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http://dx.doi.org/10.4196/kjpp.2011.15.2.115

Matrix Metalloproteinase Inhibitors Attenuate Neuroinflammation Following Focal Cerebral Ischemia in Mice  

Park, Cheol-Hong (Department of Pharmacology, and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University School of Medicine)
Shin, Tae-Kyeong (Department of Pharmacology, and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University School of Medicine)
Lee, Ho-Youn (Department of Pharmacology, and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University School of Medicine)
Kim, So-Jung (Department of Pharmacology, and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University School of Medicine)
Lee, Won-Suk (Department of Pharmacology, and Medical Research Center for Ischemic Tissue Regeneration, Pusan National University School of Medicine)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.15, no.2, 2011 , pp. 115-122 More about this Journal
Abstract
The aim of this study was to investigate whether matrix metalloproteinase (MMP) inhibitors attenuate neuroinflammation in an ischemic brain following photothrombotic cortical ischemia in mice. Male C57BL/6 mice were anesthetized, and Rose Bengal was systemically administered. Permanent focal ischemia was induced in the medial frontal and somatosensory cortices by irradiating the skull with cold white light. MMP inhibitors, such as doxycycline, minocycline, and batimastat, significantly reduced the cerebral infarct size, and the expressions of monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$), and indoleamine 2,3-dioxygenase (IDO). However, they had no effect on the expressions of heme oxygenase-1 and neuroglobin in the ischemic cortex. These results suggest that MMP inhibitors attenuate ischemic brain injury by decreasing the expression levels of MCP-1, TNF-${\alpha}$, and IDO, thereby providing a therapeutic benefit against cerebral ischemia.
Keywords
Matrix metalloproteinase inhibitor; Monocyte chemotactic protein-1; Tumor necrosis factor-${\alpha}$; Indoleamine 2,3-dioxygenase; Photothrombotic cortical ischemia;
Citations & Related Records
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1 Denes A, Thornton P, Rothwell NJ, Allan SM. Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation. Brain Behav Immun. 2010;24:708-723.   DOI   ScienceOn
2 Gehrmann J, Bonnekoh P, Miyazawa T, Hossmann KA, Kreutzberg GW. Immunocytochemical study of an early microglial activation in ischemia. J Cereb Blood Flow Metab. 1992; 12:257-269.   DOI
3 Otterbein LE, Choi AM. Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol. 2000;279:L1029-1037.   DOI
4 Ryter SW, Otterbein LE, Morse D, Choi AM. Heme oxygenase/ carbon monoxide signaling pathways: regulation and functional significance. Mol Cell Biochem. 2002;234-235:249-263.
5 Lee PJ, Jiang BH, Chin BY, Iyer NV, Alam J, Semenza GL, Choi AM. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem. 1997;272:5375-5381.   DOI
6 Gearing AJ, Beckett P, Christodoulou M, Churchill M, Clements J, Davidson AH, Drummond AH, Galloway WA, Gilbert R, Gordon JL, Leber TM, Mangan M, Miller K, Nayee P, Owen K, Patel S, Thomas W, Wells G, Wood LM, Woolley K. Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature. 1994;370:555-557.   DOI
7 Mackay GM, Forrest CM, Stoy N, Christofides J, Egerton M, Stone TW, Darlington LG. Tryptophan metabolism and oxidative stress in patients with chronic brain injury. Eur J Neurol. 2006;13:30-42.
8 Dittmar M, Kiourkenidis G, Horn M, Bollwein S, Bernhardt G. Cerebral ischemia, matrix metalloproteinases, and TNFalpha: MMP inhibitors may act not exclusively by reducing MMP activity. Stroke. 2004;35:e338-340.   DOI
9 Mayhan WG. Cellular mechanisms by which tumor necrosis factor-alpha produces disruption of the blood-brain barrier. Brain Res. 2002;927:144-152.   DOI   ScienceOn
10 Nemeth H, Toldi J, Vécsei L. Kynurenines, Parkinson's disease and other neurodegenerative disorders: preclinical and clinical studies. J Neural Transm Suppl. 2006;70:285-304.
11 Gregersen R, Lambertsen K, Finsen B. Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab. 2000;20:53-65.   DOI   ScienceOn
12 Mabuchi T, Kitagawa K, Ohtsuki T, Kuwabara K, Yagita Y, Yanagihara T, Hori M, Matsumoto M. Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats. Stroke. 2000;31:1735-1743.   DOI   ScienceOn
13 Wojtowicz-Praga SM, Dickson RB, Hawkins MJ. Matrix metalloproteinase inhibitors. Invest New Drugs. 1997;15:61-75.   DOI   ScienceOn
14 Kim JS, Gautam SC, Chopp M, Zaloga C, Jones ML, Ward PA, Welch KM. Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat. J Neuroimmunol. 1995;56:127-134.   DOI   ScienceOn
15 Koistinaho M, Malm TM, Kettunen MI, Goldsteins G, Starckx S, Kauppinen RA, Opdenakker G, Koistinaho J. Minocycline protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice. J Cereb Blood Flow Metab. 2005;25:460-467.   DOI   ScienceOn
16 Baggiolini M. Chemokines and leukocyte traffic. Nature. 1998;392:565-568.   DOI   ScienceOn
17 Furie MB, Randolph GJ. Chemokines and tissue injury. Am J Pathol. 1995;146:1287-1301.
18 Che X, Ye W, Panga L, Wu DC, Yang GY. Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res. 2001;902:171-177.   DOI   ScienceOn
19 Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK, Wiessner C. Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab. 2002;22:308-317.   DOI
20 Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV. Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke. 2007;38: 1345-1353.   DOI   ScienceOn
21 Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT. Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J. 2009;276:13-26.   DOI   ScienceOn
22 Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, Feuerstein GZ. Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke. 1997;28:1233- 1244.   DOI   ScienceOn
23 Thornton P, Pinteaux E, Allan SM, Rothwell NJ. Matrix metalloproteinase-9 and urokinase plasminogen activator mediate interleukin-1-induced neurotoxicity. Mol Cell Neurosci. 2008;37:135-142.   DOI   ScienceOn
24 Hamann GF, Okada Y, Fitridge R, del Zoppo GJ. Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion. Stroke. 1995;26:2120-2126.   DOI   ScienceOn
25 Belayev L, Busto R, Zhao W, Ginsberg MD. Quantitative evaluation of blood-brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res. 1996;739:88-96.   DOI   ScienceOn
26 Kamada H, Yu F, Nito C, Chan PH. Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: relation to blood-brain barrier dysfunction. Stroke. 2007;38:1044-1049.   DOI   ScienceOn
27 McColl BW, Rothwell NJ, Allan SM. Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci. 2008;28:9451- 9462.   DOI   ScienceOn
28 Fukuda S, Fini CA, Mabuchi T, Koziol JA, Eggleston LL Jr, del Zoppo GJ. Focal cerebral ischemia induces active proteases that degrade microvascular matrix. Stroke. 2004;35:998-1004.   DOI   ScienceOn
29 Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res. 1998; 12:12-26.   DOI   ScienceOn
30 del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab. 2003;23:879-894.   DOI
31 Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Crit Rev Biochem Mol Biol. 2002;37:375-536.   DOI   ScienceOn
32 Cunningham LA, Wetzel M, Rosenberg GA. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia. 2005;50:329-339.   DOI   ScienceOn
33 Horstmann S, Kalb P, Koziol J, Gardner H, Wagner S. Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke. 2003; 34:2165-2170.   DOI   ScienceOn
34 Rosell A, Ortega-Aznar A, Alvarez-Sabín J, Fernández-Cadenas I, Ribó M, Molina CA, Lo EH, Montaner J. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke. 2006;37:1399-1406.   DOI   ScienceOn
35 Shin TK, Kang MS, Lee HY, Seo MS, Kim SG, Kim CD, Lee WS. Fluoxetine and sertraline attenuate postischemic brain injury in mice. Korean J Physiol Pharmacol. 2009;13:257-263.   DOI
36 Sun Y, Jin K, Mao XO, Zhu Y, Greenberg DA. Neuroglobin is up-regulated by and protects neurons from hypoxic-ischemic injury. Proc Natl Acad Sci U S A. 2001;98:15306-15311.   DOI   ScienceOn
37 Sun Y, Jin K, Peel A, Mao XO, Xie L, Greenberg DA. Neuroglobin protects the brain from experimental stroke in vivo. Proc Natl Acad Sci U S A. 2003;100:3497-3500.   DOI   ScienceOn
38 Schroeter M, Jander S, Stoll G. Non-invasive induction of focal cerebral ischemia in mice by photothrombosis of cortical microvessels: characterization of inflammatory responses. J Neurosci Methods. 2002;117:43-49.   DOI   ScienceOn
39 Bederson JB, Pitts LH, Germano SM, Nishimura MC, Davis RL, Bartkowski HM. Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke. 1986;17:1304-1308.   DOI   ScienceOn
40 Yan YP, Sailor KA, Lang BT, Park SW, Vemuganti R, Dempsey RJ. Monocyte chemoattractant protein-1 plays a critical role in neuroblast migration after focal cerebral ischemia. J Cereb Blood Flow Metab. 2007;27:1213-1224.   DOI   ScienceOn
41 Muir KW, Tyrrell P, Sattar N, Warburton E. Inflammation and ischaemic stroke. Curr Opin Neurol. 2007;20:334-342.   DOI   ScienceOn
42 Sanni LA, Thomas SR, Tattam BN, Moore DE, Chaudhri G, Stocker R, Hunt NH. Dramatic changes in oxidative tryptophan metabolism along the kynurenine pathway in experimental cerebral and noncerebral malaria. Am J Pathol. 1998;152: 611-619.
43 Cozzi A, Carpenedo R, Moroni F. Kynurenine hydroxylase inhibitors reduce ischemic brain damage: studies with (m-nitrobenzoyl)- alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl) thiazol-2yl]-benzenesulfonamide (Ro 61-8048) in models of focal or global brain ischemia. J Cereb Blood Flow Metab. 1999; 19:771-777.   DOI
44 Marks GS, Brien JF, Nakatsu K, McLaughlin BE. Does carbon monoxide have a physiological function? Trends Pharmacol Sci. 1991;12:185-188.   DOI
45 Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997;37:517- 554.   DOI   ScienceOn
46 Geddes JW, Pettigrew LC, Holtz ML, Craddock SD, Maines MD. Permanent focal and transient global cerebral ischemia increase glial and neuronal expression of heme oxygenase-1, but not heme oxygenase-2, protein in rat brain. Neurosci Lett. 1996;210:205-208.   DOI   ScienceOn
47 Conductier G, Blondeau N, Guyon A, Nahon JL, Rovère C. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol. 2010;224:93-100.   DOI   ScienceOn
48 Panahian N, Yoshiura M, Maines MD. Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. J Neurochem.1999;72:1187-1203.
49 Fu R, Zhao ZQ, Zhao HY, Zhao JS, Zhu XL. Expression of heme oxygenase-1 protein and messenger RNA in permanent cerebral ischemia in rats. Neurol Res. 2006;28:38-45.   DOI   ScienceOn
50 Burmester T, Weich B, Reinhardt S, Hankeln T. A vertebrate globin expressed in the brain. Nature. 2000;407:520-523.   DOI   ScienceOn
51 Sriram K, O'Callaghan JP. Divergent roles for tumor necrosis factor-alpha in the brain. J Neuroimmune Pharmacol. 2007;2: 140-153.   DOI   ScienceOn
52 Brenner DA, O'Hara M, Angel P, Chojkier M, Karin M. Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha. Nature. 1989;337:661-663.   DOI   ScienceOn
53 Hanemaaijer R, Koolwijk P, le Clercq L, de Vree WJ, van Hinsbergh VW. Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester. Biochem J. 1993;296:803-809.   DOI
54 Gong C, Qin Z, Betz AL, Liu XH, Yang GY. Cellular localization of tumor necrosis factor alpha following focal cerebral ischemia in mice. Brain Res. 1998;801:1-8.   DOI
55 Heyes MP, Saito K, Devinsky O, Nadi NS. Kynurenine pathway metabolites in cerebrospinal fluid and serum in complex partial seizures. Epilepsia. 1994;35:251-257.   DOI   ScienceOn
56 Yang GY, Gong C, Qin Z, Liu XH, Lorris Betz A. Tumor necrosis factor alpha expression produces increased blood-brain barrier permeability following temporary focal cerebral ischemia in mice. Brain Res Mol Brain Res. 1999;69:135-143.   DOI
57 Crowley JS, Markey SP, Heyes MP. Kynurenine pathway enzymes in brain: responses to ischemic brain injury versus systemic immune activation. J Neurochem. 1993;61:2061-2070.   DOI   ScienceOn
58 Heyes MP, Saito K, Jacobowitz D, Markey SP, Takikawa O, Vickers JH. Poliovirus induces indoleamine-2,3-dioxygenase and quinolinic acid synthesis in macaque brain. FASEB J. 1992;6:2977-2989.   DOI
59 Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab. 2000;20:1681-1689.   DOI
60 Minami M, Satoh M. Chemokines and their receptors in the brain: pathophysiological roles in ischemic brain injury. Life Sci. 2003;74:321-327.   DOI   ScienceOn
61 Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stressassociated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21: 1393-1400.   DOI
62 Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke. 1998;29:1020-1030.   DOI   ScienceOn
63 Wang X, Yue TL, Barone FC, Feuerstein GZ. Monocyte chemoattractant protein-1 messenger RNA expression in rat ischemic cortex. Stroke. 1995;26:661-665.   DOI   ScienceOn
64 Chen Y, Hallenbeck JM, Ruetzler C, Bol D, Thomas K, Berman NE, Vogel SN. Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells. J Cereb Blood Flow Metab. 2003;23:748-755.   DOI
65 Lakhan SE, Kirchgessner A, Hofer M. Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med. 2009;7:97.   DOI
66 Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia. 2002;39:279-291.   DOI   ScienceOn
67 Mun-Bryce S, Rosenberg GA. Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab. 1998;18: 1163-1172.   DOI