丁慧敏;李彦杰;华晓琼;郝晨源;赵楠楠;孙孟艳;郝晓丹;

• 1:河南中医药大学
• 2:河南省中医院
• 3:第四军医大学

摘要(Abstract)：

新型冠状病毒（Severe acute respiratory syndrome coronavirus 2,SARS-CoV-2）目前仍在全球肆虐传播，在引发2019新冠肺炎（Corona virus disease 2019,COVID-19）的同时，还能造成感染者中枢神经系统的损伤。缺血性脑卒中是COVID-19相关神经系统损伤常见病之一。本文归纳出SARS-CoV-2进入中枢的途径，以及该病毒是如何通过介导氧化应激反应、肾素-血管紧张素系统的失调、攻击血管内皮细胞、激活NLRP3炎症小体、释放中性粒细胞胞外陷阱、引发细胞因子风暴等一系列分子机制导致缺血性脑卒中的发病，以期为疾病的临床预防和治疗提供一些新的见解和思路。

关键词(KeyWords)： SARS-CoV-2;缺血性脑卒中;神经系统损伤;COVID-19

Abstract:

Keywords:

基金项目(Foundation): 河南省中医药科学研究专项课题（项目号：2019ZYBJ14）,题目：祛痰治呛方穴位贴敷治疗脑卒中后吞咽障碍的临床研究;; 河南省中医药拔尖人才培养项目（项目号：豫中医科教[2018]35号）~~

作者(Authors): 丁慧敏;李彦杰;华晓琼;郝晨源;赵楠楠;孙孟艳;郝晓丹;

DOI: 10.13242/j.cnki.bingduxuebao.004189

参考文献(References)：

• [1] WHO. COVID-19 weekly epidemiological update[J/OL]. https：//www. who. int/emergencies/diseases/novel-coronavirus-2019/situation-reports.
• [2] Kumar D, Jahan S, Khan A, Siddiqui A J, Redhu N S,Wahajuddin, Khan J, Banwas S, Alshehri B,Alaidarous M. Neurological manifestation of SARS-CoV-2 induced inflammation and possible therapeutic strategies against COVID-19[J]. Mol Neurobiol, 2021,58(7):3417-3434.
• [3] Reichard R R, Kashani K B, Boire N A,Constantopoulos E, Guo Y, Lucchinetti C F.Neuropathology of COVID-19:a spectrum of vascular and acute disseminated encephalomyelitis(ADEM)-like pathology[J]. Acta Neuropathol, 2020, 140(1):1-6.
• [4] Ramani A, Müller L, Ostermann P N, Gabriel E,Abida-Islam P, Müller-Schiffmann A, Mariappan A,Goureau O, Gruell H, Walker A, Andrée M, Hauka S, Houwaart T, Dilthey A, Wohlgemuth K, Omran H, Klein F, Wieczorek D, Adams O, Timm J, Korth C, Schaal H, Gopalakrishnan J. SARS-CoV-2 targets neurons of 3D human brain organoids[J/OL]. EMBO J,2020, 39(20):e106230.
• [5] Sylaja P N, Srivastava M V P, Shah S, Bhatia R,Khurana D, Sharma A, Pandian J D, Kalia K, Sarmah D, Nair S S, Yavagal D R, Bhattacharya P. The SARS-CoV-2/COVID-19 pandemic and challenges in stroke care in India[J]. Ann N Y Acad Sci, 2020, 1473(1).
• [6] Katsanos A H, Palaiodimou L, Zand R, Yaghi S,Kamel H, Navi B B, Turc G, Romoli M, Sharma V K, Mavridis D, Shahjouei S, Catanese L, Shoamanesh A, Vadikolias K, Tsioufis K, Lagiou P, Alexandrov A V, Tsiodras S, Tsivgoulis G. The impact of SARSCoV-2 on stroke epidemiology and care:a meta-analysis[J]. Ann Neurol, 2021, 89(2):380-388.
• [7] Morassi M, Bagatto D, Cobelli M, D'Agostini S, Gigli G L, BnàC, Vogrig A. Stroke in patients with SARSCoV-2 infection:case series[J]. J Neurol, 2020, 267(8):2185-2192.
• [8] Yang H, Rao Z. Structural biology of SARS-CoV-2 and implications for therapeutic development[J]. Nat Rev Microbiol, 2021, 19(11):685-700.
• [9] Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H,Geng Q, Auerbach A, Li F. Structural basis of receptor recognition by SARS-CoV-2[J]. Nature, 2020, 581(7807):221-224.
• [10]Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z,Lu G, Qiao C, Hu Y, Yuen K-Y, Wang Q, Zhou H,Yan J, Qi J. Structural and functional basis of SARSCoV-2 entry by using human ACE2[J]. Cell, 2020,181(4).
• [11]Jackson C B, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells[J]. Nat Rev Mol Cell Biol, 2022, 23(1).
• [12]Li Y, Li M, Wang M, Zhou Y, Chang J, Xian Y,Wang D, Mao L, Jin H, Hu B. Acute cerebrovascular disease following COVID-19:a single center,retrospective, observational study[J]. Stroke Vasc Neurol, 2020, 5(3):279-284.
• [13]Shahjouei S, Naderi S, Li J, Khan A, Chaudhary D,Farahmand G, Male S, Griessenauer C, Sabra M,Mondello S, Cernigliaro A, Khodadadi F, Dev A,Goyal N, Ranji-Burachaloo S, Olulana O, Avula V,Ebrahimzadeh S A, Alizada O, Hanc?M M, Ghorbani A, Vaghefi Far A, Ranta A, Punter M, Ramezani M,Ostadrahimi N, Tsivgoulis G, Fragkou P C, NowrouziSohrabi P, Karofylakis E, Tsiodras S, Neshin Aghayari Sheikh S, Saberi A, Niemel?M, Rezai Jahromi B,Mowla A, Mashayekhi M, Bavarsad Shahripour R,Sajedi S A, Ghorbani M, Kia A, Rahimian N, Abedi V, Zand R. Risk of stroke in hospitalized SARS-CoV-2infected patients:A multinational study[J]. EBio Medicine, 2020, 59:102939.
• [14]Vogrig A, Gigli G L, BnàC, Morassi M. Stroke in patients with COVID-19:clinical and neuroimaging characteristics[J]. Neuroscience Letters, 2021, 743:135564.
• [15]Jiao L, Yang Y, Yu W, Zhao Y, Long H, Gao J, Ding K, Ma C, Li J, Zhao S, Wang H, Li H, Yang M, Xu J, Wang J, Yang J, Kuang D, Luo F, Qian X, Xu L,Yin B, Liu W, Liu H, Lu S, Peng X. The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys[J]. Signal Transduct Target Ther, 2021, 6(1):169.
• [16]Bostanc?kl?o?lu M. Temporal correlation between neurological and gastrointestinal symptoms of SARSCoV-2[J/OL]. Inflamm Bowel Dis, 2020, 26(8):e89-e91.
• [17]Ballabh P, Braun A, Nedergaard M. The blood-brain barrier:an overview:structure, regulation, and clinical implications[J]. Neurobio Dis, 2004, 16(1).
• [18]Zhang L, Zhou L, Bao L, Liu J, Zhu H, Lv Q, Liu R,Chen W, Tong W, Wei Q, Xu Y, Deng W, Gao H,Xue J, Song Z, Yu P, Han Y, Zhang Y, Sun X, Yu X, Qin C. SARS-CoV-2 crosses the blood-brain barrier accompanied with basement membrane disruption without tight junctions alteration[J]. Signal Transduct Target Ther, 2021, 6(1):337.
• [19]Li H, Xue Q, Xu X. Involvement of the nervous system in SARS-CoV-2 infection[J]. Neurotox Res, 2020, 38(1):1-7.
• [20]Pellegrini L, Albecka A, Mallery D L, Kellner M J,Paul D, Carter A P, James L C, Lancaster M A. SARS-CoV-2 infects the brain choroid plexus and disrupts the Blood-CSF barrier in human brain organoids[J]. Cell Stem Cell, 2020, 27(6).
• [21]Poredos P, Jezovnik M K. Endothelial dysfunction and venous thrombosis[J]. Angiology, 2018, 69(7):564-567.
• [22]Roumenina L T, Rayes J, Frimat M, Fremeaux-Bacchi V. Endothelial cells:source, barrier, and target of defensive mediators[J]. Immunol Rev, 2016, 274(1):307-329.
• [23]Pons S, Arnaud M, Loiselle M, Arrii E, Azoulay E,Zafrani L. Immune consequences of endothelial cells'activation and dysfunction during sepsis[J]. Crit Care Clin, 2020, 36(2):401-413.
• [24]Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens T S, Herrler G,Wu N-H, Nitsche A, Müller M A, Drosten C,P?hlmann S. SARS-CoV-2 cell entry depends on ACE2and TMPRSS2 and is blocked by a clinically proven protease inhibitor[J]. Cell, 2020, 181(2).
• [25]Wu C-H, Mohammadmoradi S, Chen J Z, Sawada H,Daugherty A, Lu H S. Renin-Angiotensin system and cardiovascular functions[J]. Arterioscler Thromb Vasc Bio, 2018, 38(7):e108-e116.
• [26]Forrester S J, Booz G W, Sigmund C D, Coffman T M, Kawai T, Rizzo V, Scalia R, Eguchi S.Angiotensin II Signal Transduction:An update on mechanisms of physiology and pathophysiology[J].Physiol Rev, 2018, 98(3):1627-1738.
• [27]Santos R A S, Sampaio W O, Alzamora A C, MottaSantos D, Alenina N, Bader M, Campagnole-Santos M J. The ACE2/Angiotensin-（1-7）/MAS axis of the Renin-Angiotensin system:focus on Angiotensin-（1-7）[J].Physiol Rev, 2018, 98(1):505-553.
• [28]Lou M, Yuan D, Liao S, Tong L, Li J. Potential mechanisms of cerebrovascular diseases in COVID-19patients[J]. J Neurovirol, 2021, 27(1):35-51.
• [29]Chen J, Zhao Y, Chen S, Wang J, Xiao X, Ma X,Penchikala M, Xia H, Lazartigues E, Zhao B, Chen Y.Neuronal over-expression of ACE2 protects brain from ischemia-induced damage[J]. Neuropharmacology,2014, 79:550-558.
• [30]Klok F A, Kruip M J H A, van der Meer N J M,Arbous M S, Gommers D A M P J, Kant K M,Kaptein F H J, van Paassen J, Stals M A M, Huisman M V, Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19[J]. Thromb Res, 2020, 191:145-147.
• [31]Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J,Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China:a retrospective cohort study[J]. Lancet, 2020, 395(10229):1054-1062.
• [32]Griffin D O, Jensen A, Khan M, Chin J, Chin K, Saad J, Parnell R, Awwad C, Patel D. Pulmonary embolism and increased levels of d-Dimer in patients with coronavirus disease[J]. Emerg Infect Dis, 2020, 26(8):1941-1943.
• [33]Amara U, Rittirsch D, Flierl M, Bruckner U, Klos A,Gebhard F, Lambris J D, Huber-Lang M. Interaction between the coagulation and complement system[J].Adv Exp Med Bio, 2008, 632:71-79.
• [34]Magro C, Mulvey J J, Berlin D, Nuovo G, Salvatore S, Harp J, Baxter-Stoltzfus A, Laurence J.Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19infection:A report of five cases[J]. Transl Res,2020, 220.
• [35]Abdennour L, Zeghal C, Dème M, Puybasset L.[Interaction brain-lungs][J]. Ann Fr Anesth Reanim,2012, 31(6):e101-e107.
• [36]Kashani K B. Hypoxia in COVID-19:Sign of severity or cause for poor outcomes[J]. Mayo Clin Proc, 2020, 95(6):1094-1096.
• [37]Sekhon M S, Ainslie P N, Griesdale D E. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest:a"two-hit"model[J]. Crit Care, 2017, 21(1):90.
• [38]Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y,Qiu Y, Wang J, Liu Y, Wei Y, Xia J a, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China:a descriptive study[J]. Lancet, 2020,395(10223):507-513.
• [39]Yuan T, Yang T, Chen H, Fu D, Hu Y, Wang J,Yuan Q, Yu H, Xu W, Xie X. New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis[J]. Redox Biol, 2019, 20:247-260.
• [40]Di Marco E, Jha J C, Sharma A, Wilkinson-Berka J L,Jandeleit-Dahm K A, de Haan J B. Are reactive oxygen species still the basis for diabetic complications?[J]. Clin Sci(Lond), 2015, 129(2):199-216.
• [41]Fuchs T A, Abed U, Goosmann C, Hurwitz R,Schulze I, Wahn V, Weinrauch Y, Brinkmann V,Zychlinsky A. Novel cell death program leads to neutrophil extracellular traps[J]. J Cell Biol, 2007, 176(2):231-241.
• [42]Clark S R, Ma A C, Tavener S A, McDonald B,Goodarzi Z, Kelly M M, Patel K D, Chakrabarti S,McAvoy E, Sinclair G D, Keys E M, Allen-Vercoe E,Devinney R, Doig C J, Green F H Y, Kubes P. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood[J]. Nat Med, 2007, 13(4):463-469.
• [43]Veras F P, Pontelli M C, Silva C M, Toller-Kawahisa J E, de Lima M, Nascimento D C, Schneider A H,CaetitéD, Tavares L A, Paiva I M, Rosales R, Colón D, Martins R, Castro I A, Almeida G M, Lopes M I F, Benatti M N, Bonjorno L P, Giannini M C, Luppino-Assad R, Almeida S L, Vilar F, Santana R, Bollela V R, Auxiliadora-Martins M, Borges M, Miranda C H,Pazin-Filho A, da Silva L L P, Cunha L D, Zamboni D S, Dal-Pizzol F, Leiria L O, Siyuan L, Batah S, Fabro A, Mauad T, Dolhnikoff M, Duarte-Neto A, Saldiva P, Cunha T M, Alves-Filho J C, Arruda E, LouzadaJunior P, Oliveira R D, Cunha F Q. SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology[J]. J Exp Med, 2020, 217(12).
• [44]Barnes B J, Adrover J M, Baxter-Stoltzfus A, Borczuk A, Cools-Lartigue J, Crawford J M, Da?ler-Plenker J,Guerci P, Huynh C, Knight J S, Loda M, Looney M R, McAllister F, Rayes R, Renaud S, Rousseau S,Salvatore S, Schwartz R E, Spicer J D, Yost C C,Weber A, Zuo Y, Egeblad M. Targeting potential drivers of COVID-19:Neutrophil extracellular traps[J].J Exp Med, 2020, 217(6).
• [45]Paniri A, Akhavan-Niaki H. Emerging role of IL-6 and NLRP3 inflammasome as potential therapeutic targets to combat COVID-19:Role of lncRNAs in cytokine storm modulation[J]. Life Sci, 2020, 257:118114.
• [46]Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J.Thioredoxin-interacting protein links oxidative stress to inflammasome activation[J]. Nat Immunol, 2010, 11(2):136-140.
• [47]Murakami T, Ockinger J, Yu J, Byles V, McColl A,Hofer A M, Horng T. Critical role for calcium mobilization in activation of the NLRP3 inflammasome[J]. Proc Natl Acad Sci U S A, 2012, 109(28):11282-11287.
• [48]Kilinc M, Gürsoy-Ozdemir Y, Gürer G, Erdener S E,Erdemli E, Can A, Dalkara T. Lysosomal rupture,necroapoptotic interactions and potential crosstalk between cysteine proteases in neurons shortly after focal ischemia[J]. Neurobiol Dis, 2010, 40(1):293-302.
• [49]Hu H-J, Song M. Disrupted ionic homeostasis in ischemic stroke and new therapeutic targets[J]. J Stroke Cerebrovasc Dis, 2017, 26(12):2706-2719.
• [50]Junqueira C, Crespo?，Ranjbar S, de Lacerda L B,Lewandrowski M, Ingber J, Parry B, Ravid S, Clark S, Schrimpf M R, Ho F, Beakes C, Margolin J,Russell N, Kays K, Boucau J, Das Adhikari U, Vora S M, Leger V, Gehrke L, Henderson L, Janssen E,Kwon D, Sander C, Abraham J, Goldberg M B, Wu H, Mehta G, Bell S, Goldfeld A E, Filbin M R,Lieberman J. FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation[J]. Nature, 2022.
• [51]Di Virgilio F, Dal Ben D, Sarti A C, Giuliani A L,Falzoni S. The P2X7 receptor in infection and inflammation[J]. Immunity, 2017, 47(1):15-31.
• [52]Turrens J F. Mitochondrial formation of reactive oxygen species[J]. J Physiol, 2003, 552(Pt 2):335-344.
• [53]Shi J, Gao W, Shao F. Pyroptosis:gasdermin-mediated programmed necrotic cell death[J]. Trends Biochem Sci, 2017, 42(4):245-254.