essential for NF–kappa B activation [J]. Science, 1997,278 (5339):860-866.
[21] Kaloqeris TJ, Kevil CG, Laroux FS, et al. Differential monocyte adhesion and adhesion molecule expression in venous and arterial endothelial cells [J]. Am J Physiol, 1999,276(1 Pt 1):L9-L19.
[22] Williams AJ, Hale SL, Moffett JR, et al. Delayed treatment with MLN519 reduces infarction and associated neurologic deficit caused by focal ischemic brain injury in rats via anti-inflammatory mechanisms involving nuclear factor-kappaB activation, gliosis, and leukocyte infiltration[J]. J Cereb Blood Flow Metab, 2003:23(l):75-87.
[23] Williams AJ, Dave JR, Tortella FC. Neuroprotection with the proteasome inhibitor MLN519 in focal ischemic brain injury: Relation to nuclear factor kappaB (NF-kappaB), inflammatory gene expression, and leukocyte infiltration [J]. Neurochem Int, 2006,49(2):106-112.
[24] Elliott PJ, Zollner TM, Boehncke WH. Proteasome inhibition: a new anti-inflammatory strategy[J]. J Mol Med, 2003,81(4):235-245.
[25] Qiu JH, Asai A, Chi S, et al. Proteasome inhibitors induce cytochrome c Caspase- 3-like protease-mediated apoptosis in cultured cortical neurons[J]. J Neurosci, 2000,20(1): 259-265.
[26] Morris DC, Zhang L, Zhang ZG, et al. Extension of the therapeutic window for recombinant tissue plasminogen activator with argatroban in a rat model of embolic stroke[J]. Stroke, 2001,32(11):2635-2640.
[27] Rajkumar SV, Richardson PG, Hideshima T, et al. Proteasome inhibition as a novel therapeutic target in human cancer[J]. J Clin Oncol, 2005,23(3):630-639.
[28] Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma[J]. N Engl J Med, 2003,348(26):2609-26.
[29] Sinn DI, Lee ST, Chu K, et al. Proteasomal inhibition in intracerebral hemorrhage: neuroprotective and anti-inflammatory effects of bortezomib[J]. Neurosci Res, 2007,58(1):12-18.
[30] Yamamoto T, Maruyama W, Kato Y, et al. Selective nitration of mitochondrial complex I by peroxynitrite: involvement in mitochondria dysfunction and cell death of dopaminergic SH-SY5Y cells[J]. J Neural Transm, 2002,109(1):1-13.
[31] Gamen S, Anel A, Pérez-Galán P, et al. Doxorubicin treatment activates a Z-VAD-Sensitive caspase, which causes deltapsim loss, caspase-9 Activity, and apoptosis in Jurkat cells[J]. Exp Cell Res, 2000,258(1):223-235.
[32] Budd SL, Tenneti L, Lishnak T, et al. Mitochondrial and extramitochondral apoptotic signaling pathways in cerebrocortical neurons[J]. Proc Natl Acad Sci USA, 2000,97(11):6161-6166.
[33] Graham SH, Chen J. Programmed cell death in cerebral ischemia[J]. J Cereb Blood Flow Metab, 2001,21(2):99-109.
[34] Fiskum G. Mitochondrial participation in ischemic and traumatic neural cell death[J]. J Neurotrauma, 2000,17(10):843-855.
[35] Ow YP, Green DR, Hao Z, et al. Cytochrome c: function beyond respiration[J]. Nat Rev Mol Cell Biol, 2008,9(7):532-542.
[36] Adrain C, Martin SJ. The mitochondrial apoptosome: a killer Unleashed by thecytochromeseas[J]. Trends Biochem Sci, 2001,26(6):390-397.
[37] Daniel PT. Dissecting the pathways to death[J]. Leukemia, 2000,14(12):2035 -2044.
[38] Goonesinghe A, Mundy E, Smith M, et al. Pro-apoptotic Bid induces membrane perturbation by inserting selected lysolipids into the bilayer[J]. Biochem J, 2005, 387(1):109-118.
[39] McConkey DJ, Nutt LK. Calcium flux measurements in apoptosis[J]. Methods Cell Biol, 2001,66(2):229-246.
[40] Herrmann J, Ciechanover A, Lerman LO, et al. The ubiquitin-proteasome system in cardiovascular diseases-a hypothesis extended[J]. Cardiovasc Res, 2004,61(1): 11-21.
[41] Raasi S, Wolf DH. Ubiquitin receptors and ERAD: A network of pathways to the proteasome [J]. Sem in Cell Dev Biol, 2007,18(6):78-91.
[42] Ferrari S, Smeland S, Mercuri M. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups [J]. J Clin Oncol, 2005,23(34):8845-8852.
[43] McNaught KS, Olanow CW, Halliwell B, et al. Failure of the ubiquitin proteasome system in Parkinson’s disease[J]. Nat Rev Neurosci, 2001, 2(8): 589-594.
[44] O’Connell BC, Harper JW. Ubiquitin proteasome system (UPS): what can chromatin do for you [J] ? Curr Opin Cell Biol, 2007,19(2):206-214.
[45] Glickman MH, Maytal V. Regulating the 26S proteasome[J]. Curr Top Microbiol Immunol, 2002,268(2):43-72.
[46] Aguilar RC, Wendland B. Ubiquitin: not just for proteasomes anymore[J]. Curr Opin Cell Bio, 2003,15(2):184-190.
[47] Rohde JR, Breitkreutz A, Chenal A, et al. Type III secretion effectors of the IpaH Family are E3 ubiquitin Ligases [J]. Cell Host Microbe, 2007,1(1):77-83.
[48] Koegl M, Hoppe T, Schlenker S, et al. A novel ubiquitination factor E4 is involved in multiubiquitin chain assembly[J]. Cell, 1999,96(5):635-644.
[49] Roqers GC, Rusan NM, Roberts, DM, et al. The SCF Slimb ubiquitin ligase regulates Plk4/Sak levels to block centriole reduplication[J]. J Cell Biol, 2009, 184(2):225-239.
[50] Kim H T, Kim K P, Ledias F, et al. Certain pairs of ubiquitin-conjugating enzymes(E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages [J]. J Biol Chem, 2007,282(24): 17375-17386.
[51] Ciechanover A, Orian A, Schwartz AL. The ubiquitin-mediated proteolytic pathway: mode of action and clinical implications[J]. J Cell Biochem, 2000,34 (Suppl):40-51.
[52] Yeh ET, Gong L, Kamitani T. Ubiquitin-like proteins: new wines in new bottles[J]. Gene, 2000,248(1-2):1-14.
[53] Kisselev AF, Apoian TN, Woo KM, et al. The sizes of peptides Generated from protein by mammalian 26S and 20S proteasome[J]. J Biol Chem, 1999,274 (6): 3363-3371.
[54] Li M, Chen D, Shiloh A, et a1. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization[J]. Nature, 2002,416(6881):648-653.
[55] Meiners S, Ludwig A, Stangl V, et al. Proteasome inhibitors: Poisons and remedies[J]. Med Res Rev, 2008,28(2):309-327.
[56] Burger AM, Seth AK. The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications[J]. Eur J Cancer, 2004,40(15):2217-2229.
[57] Verhoef LG, Heinen C, Selivanova A, et al. Minimal length requirement for proteasomal degradation of ubiquitin-dependent substrates[J]. FASEB J, 2009, 23(1):123-133.
[58] Price SR, Du J, Bailey JL, et al. Molecular mechanisms regulating protein turnover in muscle[J]. Am J Kidney Dis, 2001,37(1suppl2):S112-114.
[59] Strickland E, Hakala K, Thomas PJ, et al. Recognition of misfolding proteins by PA700, the regulatory subcomplex of the 26S proteasome[J]. Biol Chem, 2000, 275(8):5565-5572.
[60] Groll M, Clausen T. Molecular shredders: how proteasome fulfill their role[J]. Curr Opin Struct Biol, 2003,13(6):665-673.
[61] Hershko A. The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle [J]. 1Cell Death Differ, 2005,12(9):1191-1197.
[62] Yano M, Kanesaki Y, Koumoto Y, et al. Chaperone activities of the 26S and 20S proteasome [J]. Curr Protein Pept Sci, 2005,6(2):197-203.
[63] Schwartz AL, Ciechanover A. The ubiquitin-proteasome pathway and pathogenesis of human diseases [J]. Annu Rev Med, 1999,50(2):57-74.
[64] Strous GJ, Govers R. The ubiquitin-proteasome system and endocytosis[J]. J Cell Sci, 1999,112(pt10):1417-1423.
[65] Knowlton JR, Jolnston SC, Whitby FG, et al. Structure of the proteasome activator REGalpha ( PA28alpha) [J]. Nature, 1997,390(6660):639-643.
[66] Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells[J]. Cancer Res, 2001,61(7):3071-3076.
[67] Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells[J]. Proc Natl Acad Sci USA, 2002, 99(22): 14374-14379.
[68] Momand J, Wu HH, Dasgupta G. MDM2-master regulator of the p53 tumor suppressor protein[J]. Gene, 2000,242(1-2):15-29.
[69] Mitsiades CS, Mitsiades N, Hideshima T, et al. Proteasome inhibition as a new therapeutic principle in hematological malignancies[J].Curr Drug Targets, 2006,7(10): 1341-1347.
[70] Jana NR, Dikshit P, Goswami A, et al. Inhibition of proteasomal function by curcumin induces apoptosis through mitochondrial pathway[J]. J Biol Chem, 2004,279(12): 11680-11685.
[71] Adams J. The development of proteasome inhibitors as anticancer drugs[J]. Cancer Cell, 2004,5(5):417-21.
[72] Lightcap ES, McCormack TA, Pien CS, et al. Proteasome inhibition measurements: clinical application [J]. Clin Chem 2000,46(5):673-683.
[73] Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer[J]. J Clin Invest, 2001,107 (2):135-142.
[74] Goldberg AL, Cascio P, Saric T, et al. The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides[J]. Mol Immunol, 2002,39(3-4):147-164.
[75] Shih SC, Sloper-Mould KE, Hicke L. Monoubiquitin carries a novel internalization sinagal that is appended to activated receptors[J]. EMBO J, 2000,19(2):187-198.
[76] Murata T, Shimotohno K. Ubiquitination and proteasome-dependent degradation of human eukaryotic translation initiation factor 4E[J]. J Biol Chem, 2006, 281(30): 20788-20800.
[77] Vinitsky A, Cardozo C, Sepp-Lorenzino L, et al. Inhibition of the proteolytic activity of the multicatalytic proteinase complex (proteasome) by substrate- related peptidyl- aldehydes[J]. J Biol Chem, 1994,269(47):29860-29866.
[78] Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. PhaseⅠtrial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies[J]. J Clin Oncol, 2002,20(22):4420-4427.
[79] Phillips JB, Williams AJ, Adams J,et al. Proteasome inhibitor PS519 reduces infarction and attenuates leukocyte infiltration in a rat model of focal cerebral ischemia[J]. Stroke, 2000,31(7):1686-1693.
[80] Liqhtcap ES, McCormack TA, Pien CS, et al. Proteasome inhibition measurements: clinical application[J]. Clin Chem, 2000,46(5):673-683.
[81] Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents[J]. Cancer Res, 1999,59(11):2615-2622.
[82] Aqhajanian C, Soiqnet S, Dizon DS, et al. A phaseⅠtrial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies [J]. Clin Cancer Res, 2002,8 (8):2505-2511.
[83] Tan C, Waldmann TA, Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemia[J]. Cancer Res, 2002,62(4):1083-1086.
[84] Zavrski I, Jakob C, Schmid P, et al. Proteasome: an emerging target for cancer therapy[J]. Anticancer Drugs, 2005,16(5):475-481.
[85] Stephenson D, Yin T, Smalstig EB, et al. Transcription factor nuclear Factor-kappa B is activated in neurons after focal cerebral ischemia [J]. J Cereb Blood Flow Metab, 2000,20(3):592-603.
[86] Schneider A, Martin-Villalba A, Weih F, et al. NF-kappaB is activated and promotes cell death in focal cerebral ischemia[J]. Nat Med, 1999,5(5):554-559.
[87] Seegers H, Grillon E, Trioullier Y, et al. Nuclear factor-kappa B activation in permanent intraluminal focal cerebral ischemia in the rat[J]. Neurosci Lett, 2000, 288(3):241-245.
[88] Imajoh-Ohmi S, Kawaquchi T, Sugiyama S, et al. Lactacystin, a specific inhibitor of the proteasome, induces apoptosis in human monoblast U937 cells[J]. Biochem Biophys Res Commun, 1995,217(3):1070-1077.
[89] Zhang XM, Lin H, Chen C, et al. Inhibition of ubiquitin-proteasome pathway activates a Caspase-3-like protease and induces Bcl-2 cleavage in human M-07e leukaemic cells [J]. Biochem J, 1999,340(Pt 1):127-133.
[90] Shinohara K, Tomioka M, Nakano H, et al. Apoptosis induction resulting from proteasome inhibition [J]. Biochem J, 1996,317(Pt 2):385-388.
[91] Meriin AB, Gabai VL, Yaqlom J, et al. Proteasome inhibitors activate stress kinases and induce Hsp72. Diverse effects on apoptosis [J]. J Biol Chem, 1998, 273(11): 6373-6379.
[92] Orlowski RZ, Zeger EL. Targeting the proteasome as a therapeutic strategy against haematological malignancies[J]. Expert Opin Invest Drugs 2006, 15(2): 117-130.
[93] Orlowski RZ, Kuhn DJ. Proteasome inhibitors in cancer therapy: lessons from the first decade [J]. Clin Cancer Res, 2008,14(6):1649-1657.
[94] Zavrski I, Kleeberg L, Kaiser M, et al. Proteasome as an emerging therapeutic target in cancer [J]. Curr Pharm Design, 2007, 13(5):471-485.
[95] Meiners S, Ludwig A, Stangl V, et al. Proteasome inhibitors: poisons and remedies [J]. Med Res Rev, 2008,28(2):309-327.
[96] Kane RC, Bross PF, Farrell AT, et al. Velcade: U. S. FDA approval for the treatment of multiple myeloma progressing on prior therapy [J]. Oncologist, 2003,8(6):508-513.
[97] Voorhees PM, Dees EC, O’Nell B, et al. The proteasome as a target for cancer therapy [J]. Clin Cancer Res, 2003,9(17):6316-6325.
[98] Xiao D, Zhu SP, Gu ZL. Quercetin induced apoptosis in human leukemia HL-60 cells[J]. Zhongguo Yao Li Xue Bao, 1997,18(3):280-283.
[99] Sadoul R, Fernandez PA, Quiquerez AL, et al. Involvement of the proteasome in the programmed cell death of NGF-deprived sympathetic neurons[J]. EMBO J, 1996,15(15):3845-3852.
[100] Grimm LM, Goldberg AL, Poirier GG, et al. Proteasomes play an essential role in thymocyte apoptosis[J]. EMBO J, 1996,15(15):3835-3844.
[101] Canu N, Barbato C, Ciotti MT, et al. Proteasome involvement and accumulation of ubiquitinated proteins in cerebellar granule neurons undergoing apoptosis[J]. J Neurosci, 2000,20(2):589-599.
[102] Sawada H, Kohno R, Kihara T, et al. Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes alpha-synuclein inclusions[J]. J Biol Chem, 2004,279(11):10710-10719.
[103] Orlowski RZ. The role of the ubiquitin-proteasome pathway in apoptosis[J]. Cell Death Differ, 1999,6(4):303-313.
[104] Masdehors P, Omura S, Merle-Béral H, et al. Increased sensitivity of CLL- derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin[J]. Br J Haematol, 1999,105(3):752-757.
[105] Fenteany G, Schreiber SL. Lactacystin, proteasome function, and cell fate[J]. J Biol Chem, 1998,273(15):8545-8548.
[106] LeBlanc R, Catley LP, Hideshima T, et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model[J]. Cancer Res, 2002,62(17):4996-5000.
[107] Adams J. Development of the Proteasome Ihibitor PS-341[J]. Oncologist, 2002,7(1):9-16.
[108] Rajkumar SV, Richardson PG, Hideshima T, et al. Proteasome inhibition as a novel therapeutic target in human cancer[J]. J Clin Oncol, 2005,23(3):630-639.
[109] Drexler HC, Risau W, Konerding MA. Inhibition of proteasome function induces programmed cell death in proliferating endothelial cells[J]. FASEB J, 2000,14(1): 65-77.
[110] Zheng Z, Yenari MA. Post-ischemic inflammation: molecular mechanisms and therapeutic implications[J]. Neurol Res, 2004,26(8):884-892.
[111] Kawamura S, Li Y, Shirasawa M, et al. Reversible middle cerebral artery occlusion in rats using an intraluminal thread technique[J]. Surg Neurol, 1994,41(5):368-373.
[112] Ludwig H, Khayat D, Giaccone G, et al. Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies[J]. Cancer, 2005,104(9): 1794-1807.
[113] Zhang L, Zhang ZG, Zhang RL, et al. Postischemic (6-h) treatment with recombinant human tissue plasminogen activator and proteasome inhibitor PS-519 reduces infarction in a rat model of embolic focal cerebral ischemia[J]. Stroke, 2001,32(12):2926-2931.
[114] Henninger N, Sicard KM, Bouley J, et al. The proteasome inhibitor VELCADE reduces infarction in rat models of focal cerebral ischemia[J]. Neurosci Lett, 2006,398(3):300-305.
[115] Schulze-Osthoff K, Ferrari D, Riehemann K, et al. Regulation of NF-kappaB activation by MAP kinase cascades[J]. Immunobiology, 1997,198(1-3):35-49.
[116] Aggarwal BB. Nuclear factor-kappa B: the enemy within[J]. Cancer Cell, 2004,6 (3):203-208.
[117] Tamatani M, Mitsuda N, Matsuzaki H,et al. A pathway of neuronal apoptosis induced by hypoxia/reoxygenation: roles of nuclear factor-kappaB and Bcl-2[J]. J Neurochem, 2000,75(2):683-93.
[118] Lam YA, Lawson TG, Velayutham M, et al. A proteasomal ATPase subunit recognizes the polyubiquitin degradation signal[J]. Nature, 2002,416(6882):763-767.
[119] Demasi M, Davies KJ. Proteasome inhibitors induce intracellular protein aggregation and cell death by an oxygen-dependent mechanism[J]. FEBS Lett, 2003,542 (1-3):89-94.
[120] Hu BR, Martone ME, Jones YZ, et al. Protein aggregation after transient cerebral ischemia[J]. J Neurosci, 2000,20(9):3191-3199.
[121] Asai A, Tanahashi N, Qiu JH, et al. Selective proteasomal dysfunction in the hippocampal CA1 region after transient forebrain ischemia[J]. J Cereb Blood Flow Metab, 2002,22(6):705-710.
[122] Youdim MB, Amit T, Falach-Yoqev M, et al. The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the Neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline[J]. Biochem Pharmacol, 2003,66(8): 1635-1641.
[123] Dimmeler S, Breitschopf K, Haendeler J, et al. Dephosphorylation targets Bcl-2 for ubiquitin-dependent degradation: a link between the apoptosome and the proteasome pathway[J]. J Exp Med, 1999,189(11):1815-1822.
[124] Rideout HJ, Wang Q, Park DS, et al. Cyclin-dependent kinase activity is required for apoptotic death but not inclusion formation in cortical neurons after proteasomal inhibition[J]. J Neurosci, 2003,23(4):1237-1245.
[125] Johnston JA, Ward CL, Kopito RR. Aggresomes: a cellular response to misfolded proteins[J]. J Cell Biol, 1998,143(7):1883-1898.
[126] Lipton P. Ischemic cell death in brain neurons[J]. Physiol Rev, 1999,79(4): 1431-1568.
[127] Zhai Q, Wang J, Kim A, et al. Involvement of the ubiquitin-proteasome system in the early stages of wallerian degeneration[J]. Neuron, 2003,39(2):217-225.
[128]曹三勇,徐胜利,陈彪.蛋白酶体抑制剂对神经细胞的双重作用[J].脑与神经疾病杂志, 2006,14(4):274-277.
[129] Bobba A, Canu N, Atlante A, et al. Proteasome inhibitors prevent cytochrome c release during apoptosis but not in excitotoxic death of cerebellar granule neurons [J]. FEBS Lett, 2002,515(1-3):8-12.
[130] Keller JN, Markesbery WR. Proteasome inhibition results in increased poly-ADP- ribosylation: implications for neuron death[J]. J Neurosci Res, 2000, 61(4): 436-442.
[131] Kollmar R, Henninger N, Bardutzky J, et al. Combination therapy of moderate hypothermia and thrombolysis in experimental thromboembolic stroke-an MRI study[J]. Exp Neurol. 2004,190(1):204-212.
[132] Toomey JR, Valocik RE, Koster PF, et al. Inhibition of factor IX(a) is protective in a rat model of thromboembolic stroke[J]. Stroke. 2002,33(2):578-585.
[133] Fujimura M, Gasche Y, Morita-Fujimura Y, et al. Early appearance of activated matrix metalloproteinase-9 and blood brain barrier disruption in mice after focal cerebral ischemia and reperfusion[J]. Brain Res, 1999,842(1):92-100.
[134] McNaught KS, Belizaire R, Isacson O, et al. Altered proteasomal function in sporadic Parkinson’s disease[J]. Exp Neurol, 2003,179(1):38-46.
[135] McNaught KS, Mytilineou C, Jnobaptiste R, et al. Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures [J]. J Neurochem, 2002,81(2):301-306.
[136] Ding Q, Bruce-Keller AJ, Chen Q, et al. Analysis of gene expression in neural cells subject to chronic proteasome inhibition[J]. Free Radic Biol Med, 2004,36(4): 445-455.
[137] Golab J, BauerTM, Daniel V, et al. Role of the ubiquitin-proteasome pathway in the diagnosis of human diseases[J]. Clin Chim Acta, 2004,340(1-2):27-40.
[138] Ardley HC, Robinson PA. The role of ubiquitin-protein ligases in neurodegenerative disease[J]. Neurodeqener Dis, 2004,1(2-3):71-87.
[139] Jnaa NR, Nukina N. Recent advances in understanding the pathogenesis of polyglutamine deseases: involvement of molecular chaperones and ubiquitin- proteasome pathway[J]. J Chem Neuroanat, 2003,26(2):95-101.
[140] Orlowski RZ, Eswara JR, Lafond-Walker A, et al. Tumor growth inhibition induced in a murine model of human Burkitt’s Lymphoma by a proteasome inhibitor[J]. Cancer Res, 1998,58(19):4342-4348.
[141] Goy A, Younes A, McLaughlin P, et al. PhaseⅡstudy of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma[J]. J Clin Oncol, 2005,23(4):667-675.
[142] Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma[J]. N Engl J Med, 2003,348(26):2609-2617.
[143] Wallace KB, Eells JT, Madeira VM, et al. Mitochondria-mediated cell injury. Sympo- i. sium overview[J]. Fundam Appl Toxicol, 1997,38(1):23-37.
[144] Green DR, Reed JC. Mitochondria and apoptois[J]. Science, 1999,281(5381): 1309- 1312.
[145] Sims NR, Anderson MF, Hobbs LM, et al. Brain mitochondrial response to postischemic reperfusion :A role for calcium and hydrogen peroxide[J]? Dev Neurosci, 2000,22(5-6):366-375.
[146] Rao AM, Hatcher JF, Dempsey RJ. Lipid alterations in transient forebrain ischemia: possible new mechanisms of CDP-choline neuroprotection[J]. J Neurochem, 2000, 75(6):2528-2535.
[147] Lemasters JJ, Nieminen AL, Qian T, et al. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy[J]. Biochim Biophys Acta, 1998,1366(1-2):177-196.
[148] Kroemer G, Zamzami N, Susin SA. Mitochondrial control of apoptosis[J]. Immunol Today, 1997,18(1):44-51.
[149] Ferrer I, Planas AM. Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra [J]. J Neuropathol Exp Neurol, 2003,62(4):329-339.
[150] Zheng Z, Zhao H, Steinberg GK, et al. Cellular and molecular events underlying ischemia-induced neuronal apoptosis[J]. Drug News Perspect, 2003,16(8): 497-503.
[151] Kroemer G, Reed JC. Mitochondrial control of cell death[J]. Nat Med, 2000,6 (5): 513-519.
[152] Haeberlein SL. Mitochondrial function in apoptotic neuronal cell death [J]. Neurochem Res, 2004,29(3):521-530.
[153] Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death[J]. Physiol Rev, 2007,87(1):99-163.
[154] Martinou JC, Desagher S, Antonsson B. Cytochrome c release from mitochondria: all or nothing[J]. Nat Cell Biol, 2000, 2(3):E41-43.
[155] Haga N, Fujita N, Tsuruo T. Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis[J]. Oncogene, 2003,22(36):5579-5585.
[156] Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade[J]. Cell, 1997,91(4):479-489.
[157] Mronga T, Stahnke T, Goldbaum O, et al. Mitochondrial pathway is involved in hydrogen-peroxide-induced apoptotic cell death of oligodendrocytes[J]. Glia, 2004,46(4): 446-455.
[158] Lauber K, Appel HA, Schlosser SF, et al. The adapter protein apoptotic protease- activating factor-1 (Apaf-1) is proteolytically processed during apoptosis [J]. J Biol Chem, 2001, 276(32):29772-29781.
[159] Fu WN, Kelsey SM, Newland AC, et al. Apaf-1 XL is an inactive isoform comparedwith Apaf-1L [J]. Biochem Biophys Res Commun, 2001,282(1): 268-272.
[160] Benedict MA, Hu Y, Inohara N, et al. Expression and functional analysis of Apaf-1 isoforms. Extra Wd-40 repeat is required for cytochrome c binding and regulated activation of procaspase-9[J]. J Biol Chem, 2000,275(12):8461-8468.
[161] Yu X, Wang L, Acehan D, et al. Three-dimensional structure of a double apoptosome formed by the Drosophila Apaf-1 related killer[J]. J Mol Biol, 2006, 355(3):577-589.
[162] Fridman JS, Lowe SW. Control of apoptosis by p53[J]. Oncogene, 2003,22(56): 9030- 9040.
[163] Stennicke HR, Salvesen GS. Properties of Caspases[J]. Biochim Biophys Acta, 1998,1387(1-2):17-31.
[164] Jia L, Srinivasula SM, Liu FT, et al. Apaf-1 protein deficiency confers resistance to cytochrome c-dependent apoptosis in human leukemic cells[J]. Blood, 2001,98(2): 414-421.
[165] Assefa Z, Vantieghem A, Garmyn M, et al. p38 mitogen-activated protein kinase regulates a novel, Caspase-independent pathway for the mitochondrial cytochrome c release in ultraviolet B radiation-induced apoptosis[J]. J Biol Chem, 2000, 275(28):21416-21421.
[166] Shibata M, Hattori H, Sasaki T, et al. Subcellular localization of a promoter and an inhibitor of apoptosis (Smac/DIABLO and XIAP) during brain ischemia/ reperfusion [J]. Neuroreport, 2002,13(15):1985-1988.
[167] Fleisher TA. Apoptosis[J]. Ann Allergy Asthma Immunol, 1997,78(3):245-249.
[168] MatéMJ, Ortiz-Lombardía M, Boitel B, et al. The crystal structure of the mouse apoptosis-inducing factor AIF[J]. Nat Struct Biol, 2002,9(6):442-446.
[169] Du C, Fang M, Li Y, et al. Smac, a mitochondrial protein that promotes cytochrome c dependent caspase activation by eliminating IAP inhibition[J]. Cell, 2000,102(1): 33-42.
[170] Wu C, Fujihara H, Yao J, et al. Different expression patterns of Bcl-2, Bcl-xl, and Bax proteins after sublethal forebrain ischemia in C57Black/Crj6 Mouse Striatum[J]. Stroke, 2003, 34(7):1803-1808.
[171] Adams JM, Cory S. Life-or-death decisions by the Bcl-2 protein family[J]. TrendsBiochem Sci, 2001,26(1):61-66.
[172] Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis[J]. Genes Dev, 1999,13(15):1899-1911.
[173] MA, Gross. Mitochondrial carries and pores: key regulators of the mitochondrial apoptotic program[J]? Apoptosis, 2007,12(5):869-876.
[174] Schwarz CS, Evert BO, Seyfried J, et al. Overexpression of bcl-2 results in reduction of cytochrome c content and inhibition of complex I activity[J]. Biochem Biophys Res Commun, 2001,280(4):1021-1027.
[175] Hsu SY, Hsueh AJ. Tissue-specific Bcl-2 protein partners in apoptosis: An ovarian paradigm[J]. Physiol Rev, 2000,80(2):593-614.
[176] Orrenius S. Mitochondrial regulation of apoptotic cell death[J]. Toxicol Lett, 2004, 149(1-3):19-23.
[177] Swanton E, Savory P, Cosulich S. Bcl-2 regulates a caspase-3/caspase-2 apoptotic cascade in cytosolic extracts[J]. Oncogene, 1999, 18(10):1781-1787.
[178] Crompton M, Barksby E, Johnson N, et al. Mitochondrial intermembrane junctional complexes and their involvement in cell death[J]. Biochimie, 2000,84(1-2):143-152.
[179] Shimizu S, Ide T, Yanagida T, et al. Electrophysiological study of a novel large pore formed by Bax and the voltage dependent anion channel that is permeable to cytochrome c[J]. J Biol Chem, 2000,275(16):12321-12325.
[180] Burlacu A. Regulation of apoptosis by Bcl-2 family proteins[J]. J Cell Mol Med, 2003,7(3):249-257.
[181] Kuwana T, Mackey MR, Perkins G, et al. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane[J]. Cell, 2002,111 (3): 331-342.
[182] Budihardjo I, Oliver H, Lutter M, et al. Biochemical pathways of caspase activation during apoptosis[J]. Annu Rev Cell Dev Biol, 1999,15(1):269-290.
[183] Endres M, Engelhardt B, Koistinaho J, et al. Improving outcome after stroke: overcoming the translational roadblock[J]. Cerebrovasc Dis, 2008,25(3):268-278.
[184] Huang Y, McNamara JO, et al. Ischemic stroke:“acidotoxicity”is a perpetrator[J]. Cell, 2004,118(6):665-666.
[185] Chan, Pak H, et al. Reactive oxygen radicals in signaling and damage in the ischemic brain[J]. J Cereb Blood Flow Metab, 2001,21(1):2-14.
[186] Liu, Hsueh-Ning L, Walter E, et al. AMPA receptor-mediated toxicity in oligodendrocyte progenitors involves free radical generation and activation of JNK, calpain and Caspase-3[J]. J Neurochem, 2002,82(2):398-409.
[187] Ali, Carine, Nicole, et al. Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitoxicity in the brain[J]. J Cerebral Blood Flow Metab, 2000,20(6):956-966.
[188] Ramachandran A, Ceaser E, Darley-Usmar VM. Chronic exposure to nitric oxide alters the free iron pool in endothelial cells: role of mitochondrial respiratory complexes and heat shock proteins[J]. Proc Natl Acad Sci USA, 2004, 101(1):384-389.
[189] Dela Monte SM, Neely TR, Cannon J, et al. Oxidative stress and hypoxia-like injury cause Alzheimer-type molecular abnormalities in central nervous system neurons [J]. Cell Mol Life Sci, 2000, 57(10):1471-1481.
[190] Huang CY, Fujimura M, Noshita N, et al. SOD1 down-regulates NF-kappaB and c-Myc expression in mice after transient focal cerebral ischemia[J]. J Cereb Blood Flow Metab, 2001,21(2):163-173.
[191] Neumar RW. Molecular mechanisma of ischemic neuronal injury. Ann Emerg Med 2000,36(5):483- 506.
[192] Paschen W, Doutheil J. Disturbance of endoplasmic reticulum functions: a key mechanism underlying cell damage[J]? Acta Neurochir Suppl, 1999,73:1-5.
[193] Bradham CA, Qian T, Streetz K, et al. The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release [J]. Mol Cell Biol, 1998,18(11):6353-6364.
[194] Kristián T, Siesj? BK. Calcium in ischemic cell death[J]. Stroke, 1998,29(3):705-718.
[195] Bosetti F, Yu G, Zucchi R, et al. Myocardial ischemic preconditioning and mitochondrial F1F0-ATPase activity[J]. Mol Cell Biochem, 2000, 215(1-2): 31-37.
[196] Yuan J, Yankner BA. Apoptosis in the nervous system[J]. Nature, 2000, 407(6805): 802-809.
[197] Kroemer G, Dallaporta B, Resche-Rigon M. The mitochondrial death/life regulator in apoptosis and necrosis[J]. Annu Rev Physiol,1998,60(1):619-642.
[198] Nakamura K, Bossy-Wetzel E, Burns K, et al. Changes in endoplasmic reticulum luminal environment affect cell sensitivity to apoptosis[J]. J Cell Biol, 2000, 150(4):731-740.
[199] Suzuki S, Higuchi M, Proske RJ, et al. Implication of mitochondria-derived reactive oxygen species, cytochrome C and Caspase-3 in N-(4-hydroxyphenyl) retinamideinduced apoptosis in cervical carcinoma cells[J]. Oncogene, 1999, 18 (46):6380-6387.
[200] Shiraishi H, Okamoto H, Yoshimura A, et al. ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1[J]. J Cell Sci, 2006,119(pt19):3958-3966.
[201] Fujimura M, Morita-Fujimura Y, Murakami K, et al. Cytosolic redistribution of cytochrome c after transient focal cerebral ischemia in rats [J]. J Cereb Blood Flow Metab, 1998,18(11):1239-1247.
[202] Fujimura M, Morita-Fujimura Y, Kawase M, et al. Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome and subsequent DNA fragment-ation after permanent focal cerebral ischemia in mice[J]. J Neurosci, 1999, 19(9):3414-3422.
[203] Green DR. Apoptotic pathway: the roads to ruin[J]. Cell,1998,94(6):695-698.
[204] Guégan C, Sola B. Early and sequential recruitment of apoptotic effectors after focal permanent ischemia in mice[J]. Brain Res, 2000,856(1-2):93-100.
[205] Ashkenazi A, Dixit VM. Death receptors: signaling and modulation[J]. Science, 1998, 281(5381):1305-1308.
[206] Breckenridge DG, Stojanovic M, Marcellus RC, et al. Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol [J]. J Cell Biol, 2003, 160 (7):1115-1127.
[207] Wang B, Nguyen M, Breckenridge DG, et al. Uncleaved BAP31 in association with A4 protein at the endoplasmic reticulum is an inhibitor of Fas-initiated release ofcytochrome c from mitochondria[J]. J Biol Chem, 2003,278 (16):14461-14468.
[208] Longa EZ, Weinstein PR, Carlson S, et al. Reversible middle cerebral artery occlusion without craniectomy in the rats[J]. Stroke, 1989,20(1):84-91.
[209] Sakamoto A, Ohnishi ST, Ohnishi T, et al. Relationship between free radical production and lipid peroxidation during ischemia-reperfusion injury in the rat brain[J]. Brain Res, 1991,554(1-2):186-192.
[210] Traystman RJ, Kirsch JR, Koehler RC. Oxygen radical mechanisms of brain injury following ischemia and reperfusion[J]. J Appl Physiol, 1991,71(4): 1185-1195
[211] Watanabe T, Yuki S, Egawa M, et al. Protective effects of MCI-186 on cerebral ischemia: possible involvement of free radical scavenging and antioxidant actions[J]. J Pharmacol Exp Ther, 1994,268(3):1597-1604.
[212] Zhai QH, Futrell N, Chen FJ. Gene expression of IL-10 in relationship to TNF-alpha, IL-1beta and IL-2 in the rat brain following middle cerebral artery occlusion [J]. J Neurol Sci, 1997,152(2):119-124.
[213] Gibson RM, Rothwell NJ, Le Feuvre RA. CNS injury: the role of the cytokine IL-1[J]. Vet J, 2004,168(3):230-237.
[214] Mercurio F, Manning AM. Multiple signals converging on NF-kappaB[J]. Curr Opin Cell Biol, 1999,11(2):226-232.
[215] DeGraba TJ. The role of inflammation after acute stroke: utility of pursing anti-adhesion molecule therapy[J]. Neurology, 1998,51(3Suppl3):S62-68.
[216] Mergenthaler P, Dirnagl U, Meisel A. Pathophysiology of stroke: Lessons from animal models[J]. Metab Brain Dis, 2004,19(3-4):151-167.
[217] Danton GH, Dietrich WD. Inflammatory mechanisms after ischemia and stroke[J]. J Neuropathol ExP Neurol, 2003,62(2):127-136.
[218] De Simoni MG, Milia P, Barba M, et al. The inflammatory response in cerebral ischemia: focus on cytokines in stroke patients[J]. Clin Exp Hypertens, 2002, 24(7-8): 535-542.
[219] Newcomb JK, Zhao X, Pike BR, et al. Temporal profile of apoptotic-like changes in neurons and astrocytes following controlled cortical impact injury in the rat[J]. Exp Neurol, 1999,158(1):76-88.
[220] Baeuerle PA, Baltimore D. NF-kappaB: ten years after[J]. Cell, 1996,87(l):13-20.
[221] Gorlich D, Kutay U. Transport between the cell nucleus and the cytoplasm [J]. Annu Rev Cell Dev Biol, 1999,15(4):607-660.
[222] Birbach A, Gold P, Binder BR, et al. Signaling molecules of the NF-kappa B pathway shuttle constitutively between cytoplasm and nucleus[J]. J Biol Chem, 2002,277(13): 10842-10851.
[223] Stennicke HR, Salvesen GS. Properties of Caspases[J]. Biochim Biophys Acta, 1998, 1387(1-2):17-31.
[224] Wang CX, Shuaib A. Neuroprotective effects of free radical scavengers in stroke[J]. Drugs Aging, 2007,24(7):537-546.
[225] Suda S, Igarashi H, Arai Y, et al. Effect of edaravone, a free radical scavenger, on ischemic cerebral edema assessed by magnetic resonance imaging[J]. Neurol Med Chir(Tokyo), 2007,47(5):197-201.
[226] Edaravone Acute Infarction Study Group. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters[J]. Cerebrovasc Dis, 2003,15(3):222-229.
[227] Yasuoka N, Nakajima W, Ishida A, et al. Neuroprotection of edaravone on hypoxic-ischemic brain injury in neonatal rats[J]. Brain Res Dev Brain Res, 2004, 151(1-2):129-139.
[228] Higashi Y. Edaravone for the treatment of acute cerebral infarction: role of endothelium-derived nitric oxide and oxidative stress[J]. Expert Opin Pharmacother, 2009,10(2):323-331.
[229] Xiao B, Bi FF, Hu YQ, et al. Edaravone neuroprotection effected by suppressing the gene expression of the Fas signal pathway following transient focal ischemia in rats[J]. Neurotox Res, 2007,12(3):155-162.
[230] Wen J, Watanabe K, Ma M, et al. Edaravone inhibits JNK-c-Jun pathway and restores anti-oxidative defense after ischemia-reperfusion injury in aged rats [J]. Biol Pharm Bull, 2006,29(4):713-718.
[231] Takizawa S, Izuhara Y, Kitao Y, et al. A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia[J].Brain Res, 2007,5(1183):124-137.
[232]冯加纯,饶明俐,张淑琴.自由基在大鼠全脑缺血再灌注损伤中的作用机理及保精增智液的保护作用[J].中风与神经疾病杂志, 1995,12(3):135-137.
[233] Tomatsuri N, Yoshida N, Takaqi T, et al. Edaravone, a newly developed radical scavenger, protects against ischemia-reperfusion injury of the small intesine in rats [J]. Int J Mol Med, 2004,13(1):105-109.
[234] Haeberlein SL. Mitochondrial function in apoptotic neuronal cell death [J]. Neurochem Res, 2004,29(3):521-530.
[235] Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death[J]. Physiol Rev, 2007,87(1):99-163.
[236] Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade[J]. Cell, 1997,91(4):479-489.
[237] Acehan D, Jiang X, Morgan DG, et al. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding and activation [J]. Mol Cell, 2002,9(2):423-432.
[238] Yoshida H, Kong YY, Yoshida R, et al. Apaf-1 is required for mitochondrial pathways of apoptosis and brain development[J]. Cell, 1998,94(6):739-750.
[239]薛晶,冯加纯.依达拉奉对中枢神经系统疾病治疗作用及机制的研究进展[J].临床荟萃, 2008,23(15):1137-1139.
[240] Huang L, Chen CH. Proteasome regulators: activators and inhibitors[J]. Curr Med Chem, 2009,16(8):931-939.
[241] Moore BS, Eustáguio AS, McGlinchey RP. Advances in and applications of proteasome inhibitors[J]. Curr Opin Chem Biol, 2008,12(4):434-440.
[242] Park JW, Kim KM, Oh kj, et al. Proteasome inhibition promotes functional recovery after peripheral nerve reperfusion injury[J]. J Trauma, 2009,66(3): 743-748.
[243] Park JW, Qi WN, Cai Y, et al. Proteasome inhibitor attenuates skeletal muscle reperfusion injury by blocking the pathway of nuclear factor-kappaB activation[J]. Plast Reconstr Surg, 2007,120(7):1808-1818.
[244] Lanzani F, Mattavelli L, Frigeni B, et al. Role of pre-existing neuropathy on thecourse of bortezomib-induced peripheral neurotoxicity[J]. J Peripher Nerv Syst, 2008,13(4):267-274.
[245] Richardson PG, Sonneveld P, Schuster MW, et al. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline[J]. Br J Haematol, 2009,144(6):895-903.
[246] Gilardini A, Marmiroli P, Cavaletti G.. Proteasome inhibition: a promoising strategy for treating cancer, but what about neurotoxicity[J]? Curr Med Chem, 2008,15(29): 3025-3035.