{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:49:42Z","timestamp":1790758182433,"version":"4.1.0"},"reference-count":70,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017R1C1B3002626"],"award-info":[{"award-number":["NRF-2017R1C1B3002626"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Health and Welfare of Korea","award":["HI14C2180"],"award-info":[{"award-number":["HI14C2180"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Stroke is one of the leading causes of death and disability worldwide. However, treatment options for ischemic stroke remain limited. Matrix-metalloproteinases (MMPs) contribute to brain damage during ischemic strokes by disrupting the blood-brain barrier (BBB) and causing brain edemas. Carnosine, an endogenous dipeptide, was found by us and others to be protective against ischemic brain injury. In this study, we investigated whether carnosine influences MMP activity. Brain MMP levels and activity were measured by gelatin zymography after permanent occlusion of the middle cerebral artery (pMCAO) in rats and in vitro enzyme assays. Carnosine significantly reduced infarct volume and edema. Gelatin zymography and in vitro enzyme assays showed that carnosine inhibited brain MMPs. We showed that carnosine inhibited both MMP-2 and MMP-9 activity by chelating zinc. Carnosine also reduced the ischemia-mediated degradation of the tight junction proteins that comprise the BBB. In summary, our findings show that carnosine inhibits MMP activity by chelating zinc, an essential MMP co-factor, resulting in the reduction of edema and brain injury. We believe that our findings shed new light on the neuroprotective mechanism of carnosine against ischemic brain damage.<\/jats:p>","DOI":"10.3390\/ijms22147495","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T22:25:31Z","timestamp":1626215131000},"page":"7495","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases"],"prefix":"10.3390","volume":"22","author":[{"given":"Eun-Hye","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Sun","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donggeun","family":"Shin","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghyun","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungbin","family":"Choi","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young-Jun","family":"Shin","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyeong-A","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dabi","family":"Noh","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet B.","family":"Caglayan","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Istanbul Medipol University, 34810 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.K.","family":"Rajanikant","sequence":"additional","affiliation":[{"name":"School of Biotechnology, National Institute of Technology Calicut, Calicut 673601, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arshad","family":"Majid","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2TN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0583-2116","authenticated-orcid":false,"given":"Ok-Nam","family":"Bae","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.brainres.2017.06.029","article-title":"Dihydrocapsaicin (DHC) enhances the hypothermia-induced neuroprotection following ischemic stroke via PI3K\/Akt regulation in rat","volume":"1671","author":"Wu","year":"2017","journal-title":"Brain Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tran-Dinh, A., Levoye, A., Couret, D., Galle-Treger, L., Moreau, M., Delbosc, S., Hoteit, C., Montravers, P., Amarenco, P., and Huby, T. (2020). High-Density Lipoprotein Therapy in Stroke: Evaluation of Endothelial SR-BI-Dependent Neuroprotective Effects. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010106"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Shekhar, S., Liu, Y., Wang, S., Zhang, H., Fang, X., Zhang, J., Fan, L., Zheng, B., Roman, R.J., and Wang, Z. (2021). Novel Mechanistic Insights and Potential Therapeutic Impact of TRPC6 in Neurovascular Coupling and Ischemic Stroke. Int. J. Mol. Sci., 22.","DOI":"10.20944\/preprints202101.0458.v1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1517\/14728222.12.2.159","article-title":"Tissue-type plasminogen activator as a therapeutic target in stroke","volume":"12","author":"Gravanis","year":"2008","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e604","DOI":"10.1016\/j.wneu.2018.11.232","article-title":"Intra-Arterial Tissue Plasminogen Activator Is a Safe Rescue Therapy with Mechanical Thrombectomy","volume":"123","author":"Anadani","year":"2019","journal-title":"World Neurosurg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1001\/archneur.62.11.1763","article-title":"Mechanical thrombectomy following intravenous thrombolysis in the treatment of acute stroke","volume":"62","author":"Lansberg","year":"2005","journal-title":"Arch. Neurol."},{"key":"ref_7","first-page":"1","article-title":"Tissue Plasminogen Activator: Side Effects and Signaling","volume":"1","author":"Lin","year":"2014","journal-title":"J. Drug Des. Res."},{"key":"ref_8","first-page":"81","article-title":"Hemorrhagic transformation after cerebral infarction: Current concepts and challenges","volume":"2","author":"Zhang","year":"2014","journal-title":"Ann. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1016\/S0140-6736(12)60738-7","article-title":"Recombinant tissue plasminogen activator for acute ischaemic stroke: An updated systematic review and meta-analysis","volume":"379","author":"Wardlaw","year":"2012","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3171\/2020.5.JNS192737","article-title":"Direct carotid puncture for mechanical thrombectomy in acute ischemic stroke patients with prohibitive vascular access","volume":"135","author":"Cord","year":"2020","journal-title":"J. Neurosurg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.semcdb.2014.10.004","article-title":"The blood-brain barrier-gatekeeper to neuronal homeostasis: Clinical implications in the setting of stroke","volume":"38","author":"Schoknecht","year":"2015","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S1474-4422(10)70313-6","article-title":"Neurological complications of acute ischaemic stroke","volume":"10","author":"Balami","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/S1474-4422(07)70055-8","article-title":"Brain oedema in focal ischaemia: Molecular pathophysiology and theoretical implications","volume":"6","author":"Simard","year":"2007","journal-title":"Lancet Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2918","DOI":"10.1161\/STROKEAHA.118.022001","article-title":"Early Prediction of Malignant Brain Edema After Ischemic Stroke","volume":"49","author":"Wu","year":"2018","journal-title":"Stroke"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1161\/STROKEAHA.107.490193","article-title":"Antiedema therapy in ischemic stroke","volume":"38","author":"Bardutzky","year":"2007","journal-title":"Stroke"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.1161\/STROKEAHA.115.010665","article-title":"Clinically Confirmed Stroke With Negative Diffusion-Weighted Imaging Magnetic Resonance Imaging: Longitudinal Study of Clinical Outcomes, Stroke Recurrence, and Systematic Review","volume":"46","author":"Makin","year":"2015","journal-title":"Stroke"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1161\/STROKEAHA.111.632943","article-title":"Ischemic cerebral damage: An appraisal of synaptic failure","volume":"43","author":"Hofmeijer","year":"2012","journal-title":"Stroke"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1161\/01.STR.0000013708.54623.DE","article-title":"Persistent defect in transmitter release and synapsin phosphorylation in cerebral cortex after transient moderate ischemic injury","volume":"33","author":"Bolay","year":"2002","journal-title":"Stroke"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/jcbfm.1988.96","article-title":"Ischemic brain edema and the osmotic gradient between blood and brain","volume":"8","author":"Hatashita","year":"1988","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1152\/physiol.00015.2009","article-title":"Molecular mechanisms of ischemic cerebral edema: Role of electroneutral ion transport","volume":"24","author":"Kahle","year":"2009","journal-title":"Physiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"618819","DOI":"10.3389\/fnagi.2020.618819","article-title":"Potential Therapies for Cerebral Edema After Ischemic Stroke: A Mini Review","volume":"12","author":"Yao","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s40478-019-0671-0","article-title":"Endothelial edema precedes blood-brain barrier breakdown in early time points after experimental focal cerebral ischemia","volume":"7","author":"Krueger","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/S0750-7658(03)00010-8","article-title":"Brain oedema following blood-brain barrier disruption: Mechanisms and diagnosis","volume":"22","author":"Payen","year":"2003","journal-title":"Ann. Fr. Anesth. Reanim."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","article-title":"Structure and function of the blood-brain barrier","volume":"37","author":"Abbott","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"157","DOI":"10.5487\/TR.2013.29.3.157","article-title":"Loss of Integrity: Impairment of the Blood-brain Barrier in Heavy Metal-associated Ischemic Stroke","volume":"29","author":"Kim","year":"2013","journal-title":"Toxicol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12987-020-00182-8","article-title":"Autophagy-mediated occludin degradation contributes to blood-brain barrier disruption during ischemia in bEnd.3 brain endothelial cells and rat ischemic stroke models","volume":"17","author":"Kim","year":"2020","journal-title":"Fluids Barriers CNS"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1161\/STROKEAHA.117.017287","article-title":"Role of Autophagy in Endothelial Damage and Blood-Brain Barrier Disruption in Ischemic Stroke","volume":"49","author":"Kim","year":"2018","journal-title":"Stroke"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"C343","DOI":"10.1152\/ajpcell.00095.2018","article-title":"Blood-brain barrier dysfunction in ischemic stroke: Targeting tight junctions and transporters for vascular protection","volume":"315","author":"Abdullahi","year":"2018","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1161\/STROKEAHA.112.673954","article-title":"Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke","volume":"44","author":"Bae","year":"2013","journal-title":"Stroke"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10152","DOI":"10.1096\/fj.201900326R","article-title":"Cilostazol ameliorates ischemia\/reperfusion-induced tight junction disruption in brain endothelial cells by inhibiting endoplasmic reticulum stress","volume":"33","author":"Nan","year":"2019","journal-title":"FASEB J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.1161\/STROKEAHA.107.488502","article-title":"Carnosine is neuroprotective against permanent focal cerebral ischemia in mice","volume":"38","author":"Rajanikant","year":"2007","journal-title":"Stroke"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1006\/bbrc.2000.3881","article-title":"Estimation of gelatinase content in rat brain: Effect of focal ischemia","volume":"278","author":"Planas","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0304-3940(97)00859-8","article-title":"Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia","volume":"238","author":"Clark","year":"1997","journal-title":"Neurosci. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S1474-4422(09)70016-X","article-title":"Matrix metalloproteinases and their multiple roles in neurodegenerative diseases","volume":"8","author":"Rosenberg","year":"2009","journal-title":"Lancet Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2144\/05381RV01","article-title":"Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors","volume":"38","year":"2005","journal-title":"Biotechniques"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1046\/j.1524-475X.1999.00423.x","article-title":"Matrix metalloproteinases in repair","volume":"7","author":"Parks","year":"1999","journal-title":"Wound Repair Regen."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Quilty, F., Byrne, A.M., Aird, J., El Mashad, S., Parra-Blanco, A., Long, A., Gilmer, J.F., and Medina, C. (2020). Impact of Deoxycholic Acid on Oesophageal Adenocarcinoma Invasion: Effect on Matrix Metalloproteinases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218042"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0033-0620(99)70003-4","article-title":"Ischemic brain edema","volume":"42","author":"Rosenberg","year":"1999","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1161\/01.STR.0000046764.57344.31","article-title":"Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke","volume":"34","author":"Castellanos","year":"2003","journal-title":"Stroke"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.freeradbiomed.2005.03.033","article-title":"Matrix metalloproteinases and free radicals in cerebral ischemia","volume":"39","author":"Rosenberg","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.neulet.2004.09.010","article-title":"Reduced brain edema and matrix metalloproteinase (MMP) expression by pre-reperfusion infusion into ischemic territory in rat","volume":"372","author":"Ding","year":"2004","journal-title":"Neurosci. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1038\/jcbfm.2013.56","article-title":"Early inhibition of MMP activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery","volume":"33","author":"Yang","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/jcbfm.2009.248","article-title":"Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement","volume":"30","author":"Bauer","year":"2010","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/sj.jcbfm.9600375","article-title":"Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat","volume":"27","author":"Yang","year":"2007","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/psc.2465","article-title":"Antinociceptive profile of potent opioid peptide AM94, a fluorinated analogue of biphalin with non-hydrazine linker","volume":"19","author":"Mollica","year":"2013","journal-title":"J. Pept. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2174\/138955713804484776","article-title":"Structure-activity relationships of biphalin analogs and their biological evaluation on opioid receptors","volume":"13","author":"Feliciani","year":"2013","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.brainres.2011.01.083","article-title":"Opioid receptor agonists reduce brain edema in stroke","volume":"1383","author":"Yang","year":"2011","journal-title":"Brain Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Albekairi, T.H., Vaidya, B., Patel, R., Nozohouri, S., Villalba, H., Zhang, Y., Lee, Y.S., Al-Ahmad, A., and Abbruscato, T.J. (2019). Brain Delivery of a Potent Opioid Receptor Agonist, Biphalin during Ischemic Stroke: Role of Organic Anion Transporting Polypeptide (OATP). Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11090467"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1124\/jpet.111.184127","article-title":"Characterization of neuroprotective effects of biphalin, an opioid receptor agonist, in a model of focal brain ischemia","volume":"339","author":"Yang","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.brainres.2013.07.004","article-title":"Role of histidine\/histamine in carnosine-induced neuroprotection during ischemic brain damage","volume":"1527","author":"Bae","year":"2013","journal-title":"Brain Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1161\/STROKEAHA.114.005183","article-title":"Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage","volume":"45","author":"Baek","year":"2014","journal-title":"Stroke"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/s41598-020-57685-5","article-title":"LRP-1 functionalized polymersomes enhance the efficacy of carnosine in experimental stroke","volume":"10","author":"Kim","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s00401-009-0541-0","article-title":"Pathology and new players in the pathogenesis of brain edema","volume":"118","author":"Nag","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1016\/j.bmc.2007.01.011","article-title":"Matrix metalloproteinases (MMPs): Chemical-biological functions and (Q)SARs","volume":"15","author":"Verma","year":"2007","journal-title":"Bioorg. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0006-8993(99)02215-5","article-title":"Endogenous mechanisms of neuroprotection: Role of zinc, copper, and carnosine","volume":"852","author":"Horning","year":"2000","journal-title":"Brain Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.pneurobio.2017.10.001","article-title":"Blood-brain barrier dysfunction and recovery after ischemic stroke","volume":"163\u2013164","author":"Jiang","year":"2018","journal-title":"Prog. Neurobiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"339","DOI":"10.5455\/medarh.2016.70.339-341","article-title":"Brain Edema After Ischaemic Stroke","volume":"70","author":"Dostovic","year":"2016","journal-title":"Med. Arch."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"707","DOI":"10.3109\/00207454.2013.872102","article-title":"The significance of matrix metalloproteinase (MMP)-2 and MMP-9 in the ischemic stroke","volume":"124","author":"Kurzepa","year":"2014","journal-title":"Int. J. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Machado, L.S., Kozak, A., Ergul, A., Hess, D.C., Borlongan, C.V., and Fagan, S.C. (2006). Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci., 7.","DOI":"10.1186\/1471-2202-7-56"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12974-019-1516-2","article-title":"Neuroinflammation: Friend and foe for ischemic stroke","volume":"16","author":"Jayaraj","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3323","DOI":"10.1161\/STROKEAHA.110.608257","article-title":"Blood-brain barrier breakdown in acute and chronic cerebrovascular disease","volume":"42","author":"Yang","year":"2011","journal-title":"Stroke"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.brainres.2015.04.024","article-title":"Matrix metalloproteinases as therapeutic targets for stroke","volume":"1623","author":"Yang","year":"2015","journal-title":"Brain Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.bbamcr.2013.12.006","article-title":"Nitric oxide-matrix metaloproteinase-9 interactions: Biological and pharmacological significance\u2014NO and MMP-9 interactions","volume":"1843","author":"Medina","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Kawahara, M., Tanaka, K.I., and Kato-Negishi, M. (2018). Zinc, Carnosine, and Neurodegenerative Diseases. Nutrients, 10.","DOI":"10.3390\/nu10020147"},{"key":"ref_65","first-page":"807","article-title":"Interactions between carnosine and zinc and copper: Implications for neuromodulation and neuroprotection","volume":"65","author":"Trombley","year":"2000","journal-title":"Biochemistry"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1111\/1440-1681.12587","article-title":"Characterisation of a mouse cerebral microvascular endothelial cell line (bEnd.3) after oxygen glucose deprivation and reoxygenation","volume":"43","author":"Ku","year":"2016","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Kim, D., Kim, K.A., Kim, J.H., Kim, E.H., and Bae, O.N. (2020). Methylglyoxal-Induced Dysfunction in Brain Endothelial Cells via the Suppression of Akt\/HIF-1alpha Pathway and Activation of Mitophagy Associated with Increased Reactive Oxygen Species. Antioxidants, 9.","DOI":"10.3390\/antiox9090820"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Kim, D., Kim, E.H., Choi, S., Lim, K.M., Tie, L., Majid, A., and Bae, O.N. (2021). A Commonly Used Biocide 2-N-octyl-4-isothiazolin-3-oneInduces Blood-Brain Barrier Dysfunction via Cellular Thiol Modification and Mitochondrial Damage. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052563"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.nbd.2008.08.005","article-title":"Blood-brain barrier tight junction permeability and ischemic stroke","volume":"32","author":"Sandoval","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Szarka, N., Toth, L., Czigler, A., Kellermayer, Z., Ungvari, Z., Amrein, K., Czeiter, E., Bali, Z.K., Tadepalli, S.A., and Wahr, M. (2019). Single Mild Traumatic Brain Injury Induces Persistent Disruption of the Blood-Brain Barrier, Neuroinflammation and Cognitive Decline in Hypertensive Rats. Int. J. Mol. 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