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Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article (Mini-Review)

Protective Effects and Mechanisms of Action of Ulinastatin against Cerebral Ischemia-Reperfusion Injury

Author(s): Bing Lv, Xiao-Ming Jiang, Da-Wei Wang, Jing Chen, Dong-Feng Han* and Xiao-Liang Liu*

Volume 26 , Issue 27 , 2020

Page: [3332 - 3340] Pages: 9

DOI: 10.2174/1381612826666200303114955

Price: $65

Abstract

Background: Cerebral ischemia-reperfusion injury is an extremely complicated pathological process that is clinically characterized by high rates of disability and mortality. It is imperative to explore some effective neuroprotective agents for its treatment. Ulinastatin is a protease inhibitor with anti-inflammatory and antioxidant activity. For the past few years, new studies of ulinastatin for the treatment of ischemic brain injury have emerged.

Objective: We conducted a review to summarize the mechanisms of ulinastatin and analyze its neuroprotective action against cerebral ischemia–reperfusion injury.

Methods: We reviewed and summarized pertinent reports published between 1993 and 2019 from PubMed, Web of Science, and Embaseby searching for the scientific terms ulinastatin, cerebral ischemia–reperfusion injury, neuroprotective, stroke, cardiac arrest, and brain edema.

Results: The protective mechanisms of ulinastatin in the key steps of cerebral ischemia–reperfusion injury include inhibition of inflammatory response, oxidative stress, neuronal apoptosis, neuronal autophagy, and aquaporin- 4 expression as well as improvement in blood–brain barrier permeability. In addition, we provide a perspective on potential research directions and clinical safety.

Conclusion: Ulinastatin seems to have the potential to alleviate cerebral ischemia–reperfusion injury. These findings may be valuable to further promote the research and development of drug candidates and provide novel and reliable references for rational drug use.

Keywords: ulinastatin, brain, cerebral ischemia–reperfusion injury, neuroprotective, inflammation, oxidative stress.

[1]
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367(9524): 1747-57.
[http://dx.doi.org/10.1016/S0140-6736(06)68770-9] [PMID: 16731270]
[2]
Torres-Cuevas I, Corral-Debrinski M, Gressens P. Brain oxidative damage in murine models of neonatal hypoxia/ischemia and reoxygenation. Free Radic Biol Med 2019; 142: 3-15.
[http://dx.doi.org/10.1016/j.freeradbiomed.2019.06.011] [PMID: 31226400]
[3]
Girbovan C, Plamondon H. Resveratrol downregulates type-1 glutamate transporter expression and microglia activation in the hippocampus following cerebral ischemia reperfusion in rats. Brain Res 2015; 1608: 203-14.
[http://dx.doi.org/10.1016/j.brainres.2015.02.038] [PMID: 25727173]
[4]
Gong G, Xiang L, Yuan L, et al. Protective effect of glycyrrhizin, a direct HMGB1 inhibitor, on focal cerebral ischemia/reperfusion-induced inflammation, oxidative stress, and apoptosis in rats. PLoS One 2014; 9(3) e89450
[http://dx.doi.org/10.1371/journal.pone.0089450] [PMID: 24594628]
[5]
Fries E, Kaczmarczyk A. Inter-alpha-inhibitor, hyaluronan and inflammation. Acta Biochim Pol 2003; 50(3): 735-42.
[http://dx.doi.org/10.18388/abp.2003_3664] [PMID: 14515153]
[6]
Pugia MJ, Valdes R Jr, Jortani SA. Bikunin (urinary trypsin inhibitor): structure, biological relevance, and measurement. Adv Clin Chem 2007; 44: 223-45.
[http://dx.doi.org/10.1016/S0065-2423(07)44007-0] [PMID: 17682344]
[7]
Nakatani K, Takeshita S, Tsujimoto H, Kawamura Y, Sekine I. Inhibitory effect of serine protease inhibitors on neutrophil-mediated endothelial cell injury. J Leukoc Biol 2001; 69(2): 241-7.
[PMID: 11272274]
[8]
Jiang W, Yu X, Sun T, et al. ADJunctive Ulinastatin in Sepsis Treatment in China (ADJUST study): study protocol for a randomized controlled trial. Trials 2018; 19(1): 133.
[http://dx.doi.org/10.1186/s13063-018-2513-y] [PMID: 29467017]
[9]
Lagoo JY, D’Souza MC, Kartha A, Kutappa AM. Role of Ulinastatin, a trypsin inhibitor, in severe acute pancreatitis in critical care setting: A retrospective analysis. J Crit Care 2018; 45: 27-32.
[http://dx.doi.org/10.1016/j.jcrc.2018.01.021] [PMID: 29413719]
[10]
Xu Q, Yan Q, Chen S. Use of ulinastatin was associated with reduced mortality in critically ill patients with sepsis. J Thorac Dis 2019; 11(5): 1911-8.
[http://dx.doi.org/10.21037/jtd.2019.05.03] [PMID: 31285884]
[11]
Wang Y, Peng C, Zhang Z, et al. Intravenous infusion of ulinastatin attenuates acute kidney injury after cold ischemia/reperfusion. Int Urol Nephrol 2019; 51(10): 1873-81.
[http://dx.doi.org/10.1007/s11255-019-02204-3] [PMID: 31332701]
[12]
Che H, Lv YF, Liu YG, Hou YX, Zhao LY. Effect of ulinastatin on myocardial ischemia reperfusion injury through ERK signaling pathway. Eur Rev Med Pharmacol Sci 2019; 23(10): 4458-64.
[PMID: 31173321]
[13]
Liu B, Huang W, Xiao X, Xu Y, Ma S, Xia Z. Neuroprotective Effect of Ulinastatin on Spinal Cord Ischemia-Reperfusion Injury in Rabbits. Oxid Med Cell Longev 2015. 2015624819
[http://dx.doi.org/10.1155/2015/624819] [PMID: 26161241]
[14]
Li X-F, Zhang X-J, Zhang C, et al. Ulinastatin protects brain against cerebral ischemia/reperfusion injury through inhibiting MMP-9 and alleviating loss of ZO-1 and occludin proteins in mice. Exp Neurol 2018; 302: 68-74.
[http://dx.doi.org/10.1016/j.expneurol.2017.12.016] [PMID: 29291404]
[15]
Liu M, Shen J, Zou F, Zhao Y, Li B, Fan M. Effect of ulinastatin on the permeability of the blood-brain barrier on rats with global cerebral ischemia/reperfusion injury as assessed by MRI. Biomed Pharmacother 2017; 85: 412-7.
[http://dx.doi.org/10.1016/j.biopha.2016.11.044] [PMID: 27916423]
[16]
Jiang X-M, Hu J-H, Wang L-L, Ma C, Wang X, Liu X-L. Ulinastatin alleviates neurological deficiencies evoked by transient cerebral ischemia via improving autophagy, Nrf-2-ARE and apoptosis signals in hippocampus. Physiol Res 2018; 67(4): 637-46.
[http://dx.doi.org/10.33549/physiolres.933780] [PMID: 29750875]
[17]
Hui L, Shen F, Chang H, Li X, Gao G, Ma J. Effects of ulinastatin on cerebral oxygen metabolism and CRP levels in patients with severe traumatic brain injury. Exp Ther Med 2014; 7(6): 1683-6.
[http://dx.doi.org/10.3892/etm.2014.1666] [PMID: 24926366]
[18]
Li X, Su L, Zhang X, et al. Ulinastatin downregulates TLR4 and NF-kB expression and protects mouse brains against ischemia/reperfusion injury. Neurol Res 2017; 39(4): 367-73.
[http://dx.doi.org/10.1080/01616412.2017.1286541] [PMID: 28191863]
[19]
Xiong L, Sun L, Liu S, Zhu X, Teng Z, Yan J. The Protective Roles of Urinary Trypsin Inhibitor in Brain Injury Following Fat Embolism Syndrome in a Rat Model. Cell Transplant 2019; 28(6): 704-12.
[PMID: 30449147]
[20]
Sui B, Li Y, Ma L. Postconditioning improvement effects of ulinastatin on brain injury following cardiopulmonary resuscitation. Exp Ther Med 2014; 8(4): 1301-7.
[http://dx.doi.org/10.3892/etm.2014.1876] [PMID: 25187844]
[21]
Hu CL, Xia JM, Cai J, et al. Ulinastatin attenuates oxidation, inflammation and neural apoptosis in the cerebral cortex of adult rats with ventricular fibrillation after cardiopulmonary resuscitation. Clinics (São Paulo) 2013; 68(9): 1231-8.
[http://dx.doi.org/10.6061/clinics/2013(09)10] [PMID: 24141840]
[22]
Koga Y, Fujita M, Tsuruta R, et al. Urinary trypsin inhibitor suppresses excessive superoxide anion radical generation in blood, oxidative stress, early inflammation, and endothelial injury in forebrain ischemia/reperfusion rats. Neurol Res 2010; 32(9): 925-32.
[http://dx.doi.org/10.1179/016164110X12645013515133] [PMID: 20223106]
[23]
Jiang X-M, Hu J-H, Wang L-L, Ma C, Wang X, Liu X-L. Effects of ulinastatin on global ischemia via brain pro-inflammation signal. Transl Neurosci 2016; 7(1): 158-63.
[http://dx.doi.org/10.1515/tnsci-2016-0023] [PMID: 28123836]
[24]
Hu HX, Xu DH, Ju WN, Ma C, Wang X, Liu XL. Neuroprotection of ulinastatin on transient cerebral ischemia via antioxidative mechanisms. J Biol Regul Homeost Agents 2018; 32(2): 283-8.
[PMID: 29685007]
[25]
Hu HX, Zhu MQ, Sun YC, Ma C, Wang X, Liu XL. Xuebijing enhances neuroprotective effects of ulinastatin on transient cerebral ischemia via Nrf2-are signal pathways in the hippocampus. J Biol Regul Homeost Agents 2018; 32(5): 1143-9.
[PMID: 30334406]
[26]
Cho Y-S, Shin M-S, Ko I-G, et al. Ulinastatin inhibits cerebral ischemia-induced apoptosis in the hippocampus of gerbils. Mol Med Rep 2015; 12(2): 1796-802.
[http://dx.doi.org/10.3892/mmr.2015.3612] [PMID: 25891426]
[27]
Liu S, Xu J, Gao Y, et al. Multi-organ protection of ulinastatin in traumatic cardiac arrest model. World J Emerg Surg 2018; 13: 51.
[http://dx.doi.org/10.1186/s13017-018-0212-3] [PMID: 30459824]
[28]
Ma C, Han D-F, Jin H, Cheng Y-Y, Hu H-X, Wang X. A Combination of Ulinastatin and Xuebijing Amplifies Neuroprotection after Transient Cerebral Ischemia via Attenuating Apoptosis Signal Pathways in Hippocampus. Curr Pharm Des 2018; 24(44): 5342-7.
[http://dx.doi.org/10.2174/1381612825666190206224134] [PMID: 30727870]
[29]
Chen H-M, Huang H-S, Ruan L, He Y-B, Li X-J. Ulinastatin attenuates cerebral ischemia-reperfusion injury in rats. Int J Clin Exp Med 2014; 7(5): 1483-9.
[PMID: 24995117]
[30]
Zheng Z, Yenari MA. Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol Res 2004; 26(8): 884-92.
[http://dx.doi.org/10.1179/016164104X2357] [PMID: 15727272]
[31]
Shinohara N, Nakamura T, Abe Y, et al. d-Allose Attenuates Overexpression of Inflammatory Cytokines after Cerebral Ischemia/Reperfusion Injury in Gerbil. J Stroke Cerebrovasc Dis 2016; 25(9): 2184-8.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.01.030] [PMID: 27342700]
[32]
Wang D, Jiang Q, Du X. Protective effects of scopolamine and penehyclidine hydrochloride on acute cerebral ischemia-reperfusion injury after cardiopulmonary resuscitation and effects on cytokines. Exp Ther Med 2018; 15(2): 2027-31.
[PMID: 29434800]
[33]
Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11(5): 373-84.
[http://dx.doi.org/10.1038/ni.1863] [PMID: 20404851]
[34]
Kobayashi K, Hernandez LD, Galán JE, Janeway CA Jr, Medzhitov R, Flavell RA. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 2002; 110(2): 191-202.
[http://dx.doi.org/10.1016/S0092-8674(02)00827-9] [PMID: 12150927]
[35]
Yang Y, Zhou H, Yang Y, et al. Lipopolysaccharide (LPS) regulates TLR4 signal transduction in nasopharynx epithelial cell line 5-8F via NFkappaB and MAPKs signaling pathways. Mol Immunol 2007; 44(5): 984-92.
[http://dx.doi.org/10.1016/j.molimm.2006.03.013] [PMID: 16675017]
[36]
Harari OA, Liao JK. NF-κB and innate immunity in ischemic stroke. Ann N Y Acad Sci 2010; 1207: 32-40.
[http://dx.doi.org/10.1111/j.1749-6632.2010.05735.x] [PMID: 20955423]
[37]
Adrie C, Adib-Conquy M, Laurent I, et al. Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circulation 2002; 106(5): 562-8.
[http://dx.doi.org/10.1161/01.CIR.0000023891.80661.AD] [PMID: 12147537]
[38]
Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282(5396): 2085-8.
[http://dx.doi.org/10.1126/science.282.5396.2085] [PMID: 9851930]
[39]
Lehnardt S, Lehmann S, Kaul D, et al. Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. J Neuroimmunol 2007; 190(1-2): 28-33.
[http://dx.doi.org/10.1016/j.jneuroim.2007.07.023] [PMID: 17854911]
[40]
Qiu J, Nishimura M, Wang Y, et al. Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 2008; 28(5): 927-38.
[http://dx.doi.org/10.1038/sj.jcbfm.9600582] [PMID: 18000511]
[41]
Zhang L, Wang Y, Ma J, et al. Exogenous MSCs ameliorate hypoxia/reoxygenation injury in renal tubular epithelial cells through JAK/STAT signaling pathway-mediated regulation of HMGB1. Am J Transl Res 2017; 9(5): 2412-20.
[PMID: 28559991]
[42]
Wu Y, Xu J, Xu J, Zheng W, Chen Q, Jiao D. Study on the mechanism of JAK2/STAT3 signaling pathway-mediated inflammatory reaction after cerebral ischemia. Mol Med Rep 2018; 17(4): 5007-12.
[http://dx.doi.org/10.3892/mmr.2018.8477] [PMID: 29393445]
[43]
Li W, Tan C, Liu Y, et al. Resveratrol ameliorates oxidative stress and inhibits aquaporin 4 expression following rat cerebral ischemia-reperfusion injury. Mol Med Rep 2015; 12(5): 7756-62.
[http://dx.doi.org/10.3892/mmr.2015.4366] [PMID: 26458999]
[44]
Zhang C, Shen M, Teng F, et al. Ultrasound-Enhanced Protective Effect of Tetramethylpyrazine via the ROS/HIF-1A Signaling Pathway in an in Vitro Cerebral Ischemia/Reperfusion Injury Model. Ultrasound Med Biol 2018; 44(8): 1786-98.
[http://dx.doi.org/10.1016/j.ultrasmedbio.2018.04.005] [PMID: 29793852]
[45]
Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA 1994; 91(21): 9926-30.
[http://dx.doi.org/10.1073/pnas.91.21.9926] [PMID: 7937919]
[46]
Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 1997; 236(2): 313-22.
[http://dx.doi.org/10.1006/bbrc.1997.6943] [PMID: 9240432]
[47]
Yamamoto T, Suzuki T, Kobayashi A, et al. Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol 2008; 28(8): 2758-70.
[http://dx.doi.org/10.1128/MCB.01704-07] [PMID: 18268004]
[48]
Luo Y, Cui HX, Jia A, Jia SS, Yuan K. The Protective Effect of the Total Flavonoids of Abelmoschus esculentus L. Flowers on Transient Cerebral Ischemia-Reperfusion Injury Is due to Activation of the Nrf2-ARE Pathway. Oxid Med Cell Longev 2018. 20188987173
[http://dx.doi.org/10.1155/2018/8987173] [PMID: 30174782]
[49]
Xu X, Zhang L, Ye X, et al. Nrf2/ARE pathway inhibits ROS-induced NLRP3 inflammasome activation in BV2 cells after cerebral ischemia reperfusion. Inflamm Res 2018; 67(1): 57-65.
[http://dx.doi.org/10.1007/s00011-017-1095-6] [PMID: 28956063]
[50]
Mattson MP, Duan W, Pedersen WA, Culmsee C. Neurodegenerative disorders and ischemic brain diseases. Apoptosis 2001; 6(1-2): 69-81.
[http://dx.doi.org/10.1023/A:1009676112184] [PMID: 11321043]
[51]
Li P, Shen M, Gao F, et al. An Antagomir to MicroRNA-106b-5p Ameliorates Cerebral Ischemia and Reperfusion Injury in Rats Via Inhibiting Apoptosis and Oxidative Stress. Mol Neurobiol 2017; 54(4): 2901-21.
[http://dx.doi.org/10.1007/s12035-016-9842-1] [PMID: 27023223]
[52]
Huang X, Ding J, Li Y, et al. Exosomes derived from PEDF modified adipose-derived mesenchymal stem cells ameliorate cerebral ischemia-reperfusion injury by regulation of autophagy and apoptosis. Exp Cell Res 2018; 371(1): 269-77.
[http://dx.doi.org/10.1016/j.yexcr.2018.08.021] [PMID: 30142325]
[53]
Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74(4): 609-19.
[http://dx.doi.org/10.1016/0092-8674(93)90509-O] [PMID: 8358790]
[54]
Tian F, Yuan C, Yue H. MiR-138/SIRT1 axis is implicated in impaired learning and memory abilities of cerebral ischemia/reperfusion injured rats. Exp Cell Res 2018; 367(2): 232-40.
[http://dx.doi.org/10.1016/j.yexcr.2018.03.042] [PMID: 29614311]
[55]
Hwang J-Y, Gertner M, Pontarelli F, et al. Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die. Cell Death Differ 2017; 24(2): 317-29.
[http://dx.doi.org/10.1038/cdd.2016.140] [PMID: 27935582]
[56]
Sun D, Wang W, Wang X, et al. bFGF plays a neuroprotective role by suppressing excessive autophagy and apoptosis after transient global cerebral ischemia in rats. Cell Death Dis 2018; 9(2): 172.
[http://dx.doi.org/10.1038/s41419-017-0229-7] [PMID: 29416039]
[57]
Qiao L, Fu J, Xue X, et al. Neuronalinjury and roles of apoptosis and autophagy in a neonatal rat model of hypoxia-ischemia-induced periventricular leukomalacia. Mol Med Rep 2018; 17(4): 5940-9.
[http://dx.doi.org/10.3892/mmr.2018.8570] [PMID: 29436652]
[58]
Lu Q, Harris VA, Kumar S, Mansour HM, Black SM. Autophagy in neonatal hypoxia ischemic brain is associated with oxidative stress. Redox Biol 2015; 6: 516-23.
[http://dx.doi.org/10.1016/j.redox.2015.06.016] [PMID: 26454246]
[59]
Jiang WW, Huang BS, Han Y, Deng LH, Wu LX. Sodium hydrosulfide attenuates cerebral ischemia/reperfusion injury by suppressing overactivated autophagy in rats. FEBS Open Bio 2017; 7(11): 1686-95.
[http://dx.doi.org/10.1002/2211-5463.12301] [PMID: 29123977]
[60]
Xu J, Huai Y, Meng N, et al. L-3-n-Butylphthalide Activates Akt/mTOR Signaling, Inhibits Neuronal Apoptosis and Autophagy and Improves Cognitive Impairment in Mice with Repeated Cerebral Ischemia-Reperfusion Injury. Neurochem Res 2017; 42(10): 2968-81.
[http://dx.doi.org/10.1007/s11064-017-2328-3] [PMID: 28620824]
[61]
Guo Q, Sayeed I, Baronne LM, Hoffman SW, Guennoun R, Stein DG. Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats. Exp Neurol 2006; 198(2): 469-78.
[http://dx.doi.org/10.1016/j.expneurol.2005.12.013] [PMID: 16445913]
[62]
Papadopoulos MC, Manley GT, Krishna S, Verkman AS. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J 2004; 18(11): 1291-3.
[http://dx.doi.org/10.1096/fj.04-1723fje] [PMID: 15208268]
[63]
Wang X, An F, Wang S, An Z, Wang S. Orientin Attenuates Cerebral Ischemia/Reperfusion Injury in Rat Model through the AQP-4 and TLR4/NF-κB/TNF-α Signaling Pathway. J Stroke Cerebrovasc Dis 2017; 26(10): 2199-214.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.05.002] [PMID: 28645524]
[64]
Yuan M, Ge M, Yin J, et al. Isoflurane post-conditioning down-regulates expression of aquaporin 4 in rats with cerebral ischemia/reperfusion injury and is possibly related to bone morphogenetic protein 4/Smad1/5/8 signaling pathway. Biomed Pharmacother 2018; 97: 429-38.
[http://dx.doi.org/10.1016/j.biopha.2017.10.082] [PMID: 29091893]
[65]
Liu X, Chen X, Zhu Y, Wang K, Wang Y. Effect of magnolol on cerebral injury and blood brain barrier dysfunction induced by ischemia-reperfusion in vivo and in vitro. Metab Brain Dis 2017; 32(4): 1109-18.
[http://dx.doi.org/10.1007/s11011-017-0004-6] [PMID: 28378105]
[66]
Zhang H, Park JH, Maharjan S, et al. Sac-1004, a vascular leakage blocker, reduces cerebral ischemia-reperfusion injury by suppressing blood-brain barrier disruption and inflammation. J Neuroinflammation 2017; 14(1): 122.
[http://dx.doi.org/10.1186/s12974-017-0897-3] [PMID: 28645333]
[67]
Gartshore G, Patterson J, Macrae IM. Influence of ischemia and reperfusion on the course of brain tissue swelling and blood-brain barrier permeability in a rodent model of transient focal cerebral ischemia. Exp Neurol 1997; 147(2): 353-60.
[http://dx.doi.org/10.1006/exnr.1997.6635] [PMID: 9344560]
[68]
Higashida T, Kreipke CW, Rafols JA, et al. The role of hypoxia-inducible factor-la, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury Laboratory investigation. J Neurosurg 2011; 114: 92-101.
[http://dx.doi.org/10.3171/2010.6.JNS10207] [PMID: 20617879]
[69]
Fan F, Yang J, Xu Y, Guan S. MiR-539 Targets MMP-9 to Regulate the Permeability of Blood-Brain Barrier in Ischemia/Reperfusion Injury of Brain. Neurochem Res 2018; 43(12): 2260-7.
[http://dx.doi.org/10.1007/s11064-018-2646-0] [PMID: 30276507]
[70]
Wu W, Zhong W, Lang B, Hu Z, He J, Tang X. Thrombopoietin could protect cerebral tissue against ischemia-reperfusion injury by suppressing NF-κB and MMP-9 expression in rats. Int J Med Sci 2018; 15(12): 1341-8.
[http://dx.doi.org/10.7150/ijms.27543] [PMID: 30275761]
[71]
Zhang W, Song JK, Zhang X, et al. Salvianolic acid A attenuates ischemia reperfusion induced rat brain damage by protecting the blood brain barrier through MMP-9 inhibition and anti-inflammation. Chin J Nat Med 2018; 16(3): 184-93.
[http://dx.doi.org/10.1016/S1875-5364(18)30046-3] [PMID: 29576054]
[72]
Ma L, Zhang H, Liu YZ, Yin YL, Ma YQ, Zhang SS. Ulinastatin decreases permeability of blood-brain barrier by inhibiting expression of MMP-9 and t-PA in postoperative aged rats. Int J Neurosci 2016; 126(5): 463-8.
[http://dx.doi.org/10.3109/00207454.2015.1025394] [PMID: 26000820]
[73]
Shi J, Wu G, Zou X, Jiang K. Oleuropein protects intracerebral hemorrhage-induced disruption of blood-brain barrier through alleviation of oxidative stress. Pharmacol Rep 2017; 69(6): 1206-12.
[http://dx.doi.org/10.1016/j.pharep.2017.05.004] [PMID: 29128801]
[74]
Li C, Wang X, Cheng F, et al. Geniposide protects against hypoxia/reperfusion-induced blood-brain barrier impairment by increasing tight junction protein expression and decreasing inflammation, oxidative stress, and apoptosis in an in vitro system. Eur J Pharmacol 2019; 854: 224-31.
[http://dx.doi.org/10.1016/j.ejphar.2019.04.021] [PMID: 30995438]
[75]
Gomi S, Karp A, Greenberg JH. Regional alterations in an excitatory amino-acid transporter, blood flow, and glucose metabolism after middle cerebral artery occlusion in the rat. Exp Brain Res 2000; 130(4): 521-8.
[http://dx.doi.org/10.1007/s002219900252] [PMID: 10717793]
[76]
Mastroiacovo F, Moyanova S, Cannella M, et al. Genetic deletion of mGlu2 metabotropic glutamate receptors improves the short-term outcome of cerebral transient focal ischemia. Mol Brain 2017; 10(1): 39.
[http://dx.doi.org/10.1186/s13041-017-0319-6] [PMID: 28821279]
[77]
Nozaki K, Nishimura M, Hashimoto N. Mitogen-activated protein kinases and cerebral ischemia. Mol Neurobiol 2001; 23(1): 1-19.
[http://dx.doi.org/10.1385/MN:23:1:01] [PMID: 11642541]
[78]
Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002; 298(5600): 1911-2.
[http://dx.doi.org/10.1126/science.1072682] [PMID: 12471242]
[79]
Walton M, Sirimanne E, Williams C, Gluckman P, Dragunow M. The role of the cyclic AMP-responsive element binding protein (CREB) in hypoxic-ischemic brain damage and repair. Brain Res Mol Brain Res 1996; 43(1-2): 21-9.
[http://dx.doi.org/10.1016/S0169-328X(96)00144-1] [PMID: 9037515]
[80]
Walton M, Woodgate AM, Muravlev A, Xu R, During MJ, Dragunow M. CREB phosphorylation promotes nerve cell survival. J Neurochem 1999; 73(5): 1836-42.
[PMID: 10537041]
[81]
Park EM, Joh TH, Volpe BT, Chu CK, Song G, Cho S. A neuroprotective role of extracellular signal-regulated kinase in N-acetyl-O-methyldopamine-treated hippocampal neurons after exposure to in vitro and in vivo ischemia. Neuroscience 2004; 123(1): 147-54.
[http://dx.doi.org/10.1016/j.neuroscience.2003.08.023] [PMID: 14667449]
[82]
Laganà AS, Vitale SG, Nigro A, et al. Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs) in Dysregulated Metabolic Homeostasis, Inflammation and Cancer: Current Evidence and Future Perspectives. Int J Mol Sci 2016; 17(7): 17.
[http://dx.doi.org/10.3390/ijms17070999] [PMID: 27347932]
[83]
Vitale SG, Laganà AS, Nigro A, et al. Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions. PPAR Res 2016; 2016 6517313
[http://dx.doi.org/10.1155/2016/6517313] [PMID: 28115924]
[84]
Biscetti F, Straface G, Pitocco D, Zaccardi F, Ghirlanda G, Flex A. Peroxisome proliferator-activated receptors and angiogenesis. Nutr Metab Cardiovasc Dis 2009; 19(11): 751-9.
[http://dx.doi.org/10.1016/j.numecd.2009.04.011] [PMID: 19628379]
[85]
Khazaei M, Salehi E, Rashidi B. Pan-PPAR Agonist, Bezafibrate, Restores Angiogenesis in Hindlimb Ischemia in Normal and Diabetic Rats. Int J Pept 2012. 2012637212
[http://dx.doi.org/10.1155/2012/637212] [PMID: 22701496]
[86]
Chen Q, Hu C, Liu Y, et al. Safety and tolerability of high-dose ulinastatin after 2-hour intravenous infusion in adult healthy Chinese volunteers: A randomized, double-blind, placebo-controlled, ascending-dose study. PLoS One 2017; 12(5) e0177425
[http://dx.doi.org/10.1371/journal.pone.0177425] [PMID: 28493932]

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