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Protein & Peptide Letters

Author(s): Zhigang Qin* and Younian Xu

DOI: 10.2174/0109298665254683231122065717

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Dexmedetomidine Alleviates Brain Ischemia/Reperfusion Injury by Regulating Metastasis-associated Lung Adenocarcinoma Transcript 1/MicroRNA-140-5p/ Nuclear Factor Erythroid-derived 2-like 2 Axis

Page: [116 - 127] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Background: Dexmedetomidine (Dex) is widely used in perioperative anesthesia, and recent studies have reported that it protects organs from ischemia/reperfusion (I/R) injury.

Objectives: This study was performed to investigate the role of Dex in alleviating cerebral I/R injury and its regulatory effects on metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-140-5p (miR-140-5p)/nuclear factor erythroid-derived 2-like 2 (Nrf2) axis.

Methods: In vivo rat middle cerebral artery occlusion (MCAO) model and in vitro oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced neuronal injury model were constructed. Dex was injected into the animals or used to culture HT22 cells to observe the pharmacological effects. The neurological defect, brain water content, infarct volume of the rats, and neuron viability were evaluated. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were detected. Besides, the regulatory effects of Dex on MALAT1, miR-140-5p, and Nrf2 expression levels and regulatory relationships among them were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and dual- luciferase reporter assay.

Results: Dex significantly alleviated the neurological injury of rats with MCAO and promoted the viability of neurons. Dex treatment suppressed miR-140-5p expression, but elevated MALAT1 and Nrf2 expressions. MALAT1 knockdown down-regulated Nrf2 expression and promoted oxidative stress in neurons. Additionally, miR-140-5p directly targeted Nrf2, and it also functioned as a downstream target miRNA of MALAT1.

Conclusion: Dex, via regulating MALAT1/miR-140-5p/Nrf2 axis, plays a neuroprotective role against I/R-induced brain injury.

Graphical Abstract

[1]
Alkutbi, A.; Binmahfooz, S.; AlSaidlani, R.H.; Albeirouti, R.B.; Kamal, O.; Alalawi, H.; Aljehani, M.N.; Khared, M.; Ayoub, O.A. Clinical characteristics of ischemic stroke patients <50 years old at a university hospital: A retrospective descriptive study. Cureus, 2023, 15(8), e43752.
[http://dx.doi.org/10.7759/cureus.43752] [PMID: 37746368]
[2]
Gerschenfeld, G.; Muresan, I.P.; Blanc, R.; Obadia, M.; Abrivard, M.; Piotin, M.; Alamowitch, S. Two paradigms for endovascular thrombectomy after intravenous thrombolysis for acute ischemic stroke. JAMA Neurol., 2017, 74(5), 549-556.
[http://dx.doi.org/10.1001/jamaneurol.2016.5823] [PMID: 28319240]
[3]
Wetzel, M.D.; Wenke, J.C. Mechanisms by which hydrogen sulfide attenuates muscle function following ischemia–reperfusion injury: effects on Akt signaling, mitochondrial function, and apoptosis. J. Transl. Med., 2019, 17(1), 33.
[http://dx.doi.org/10.1186/s12967-018-1753-7] [PMID: 30665344]
[4]
Wang, Z.; Higashikawa, K.; Yasui, H.; Kuge, Y.; Ohno, Y.; Kihara, A.; Midori, Y.A.; Houkin, K.; Kawabori, M. FTY720 protects against ischemia–reperfusion injury by preventing the redistribution of tight junction proteins and decreases inflammation in the subacute phase in an experimental stroke model. Transl. Stroke Res., 2020, 11(5), 1103-1116.
[http://dx.doi.org/10.1007/s12975-020-00789-x] [PMID: 32103462]
[5]
Wang, J.; Mao, J.; Wang, R.; Li, S.; Wu, B.; Yuan, Y. Kaempferol protects against cerebral ischemia reperfusion injury through intervening oxidative and inflammatory stress induced apoptosis. Front. Pharmacol., 2020, 11, 424.
[http://dx.doi.org/10.3389/fphar.2020.00424] [PMID: 32351385]
[6]
Li, M.; Liu, M.; Cui, Q.; Zeng, M.; Li, S.; Zhang, L.; Peng, Y. Effect of dexmedetomidine on postoperative delirium in patients undergoing awake craniotomies: Study protocol of a randomized controlled trial. Trials, 2023, 24(1), 607.
[http://dx.doi.org/10.1186/s13063-023-07632-2] [PMID: 37743486]
[7]
Lyu, J.; Zhou, Y.; Zhang, M.; Tang, L.; Bao, X.; Sun, Z.; Huang, L.; Zhao, L. Neuroprotective effect of dexmedetomidine on cerebral ischemia-reperfusion injury in rats. Altern. Ther. Health Med., 2023, 29(6), 164-169.
[PMID: 37235497]
[8]
Li, J.; Wang, K.; Liu, M.; He, J.; Zhang, H.; Liu, H. Dexmedetomidine alleviates cerebral ischemia-reperfusion injury via inhibiting autophagy through PI3K/Akt/mTOR pathway. J. Mol. Histol., 2023, 54(3), 173-181.
[http://dx.doi.org/10.1007/s10735-023-10120-1] [PMID: 37186301]
[9]
Chen, Z.R.; Hong, Y.; Wen, S.H.; Zhan, Y.Q.; Huang, W.Q. Dexmedetomidine pretreatment protects against myocardial ischemia/reperfusion injury by activating STAT3 signaling. Anesth. Analg., 2023, 137(2), 426-439.
[http://dx.doi.org/10.1213/ANE.0000000000006487] [PMID: 37145970]
[10]
Akpınar, H.; Nazıroğlu, M.; Övey, İ.S.; Çiğ, B.; Akpınar, O. The neuroprotective action of dexmedetomidine on apoptosis, calcium entry and oxidative stress in cerebral ischemia-induced rats: Contribution of TRPM2 and TRPV1 channels. Sci. Rep., 2016, 6(1), 37196.
[http://dx.doi.org/10.1038/srep37196] [PMID: 27872485]
[11]
Wang, S.L.; Duan, L.; Xia, B.; Liu, Z.; Wang, Y.; Wang, G.M. Dexmedetomidine preconditioning plays a neuroprotective role and suppresses TLR4/NF-κB pathways model of cerebral ischemia reperfusion. Biomed. Pharmacother., 2017, 93, 1337-1342.
[http://dx.doi.org/10.1016/j.biopha.2017.06.051] [PMID: 28753906]
[12]
Huang, S.; Hou, D.; Zhang, L.; Pei, C.; Liang, J.; Li, J.; Yang, G.; Yu, D. LncRNA MALAT1 promoted neuronal necroptosis in cerebral ischemia-reperfusion mice by stabilizing HSP90. Neurochem. Res., 2023, 48(11), 3457-3471.
[http://dx.doi.org/10.1007/s11064-023-03991-z] [PMID: 37470906]
[13]
Wang, H.; Zheng, X.; Jin, J.; Zheng, L.; Guan, T.; Huo, Y.; Xie, S.; Wu, Y.; Chen, W. LncRNA MALAT1 silencing protects against cerebral ischemia-reperfusion injury through miR-145 to regulate AQP4. J. Biomed. Sci., 2020, 27(1), 40.
[http://dx.doi.org/10.1186/s12929-020-00635-0] [PMID: 32138732]
[14]
Zhang, X.; Tang, X.; Liu, K.; Hamblin, M.H.; Yin, K.J. Long Noncoding RNA Malat1 regulates cerebrovascular pathologies in ischemic stroke. J. Neurosci., 2017, 37(7), 1797-1806.
[http://dx.doi.org/10.1523/JNEUROSCI.3389-16.2017] [PMID: 28093478]
[15]
Zhang, W.; Meng, A. MicroRNA‑124 expression in the brains of rats during early cerebral ischemia and reperfusion injury is associated with cell apoptosis involving STAT3. Exp. Ther. Med., 2019, 17(4), 2870-2876.
[http://dx.doi.org/10.3892/etm.2019.7220] [PMID: 30906474]
[16]
Tregub, P.P.; Ibrahimli, I.; Averchuk, A.S.; Salmina, A.B.; Litvitskiy, P.F.; Manasova, Z.S.; Popova, I.A. The Role of microRNAs in epigenetic regulation of signaling pathways in neurological pathologies. Int. J. Mol. Sci., 2023, 24(16), 12899.
[http://dx.doi.org/10.3390/ijms241612899] [PMID: 37629078]
[17]
Teng, L.; Meng, R. Long Non-Coding RNA MALAT1 promotes acute cerebral infarction through mirnas-mediated hs-crp regulation. J. Mol. Neurosci., 2019, 69(3), 494-504.
[http://dx.doi.org/10.1007/s12031-019-01384-y] [PMID: 31342266]
[18]
Abdul-Muneer, P.M. Nrf2 as a potential therapeutic target for traumatic brain injury. J. Integr. Neurosci., 2023, 22(4), 81.
[http://dx.doi.org/10.31083/j.jin2204081] [PMID: 37519172]
[19]
Xu, X.; Zhang, L.; Ye, X.; Hao, Q.; Zhang, T.; Cui, G.; Yu, M. 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]
[20]
Wu, G.; Zhu, L.; Yuan, X.; Chen, H.; Xiong, R.; Zhang, S.; Cheng, H.; Shen, Y.; An, H.; Li, T.; Li, H.; Zhang, W. Britanin ameliorates cerebral ischemia–reperfusion injury by inducing the nrf2 protective pathway. Antioxid. Redox Signal., 2017, 27(11), 754-768.
[http://dx.doi.org/10.1089/ars.2016.6885] [PMID: 28186440]
[21]
Mahajan, M.; Sitasawad, S. miR-140-5p attenuates hypoxia-induced breast cancer progression by targeting Nrf2/HO-1 Axis in a keap1-independent mechanism. Cells, 2021, 11(1), 12.
[http://dx.doi.org/10.3390/cells11010012] [PMID: 35011574]
[22]
Liu, Q.Q.; Ren, K.; Liu, S.H.; Li, W.M.; Huang, C.J.; Yang, X.H. MicroRNA-140-5p aggravates hypertension and oxidative stress of atherosclerosis via targeting Nrf2 and Sirt2. Int. J. Mol. Med., 2019, 43(2), 839-849.
[PMID: 30483753]
[23]
Wan Mohammad, W.M.Z.; Zahiruddin, W.M. Sample size calculation in animal studies using resource equation approach. Malays. J. Med. Sci., 2017, 24(5), 101-105.
[http://dx.doi.org/10.21315/mjms2017.24.5.11] [PMID: 29386977]
[24]
Chen, J.; Li, Y.; Wang, L.; Zhang, Z.; Lu, D.; Lu, M.; Chopp, M. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke, 2001, 32(4), 1005-1011.
[http://dx.doi.org/10.1161/01.STR.32.4.1005] [PMID: 11283404]
[25]
Hu, H.; Sun, X.; Tian, F.; Zhang, H.; Liu, Q.; Tan, W. Neuroprotective effects of isosteviol sodium injection on acute focal cerebral ischemia in rats. Oxid. Med. Cell. Longev., 2016, 2016, 1-10.
[http://dx.doi.org/10.1155/2016/1379162] [PMID: 27047634]
[26]
Reagan-Shaw, S.; Nihal, M.; Ahmad, N. Dose translation from animal to human studies revisited. FASEB J., 2008, 22(3), 659-661.
[http://dx.doi.org/10.1096/fj.07-9574LSF] [PMID: 17942826]
[27]
Li, P.; Zhang, Y.; Liu, H. The role of Wnt/β-catenin pathway in the protection process by dexmedetomidine against cerebral ischemia/reperfusion injury in rats. Life Sci., 2019, 236, 116921.
[http://dx.doi.org/10.1016/j.lfs.2019.116921] [PMID: 31610196]
[28]
Huang, J.; Chen, L.; Yao, Z.; Sun, X.; Tong, X.; Dong, S. The role of mitochondrial dynamics in cerebral ischemia-reperfusion injury. Biomed. Pharmacother., 2023, 162, 114671.
[http://dx.doi.org/10.1016/j.biopha.2023.114671] [PMID: 37037094]
[29]
Vongsfak, J.; Pratchayasakul, W.; Apaijai, N.; Vaniyapong, T.; Chattipakorn, N.; Chattipakorn, S.C. The alterations in mitochondrial dynamics following cerebral ischemia/reperfusion injury. Antioxidants, 2021, 10(9), 1384.
[http://dx.doi.org/10.3390/antiox10091384] [PMID: 34573016]
[30]
Sun, K.; Fan, J.; Han, J. Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia/reperfusion-induced cerebral microcirculatory disturbances and neuron damage. Acta Pharm. Sin. B, 2015, 5(1), 8-24.
[http://dx.doi.org/10.1016/j.apsb.2014.11.002] [PMID: 26579420]
[31]
Zong, Y.; Wang, X.; Cui, B.; Xiong, X.; Wu, A.; Lin, C.; Zhang, Y. Decoding the regulatory roles of non-coding RNAs in cellular metabolism and disease. Mol. Ther., 2023, 31(6), 1562-1576.
[http://dx.doi.org/10.1016/j.ymthe.2023.04.012] [PMID: 37113055]
[32]
Fan, L.; Huang, X.; Chen, J.; Zhang, K.; Gu, Y.; Sun, J.; Cui, S. Long noncoding RNA MALAT1 contributes to sorafenib resistance by targeting miR-140-5p/Aurora-A signaling in hepatocellular carcinoma. Mol. Cancer Ther., 2020, 19(5), 1197-1209.
[http://dx.doi.org/10.1158/1535-7163.MCT-19-0203] [PMID: 32220970]
[33]
Ruan, W.; Li, J.; Xu, Y.; Wang, Y.; Zhao, F.; Yang, X.; Jiang, H.; Zhang, L.; Saavedra, J.M.; Shi, L.; Pang, T. MALAT1 Up-Regulator polydatin protects brain microvascular integrity and ameliorates stroke through C/EBPβ/MALAT1/ CREB/PGC-1α/PPARγ Pathway. Cell. Mol. Neurobiol., 2019, 39(2), 265-286.
[http://dx.doi.org/10.1007/s10571-018-00646-4] [PMID: 30607811]
[34]
Wang, L.Q.; Zhou, H.J. LncRNA MALAT1 promotes high glucose-induced inflammatory response of microglial cells via provoking MyD88/IRAK1/TRAF6 signaling. Sci. Rep., 2018, 8(1), 8346.
[http://dx.doi.org/10.1038/s41598-018-26421-5] [PMID: 29844328]
[35]
Cao, D.; Liu, M.; Duan, R.; Tao, Y.; Zhou, J.; Fang, W.; Zhu, J.; Niu, L.; Sun, J. The lncRNA Malat1 functions as a ceRNA to contribute to berberine-mediated inhibition of HMGB1 by sponging miR-181c-5p in poststroke inflammation. Acta Pharmacol. Sin., 2020, 41(1), 22-33.
[http://dx.doi.org/10.1038/s41401-019-0284-y] [PMID: 31431734]
[36]
Chen, J.Y.; Zhu, G.Y.; Su, X.H.; Wang, R.; Liu, J.; Liao, K.; Ren, R.; Li, T.; Liu, L. 7-deacetylgedunin suppresses inflammatory responses through activation of Keap1/Nrf2/HO-1 signaling. Oncotarget, 2017, 8(33), 55051-55063.
[http://dx.doi.org/10.18632/oncotarget.19017] [PMID: 28903401]
[37]
Zhao, L.; Qi, Y.; Xu, L.; Tao, X.; Han, X.; Yin, L.; Peng, J. MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Redox Biol., 2018, 15, 284-296.
[http://dx.doi.org/10.1016/j.redox.2017.12.013] [PMID: 29304479]