Abstract
The collapse of the blood-brain barrier (BBB) is one of the fundamental pathophysiology changes during cerebral ischemia reperfusion injury. Resveratrol has been recently reported to reduce cerebral ischemic damage by regulating the matrix metalloproteinase-9 (MMP-9). But, more direct evidence for the explanation of the BBB protected by resveratrol against cerebral ischemia reperfusion is still lacking. Therefore, the present study was aimed to investigate the regulation of BBB integrity by resveratrol after cerebral ischemia reperfusion and to determine the role of the MMP-9 and its endogenous inhibitor TIMP-1 balance in this process. Cerebral ischemia was induced by middle cerebral artery occlusion in rats. The BBB function was evaluated by brain water content and the Evans blue dye extravasation; the activities of MMP-9 and TIMP-1 were detected by using gelatin zymography analysis, and cellular apoptosis was examined by TUNEL staining. We confirmed that resveratrol reduced the cerebral ischemia reperfusion damage, brain edema, and Evans blue dye extravasation. Moreover, we found that resveratrol improved the balance of MMP-9/TIMP-1 in terms of their expressions and activities. A TIMP-1 neutralizing antibody reversed those neuroprotective effects of resveratrol. In conclusion, resveratrol attenuated the cerebral ischemia by maintaining the integrity of BBB via regulation of MMP-9 and TIMP-1.
Similar content being viewed by others
References
Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7(1):41–53
Asahi M, Asahi K, Jung JC, Del ZG, Fini ME, Lo EH (2000) Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab 20(12):1681–1689
Ashwal S, Tone B, Tian HR, Cole DJ, Pearce WJ (1998) Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion. Stroke 29(5):1037–1046, 1047
Belayev L, Busto R, Ikeda M, Rubin LL, Kajiwara A, Morgan L, Ginsberg MD (1998) Protection against blood–brain barrier disruption in focal cerebral ischemia by the type IV phosphodiesterase inhibitor BBB022: a quantitative study. Brain Res 787(2):277–285
Belayev L, Busto R, Zhao W, Fernandez G, Ginsberg MD (1999) Middle cerebral artery occlusion in the mouse by intraluminal suture coated with poly-L-lysine: neurological and histological validation. Brain Res 833(2):181–190
Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477(1–2):267–283
Chen HY, Chen TY, Lee MY, Chen ST, Hsu YS, Kuo YL, Chang GL, Wu TS, Lee EJ (2006) Melatonin decreases neurovascular oxidative/nitrosative damage and protects against early increases in the blood-brain barrier permeability after transient focal cerebral ischemia in mice. J Pineal Res 41(2):175–182
Chen F, Radisky ES, Das P, Batra J, Hata T, Hori T, Baine AM, Gardner L, Yue MY, Bu G, Del ZG, Patel TC, Nguyen JH (2013) TIMP-1 attenuates blood-brain barrier permeability in mice with acute liver failure. J Cereb Blood Flow Metab 33(7):1041–1049
Cheng G, Zhang X, Gao D, Jiang X, Dong W (2009) Resveratrol inhibits MMP-9 expression by up-regulating PPAR alpha expression in an oxygen glucose deprivation-exposed neuron model. Neurosci Lett 451(2):105–108
Desilles JP, Rouchaud A, Labreuche J, Meseguer E, Laissy JP, Serfaty JM, Lapergue B, Klein IF, Guidoux C, Cabrejo L, Sirimarco G, Lavallee PC, Schouman-Claeys E, Amarenco P, Mazighi M (2013) Blood-brain barrier disruption is associated with increased mortality after endovascular therapy. Neurology 80(9):844–851
Dong W, Gao D, Lin H, Zhang X, Li N, Li F (2008) New insights into mechanism for the effect of resveratrol preconditioning against cerebral ischemic stroke: Possible role of matrix metalloprotease-9. Med Hypotheses 70(1):52–55
Dziembowska M, Wlodarczyk J (2012) MMP9: a novel function in synaptic plasticity. Int J Biochem Cell Biol 44(5):709–713
Fujimoto M, Takagi Y, Aoki T, Hayase M, Marumo T, Gomi M, Nishimura M, Kataoka H, Hashimoto N, Nozaki K (2008) Tissue inhibitor of metalloproteinases protect blood-brain barrier disruption in focal cerebral ischemia. J Cereb Blood Flow Metab 28(10):1674–1685
Garcia JH, Wagner S, Liu KF, Hu XJ (1995) Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. statistical validation. Stroke 26(4):627–634, 635
Hao HD, He LR (2004) Mechanisms of cardiovascular protection by resveratrol. J Med Food 7(3):290–298
Ichiyama T, Kajimoto M, Suenaga N, Maeba S, Matsubara T, Furukawa S (2006) Serum levels of matrix metalloproteinase-9 and its tissue inhibitor (TIMP-1) in acute disseminated encephalomyelitis. J Neuroimmunol 172(1–2):182–186
Khan M, Dhammu TS, Sakakima H, Shunmugavel A, Gilg AG, Singh AK, Singh I (2012) The inhibitory effect of S-nitrosoglutathione on blood–brain barrier disruption and peroxynitrite formation in a rat model of experimental stroke. J Neurochem 123(Suppl 2):86–97
Lee H, Park JW, Kim SP, Lo EH, Lee SR (2009) Doxycycline inhibits matrix metalloproteinase-9 and laminin degradation after transient global cerebral ischemia. Neurobiol Dis 34(2):189–198
Lin YL, Chang HC, Chen TL, Chang JH, Chiu WT, Lin JW, Chen RM (2010) Resveratrol protects against oxidized LDL-induced breakage of the blood-brain barrier by lessening disruption of tight junctions and apoptotic insults to mouse cerebrovascular endothelial cells. J Nutr 140(12):2187–2192
Malemud CJ (2006) Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci 11:1696–1701
Marchal J, Pifferi F, Aujard F (2013) Resveratrol in mammals: effects on aging biomarkers, age-related diseases, and life span. Ann N Y Acad Sci 1290(1):67–73
Olas B, Saluk-Juszczak J, Wachowicz B (2008) D-glucaro 1,4-lactone and resveratrol as antioxidants in blood platelets. Cell Biol Toxicol 24(2):189–199
Rahal K, Schmiedlin-Ren P, Adler J, Dhanani M, Sultani V, Rittershaus AC, Reingold L, Zhu J, McKenna BJ, Christman GM, Zimmermann EM (2012) Resveratrol has antiinflammatory and antifibrotic effects in the peptidoglycan-polysaccharide rat model of Crohn’s disease. Inflamm Bowel Dis 18(4):613–623
Raval AP, Lin HW, Dave KR, Defazio RA, Della MD, Kim EJ, Perez-Pinzon MA (2008) Resveratrol and ischemic preconditioning in the brain. Curr Med Chem 15(15):1545–1551
Rosenberg GA (2002) Matrix metalloproteinases in neuroinflammation. Glia 39(3):279–291
Rosenberg GA, Estrada EY, Dencoff JE (1998) Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 29(10):2189–2195
Saha A, Sarkar C, Singh SP, Zhang Z, Munasinghe J, Peng S, Chandra G, Kong E, Mukherjee AB (2012) The blood-brain barrier is disrupted in a mouse model of infantile neuronal ceroid lipofuscinosis: amelioration by resveratrol. Hum Mol Genet 21(10):2233–2244
Sakata Y, Zhuang H, Kwansa H, Koehler RC, Dore S (2010) Resveratrol protects against experimental stroke: putative neuroprotective role of heme oxygenase 1. Exp Neurol 224(1):325–329
Shao AW, Wu HJ, Chen S, Ammar AB, Zhang JM, Hong Y. (2013) Resveratrol attenuates early brain injury after subarachnoid hemorrhage through inhibition of NF-kappaB-dependent inflammatory/MMP-9 pathway. CNS Neurosci Ther
Siflinger-Birnboim A, Del VP, Cooper JA, Blumenstock FA, Shepard JM, Malik AB (1987) Molecular sieving characteristics of the cultured endothelial monolayer. J Cell Physiol 132(1):111–117
Souvenir R, Fathali N, Ostrowski RP, Lekic T, Zhang JH, Tang J (2011) Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia. Neurobiol Dis 44(1):28–37
Stetler-Stevenson WG (2008) Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal 1(27):e6
Tan HK, Heywood D, Ralph GS, Bienemann A, Baker AH, Uney JB (2003) Tissue inhibitor of metalloproteinase 1 inhibits excitotoxic cell death in neurons. Mol Cell Neurosci 22(1):98–106
Wang X, Barone FC, White RF, Feuerstein GZ (1998) Subtractive cloning identifies tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) increased gene expression following focal stroke. Stroke 29(2):516–520
Woo MS, Park JS, Choi IY, Kim WK, Kim HS (2008) Inhibition of MMP-3 or -9 suppresses lipopolysaccharide-induced expression of proinflammatory cytokines and iNOS in microglia. J Neurochem 106(2):770–780
Xiong L, Zheng Y, Wu M, Hou L, Zhu Z, Zhang X, Lu Z (2003) Preconditioning with isoflurane produces dose-dependent neuroprotection via activation of adenosine triphosphate-regulated potassium channels after focal cerebral ischemia in rats. Anesth Analg 96(1):233–237
Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2):178–201
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Grant No. 43411C1071), the Changjiang Scholars and Innovative Research Team in University (Grant IRT1053), and the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (Grant 2012BA111B02). The authors greatly appreciate the help provided by Miss Yaoying Yu and thank Dr. Bairen Wang for carefully reading the manuscript.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Drs. Haidong Wei and Shiquan Wang contributed equally to this work.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
ESM 1
(GIF 121 kb)
Rights and permissions
About this article
Cite this article
Wei, H., Wang, S., Zhen, L. et al. Resveratrol Attenuates the Blood-Brain Barrier Dysfunction by Regulation of the MMP-9/TIMP-1 Balance after Cerebral Ischemia Reperfusion in Rats. J Mol Neurosci 55, 872–879 (2015). https://doi.org/10.1007/s12031-014-0441-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-014-0441-1