Abstract
The current study aimed to investigate the protective effect of resveratrol (RSV) on neurovascular units (NVUs) in rats induced by acute cerebral ischemia. RSV could reduce the damage to I/R rats, and the optimal concentration was 40 mg/kg/d. RSV may improve the permeability of the BBB and the destruction of its ultrastructure by upregulating ZO-1, claudin-5, and occludin to reduce the degree of brain edema after IR. Many structures in the NVUs were also damaged after I/R. RSV was found to have a protective effect on NeuN, GFAP, and LN in the NVUs. With the extension of RSV administration time, the protective effect became more significant. This protective effect may be related to the upregulation of NeuN and LN and the inhibition of the expression of GFAP. RSV could reduce neuronal apoptosis by upregulating XIAP and downregulating Smac and caspase-9. The inhibition of RSV on the increase in glial cells may be related to the inhibition of connexin 43 protein expression. RSV could inhibit the content of inflammatory factors IL-1β, IL-6, and TNF-α in the brain tissue of IR rats. RSV has a protective effect on the NVUs-induced injury, which may be related to the regulation of apoptosis and inflammatory signal pathway.
Keywords: Resveratrol, ischemia/reperfusion, BBB, neurovascular unit, claudin-5, cerebral apoplexy.
Graphical Abstract
[1]
Barakat, R.; Redzic, Z. The role of activated microglia and resident macrophages in the neurovascular unit during cerebral ischemia: Is the jury still out? Med. Princ. Pract., 2016, 25(Suppl. 1), 3-14.
[http://dx.doi.org/10.1159/000435858] [PMID: 26303836]
[http://dx.doi.org/10.1159/000435858] [PMID: 26303836]
[2]
Wang, W.; Jiang, B.; Sun, H.; Ru, X.; Sun, D.; Wang, L.; Wang, L.; Jiang, Y.; Li, Y.; Wang, Y.; Chen, Z.; Wu, S.; Zhang, Y.; Wang, D.; Wang, Y.; Feigin, V.L. Prevalence, incidence, and mortality of stroke in China: Results from a nationwide population-based survey of 480 687 adults. Circulation, 2017, 135(8), 759-771.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.025250] [PMID: 28052979]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.025250] [PMID: 28052979]
[3]
Liu, Z.; Chen, X.; Gao, Y.; Sun, S.; Yang, L.; Yang, Q.; Bai, F.; Xiong, L.; Wang, Q. Involvement of GluR2 up-regulation in neuroprotection by electroacupuncture pretreatment via cannabinoid CB1 receptor in mice. Sci. Rep., 2015, 5, 9490.
[http://dx.doi.org/10.1038/srep09490] [PMID: 25830356]
[http://dx.doi.org/10.1038/srep09490] [PMID: 25830356]
[4]
Sheth, K.N.; Smith, E.E.; Grau-Sepulveda, M.V.; Kleindorfer, D.; Fonarow, G.C.; Schwamm, L.H. Drip and ship thrombolytic therapy for acute ischemic stroke: Use, temporal trends, and outcomes. Stroke, 2015, 46(3), 732-739.
[http://dx.doi.org/10.1161/STROKEAHA.114.007506] [PMID: 25672784]
[http://dx.doi.org/10.1161/STROKEAHA.114.007506] [PMID: 25672784]
[5]
Correction To: 2018 guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from The American Heart Association/American Stroke Association. Stroke, 2018, 49(3), 138. Correction to: 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018 Jun;49(6):e233-e234
[http://dx.doi.org/10.1161/STR.0000000000000172] [PMID: 29669864] [http://dx.doi.org/10.1161/STR.0000000000000163] [PMID: 29483362 ]
[http://dx.doi.org/10.1161/STR.0000000000000172] [PMID: 29669864] [http://dx.doi.org/10.1161/STR.0000000000000163] [PMID: 29483362 ]
[6]
Matsuo, R.; Kamouchi, M.; Ago, T.; Hata, J.; Shono, Y.; Kuroda, J.; Wakisaka, Y.; Sugimori, H.; Kitazono, T. Thrombolytic therapy with intravenous recombinant tissue plasminogen activator in Japanese older patients with acute ischemic stroke: Fukuoka Stroke Registry. Geriatr. Gerontol. Int., 2014, 14(4), 954-959.
[http://dx.doi.org/10.1111/ggi.12205] [PMID: 24320947]
[http://dx.doi.org/10.1111/ggi.12205] [PMID: 24320947]
[7]
Fletcher, L.; Evans, T.M.; Watts, L.T.; Jimenez, D.F.; Digicaylioglu, M. Rapamycin treatment improves neuron viability in an in vitro model of stroke. PLoS One, 2013, 8(7)e68281
[http://dx.doi.org/10.1371/journal.pone.0068281] [PMID: 23861877]
[http://dx.doi.org/10.1371/journal.pone.0068281] [PMID: 23861877]
[8]
Hilbert, T.; Klaschik, S. The angiopoietin/TIE receptor system: Focusing its role for ischemia-reperfusion injury. Factor. Rev., 2015, 26(3), 281-291.
[http://dx.doi.org/10.1016/j.cytogfr.2014.10.013] [PMID: 25466648]
[http://dx.doi.org/10.1016/j.cytogfr.2014.10.013] [PMID: 25466648]
[9]
Atochin, D.N.; Schepetkin, I.A.; Khlebnikov, A.I.; Seledtsov, V.I.; Swanson, H.; Quinn, M.T.; Huang, P.L. A novel dual NO-donating oxime and c-Jun N-terminal kinase inhibitor protects against cerebral ischemia-reperfusion injury in mice. Neurosci. Lett., 2016, 618, 45-49.
[http://dx.doi.org/10.1016/j.neulet.2016.02.033] [PMID: 26923672]
[http://dx.doi.org/10.1016/j.neulet.2016.02.033] [PMID: 26923672]
[10]
Xue, Q.; Liu, Y.; Qi, H.; Ma, Q.; Xu, L.; Chen, W.; Chen, G.; Xu, X. A novel brain neurovascular unit model with neurons, astrocytes and microvascular endothelial cells of rat. Int. J. Biol. Sci., 2013, 9(2), 174-189.
[http://dx.doi.org/10.7150/ijbs.5115] [PMID: 23412420]
[http://dx.doi.org/10.7150/ijbs.5115] [PMID: 23412420]
[11]
Sulhan, S.; Lyon, K.A.; Shapiro, L.A.; Huang, J.H. Neuroinflammation and blood-brain barrier disruption following traumatic brain injury: Pathophysiology and potential therapeutic targets. J. Neurosci. Res., 2020, 98(1), 19-28.
[http://dx.doi.org/10.1002/jnr.24331] [PMID: 30259550]
[http://dx.doi.org/10.1002/jnr.24331] [PMID: 30259550]
[12]
Venkat, P.; Chopp, M.; Chen, J. Blood-brain barrier disruption, vascular impairment, and ischemia/reperfusion damage in diabetic stroke. J. Am. Heart Assoc., 2017, 6(6), 6.
[http://dx.doi.org/10.1161/JAHA.117.005819] [PMID: 28572280]
[http://dx.doi.org/10.1161/JAHA.117.005819] [PMID: 28572280]
[13]
Xu, D.; Bureau, Y.; McIntyre, D.C.; Nicholson, D.W.; Liston, P.; Zhu, Y.; Fong, W.G.; Crocker, S.J.; Korneluk, R.G.; Robertson, G.S. Attenuation of ischemia-induced cellular and behavioral deficits by X chromosome-linked inhibitor of apoptosis protein overexpression in the rat hippocampus. J. Neurosci., 1999, 19(12), 5026-5033.
[http://dx.doi.org/10.1523/JNEUROSCI.19-12-05026.1999] [PMID: 10366635]
[http://dx.doi.org/10.1523/JNEUROSCI.19-12-05026.1999] [PMID: 10366635]
[14]
Morizane, Y.; Honda, R.; Fukami, K.; Yasuda, H. X-linked inhibitor of apoptosis functions as ubiquitin ligase toward mature caspase-9 and cytosolic Smac/DIABLO. J. Biochem., 2005, 137(2), 125-132.
[http://dx.doi.org/10.1093/jb/mvi029] [PMID: 15749826]
[http://dx.doi.org/10.1093/jb/mvi029] [PMID: 15749826]
[15]
Saito, A.; Hayashi, T.; Okuno, S.; Nishi, T.; Chan, P.H. Oxidative stress is associated with XIAP and Smac/DIABLO signaling pathways in mouse brains after transient focal cerebral ischemia. Stroke, 2004, 35(6), 1443-1448.
[http://dx.doi.org/10.1161/01.STR.0000128416.28778.7a] [PMID: 15118177]
[http://dx.doi.org/10.1161/01.STR.0000128416.28778.7a] [PMID: 15118177]
[16]
Sáez, P.J.; Shoji, K.F.; Retamal, M.A.; Harcha, P.A.; Ramírez, G.; Jiang, J.X.; von Bernhardi, R.; Sáez, J.C. ATP is required and advances cytokine-induced gap junction formation in microglia in vitro. Mediators Inflamm., 2013, 2013216402
[http://dx.doi.org/10.1155/2013/216402] [PMID: 23737642]
[http://dx.doi.org/10.1155/2013/216402] [PMID: 23737642]
[17]
Hou, S.; Shen, P.P.; Zhao, M.M.; Liu, X.P.; Xie, H.Y.; Deng, F.; Feng, J.C. Mechanism of mitochondrial connexin43's protection of the neurovascular unit under acute cerebral ischemia-reperfusion injury. Int. J. Mol. Sci., 2016, 17(5), 679.
[http://dx.doi.org/10.3390/ijms17050679] [PMID: 27164087]
[http://dx.doi.org/10.3390/ijms17050679] [PMID: 27164087]
[18]
Shin, J.A.; Lee, K.E.; Kim, H.S.; Park, E.M. Acute resveratrol treatment modulates multiple signaling pathways in the ischemic brain. Neurochem. Res., 2012, 37(12), 2686-2696.
[http://dx.doi.org/10.1007/s11064-012-0858-2] [PMID: 22878646]
[http://dx.doi.org/10.1007/s11064-012-0858-2] [PMID: 22878646]
[19]
Yang, J.; Huang, J.; Shen, C.; Cheng, W.; Yu, P.; Wang, L.; Tang, F.; Guo, S.; Yang, Q.; Zhang, J. Resveratrol treatment in different time-attenuated neuronal apoptosis after oxygen and glucose deprivation/reoxygenation via enhancing the activation of Nrf-2 signaling pathway in vitro. Cell Transplant., 2018, 27(12), 1789-1797.
[http://dx.doi.org/10.1177/0963689718780930] [PMID: 30008229]
[http://dx.doi.org/10.1177/0963689718780930] [PMID: 30008229]
[20]
Longa, E.Z.; Weinstein, P.R.; Carlson, S.; Cummins, R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke, 1989, 20(1), 84-91.
[http://dx.doi.org/10.1161/01.STR.20.1.84] [PMID: 2643202]
[http://dx.doi.org/10.1161/01.STR.20.1.84] [PMID: 2643202]
[21]
Yang, H.; Zhang, A.; Zhang, Y.; Ma, S.; Wang, C. Resveratrol pretreatment protected against cerebral ischemia/reperfusion injury in rats via expansion of T regulatory cells. J. Stroke Cerebrovasc. Dis., 2016, 25(8), 1914-1921.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.04.014] [PMID: 27184615]
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.04.014] [PMID: 27184615]
[22]
Chang, C.; Zhao, Y.; Song, G.; She, K. Resveratrol protects hippocampal neurons against cerebral ischemia-reperfusion injury via modulating JAK/ERK/STAT signaling pathway in rats. J. Neuroimmunol., 2018, 315, 9-14.
[http://dx.doi.org/10.1016/j.jneuroim.2017.11.015] [PMID: 29306408]
[http://dx.doi.org/10.1016/j.jneuroim.2017.11.015] [PMID: 29306408]
[23]
Liu, Y.; Yang, H.; Jia, G.; Li, L.; Chen, H.; Bi, J.; Wang, C. The synergistic neuroprotective effects of combined rosuvastatin and resveratrol pretreatment against cerebral ischemia/reperfusion injury. J. Stroke Cerebrovasc. Dis., 2018, 27(6), 1697-1704.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.01.033] [PMID: 29525080]
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.01.033] [PMID: 29525080]
[24]
Jiang, X.; Andjelkovic, A.V.; Zhu, L.; Yang, T.; Bennett, M.V.L.; Chen, J.; Keep, R.F.; Shi, Y. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog. Neurobiol., 2018, 163-164, 144-171.
[http://dx.doi.org/10.1016/j.pneurobio.2017.10.001] [PMID: 28987927]
[http://dx.doi.org/10.1016/j.pneurobio.2017.10.001] [PMID: 28987927]
[25]
Li, W.; Tan, C.; Liu, Y.; Liu, X.; Wang, X.; Gui, Y.; Qin, L.; Deng, F.; Yu, Z.; Hu, C.; Chen, L. Resveratrol ameliorates oxidative stress and inhibits aquaporin 4 expression following rat cerebral ischemia-reperfusion injury. Mol. Med. Rep., 2015, 12(5), 7756-7762.
[http://dx.doi.org/10.3892/mmr.2015.4366] [PMID: 26458999]
[http://dx.doi.org/10.3892/mmr.2015.4366] [PMID: 26458999]
[26]
Weller, R.O.; Sharp, M.M.; Christodoulides, M.; Carare, R.O.; Møllgård, K. The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS. Acta Neuropathol., 2018, 135(3), 363-385.
[http://dx.doi.org/10.1007/s00401-018-1809-z] [PMID: 29368214]
[http://dx.doi.org/10.1007/s00401-018-1809-z] [PMID: 29368214]
[27]
Greene, C.; Campbell, M. Tight junction modulation of the blood brain barrier: CNS delivery of small molecules. Tissue Barriers, 2016, 4(1)e1138017
[http://dx.doi.org/10.1080/21688370.2015.1138017] [PMID: 27141420]
[http://dx.doi.org/10.1080/21688370.2015.1138017] [PMID: 27141420]
[28]
Lin, S.; Zhou, G.; Shao, W.; Fu, Z. Impact of dexmedetomidine on amino acid contents and the cerebral ultrastructure of rats with cerebral ischemia-reperfusion injury. Acta Cir. Bras., 2017, 32(6), 459-466.
[http://dx.doi.org/10.1590/s0102-865020170060000006] [PMID: 28700007]
[http://dx.doi.org/10.1590/s0102-865020170060000006] [PMID: 28700007]
[29]
Girolamo, F.; Errede, M.; Bizzoca, A.; Virgintino, D.; Ribatti, D. Central nervous system pericytes contribute to health and disease. Cells, 2022, 11(10), 1707.
[http://dx.doi.org/10.3390/cells11101707] [PMID: 35626743]
[http://dx.doi.org/10.3390/cells11101707] [PMID: 35626743]
[30]
Fisher, M. Ischemic cerebral vascular disease: An overview. Arq. Neuropsiquiatr., 1991, 49(1), 1-10.
[http://dx.doi.org/10.1590/s0004-282x1991000100001] [PMID: 1863232]
[http://dx.doi.org/10.1590/s0004-282x1991000100001] [PMID: 1863232]
[31]
Gusel’nikova, V.V.; Korzhevskiy, D.E. NeuN as a neuronal nuclear antigen and neuron differentiation marker. Acta Nat. (Engl. Ed.), 2015, 7(2), 42-47.
[http://dx.doi.org/10.32607/20758251-2015-7-2-42-47] [PMID: 26085943]
[http://dx.doi.org/10.32607/20758251-2015-7-2-42-47] [PMID: 26085943]
[32]
Kirkley, K.S.; Popichak, K.A.; Afzali, M.F.; Legare, M.E.; Tjalkens, R.B. Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity. J. Neuroinflammation, 2017, 14(1), 99.
[http://dx.doi.org/10.1186/s12974-017-0871-0] [PMID: 28476157]
[http://dx.doi.org/10.1186/s12974-017-0871-0] [PMID: 28476157]
[33]
Sun, D.; Lye-Barthel, M.; Masland, R.H.; Jakobs, T.C. Structural remodeling of fibrous astrocytes after axonal injury. J. Neurosci., 2010, 30(42), 14008-14019.
[http://dx.doi.org/10.1523/JNEUROSCI.3605-10.2010] [PMID: 20962222]
[http://dx.doi.org/10.1523/JNEUROSCI.3605-10.2010] [PMID: 20962222]
[34]
Li, W.; Huang, R.; Shetty, R.A.; Thangthaeng, N.; Liu, R.; Chen, Z.; Sumien, N.; Rutledge, M.; Dillon, G.H.; Yuan, F.; Forster, M.J.; Simpkins, J.W.; Yang, S.H. Transient focal cerebral ischemia induces long-term cognitive function deficit in an experimental ischemic stroke model. Neurobiol. Dis., 2013, 59, 18-25.
[http://dx.doi.org/10.1016/j.nbd.2013.06.014] [PMID: 23845275]
[http://dx.doi.org/10.1016/j.nbd.2013.06.014] [PMID: 23845275]
[35]
Chen, S.H.; Sun, H.; Zhang, Y.M.; Xu, H.; Yang, Y.; Wang, F.M. Effects of acupuncture at Baihui (GV 20) and Zusanli (ST 36) on peripheral serum expression of MicroRNA 124, laminin and integrin β1 in rats with cerebral ischemia reperfusion injury. Chin. J. Integr. Med., 2016, 22(1), 49-55.
[http://dx.doi.org/10.1007/s11655-015-2112-7] [PMID: 26424293]
[http://dx.doi.org/10.1007/s11655-015-2112-7] [PMID: 26424293]
[36]
Liu, L.R.; Liu, J.C.; Bao, J.S.; Bai, Q.Q.; Wang, G.Q. Interaction of microglia and astrocytes in the neurovascular unit. Front. Immunol., 2020, 11, 1024.
[http://dx.doi.org/10.3389/fimmu.2020.01024] [PMID: 32733433]
[http://dx.doi.org/10.3389/fimmu.2020.01024] [PMID: 32733433]
[37]
Li, H.; Wang, D. Mild hypothermia improves ischemic brain function via attenuating neuronal apoptosis. Brain Res., 2011, 1368, 59-64.
[http://dx.doi.org/10.1016/j.brainres.2010.10.073] [PMID: 20977899]
[http://dx.doi.org/10.1016/j.brainres.2010.10.073] [PMID: 20977899]
[38]
Li, S.; Peng, W.; Chen, X.; Geng, X.; Zhan, W.; Sun, J. Expression and role of gap junction protein connexin43 in immune challenge-induced extracellular ATP release in Japanese flounder (Paralichthys olivaceus). Shellfish Immunol., 2016, 55, 348-357.
[http://dx.doi.org/10.1016/j.fsi.2016.06.014] [PMID: 27291350]
[http://dx.doi.org/10.1016/j.fsi.2016.06.014] [PMID: 27291350]
[39]
Zhao, M.; Hou, S.; Feng, L.; Shen, P.; Nan, D.; Zhang, Y.; Wang, F.; Ma, D.; Feng, J. Vinpocetine protects against cerebral ischemia-reperfusion injury by targeting astrocytic connexin43 via the PI3K/AKT signaling pathway. Front. Neurosci., 2020, 14, 223.
[http://dx.doi.org/10.3389/fnins.2020.00223] [PMID: 32300287]
[http://dx.doi.org/10.3389/fnins.2020.00223] [PMID: 32300287]
[40]
He, Q.; Li, Z.; Wang, Y.; Hou, Y.; Li, L.; Zhao, J. Resveratrol alleviates cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy induction. Int. Immunopharmacol., 2017, 50, 208-215.
[http://dx.doi.org/10.1016/j.intimp.2017.06.029] [PMID: 28683365]
[http://dx.doi.org/10.1016/j.intimp.2017.06.029] [PMID: 28683365]
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