药学学报, 2020, 55(2): 208-217
引用本文:
姜晓慧, 郑钟原, 刘慧, 杨婷, 瞿水清, 李玉洁, 陈利娜. 脑型疟辅助治疗研究进展[J]. 药学学报, 2020, 55(2): 208-217.
JIANG Xiao-hui, ZHENG Zhong-yuan, LIU Hui, YANG Ting, QU Shui-qing, LI Yu-jie, CHEN Li-na. Current advances in research on adjuvant therapy for cerebral malaria[J]. Acta Pharmaceutica Sinica, 2020, 55(2): 208-217.

脑型疟辅助治疗研究进展
姜晓慧1,2, 郑钟原1,2, 刘慧1,2, 杨婷1,2, 瞿水清1,2, 李玉洁1,2, 陈利娜1,2
1. 中国中医科学院青蒿素研究中心, 北京100700;
2. 中国中医科学院中药研究所, 北京100700
摘要:
脑型疟(cerebral malaria,CM)是恶性疟原虫感染引起的最致命的并发症,即使经过有效抗疟药物治疗,儿童死亡率仍可高达18%,且有近三分之一的幸存者会出现神经功能缺损和认知障碍。目前CM的发病机制尚不明确,机械阻塞和免疫学说是其主流学说。CM辅助治疗的主要目的是改善临床结果和/或降低死亡率,以及预防长期神经认知缺陷。提高生存率和减少幸存者的神经损伤是新型抗疟药与辅助治疗的新策略。本文从保护血管内皮、减轻黏附阻塞效应、调节免疫平衡、干扰疟原虫代谢、神经保护、提高NO生物利用度、改善能量代谢、减轻炎症等方面,对近5年CM辅助治疗研究的进展进行系统总结,为CM的相关研究提供参考。
关键词:    脑型疟      发病机制      神经后遗症      辅助治疗      新策略     
Current advances in research on adjuvant therapy for cerebral malaria
JIANG Xiao-hui1,2, ZHENG Zhong-yuan1,2, LIU Hui1,2, YANG Ting1,2, QU Shui-qing1,2, LI Yu-jie1,2, CHEN Li-na1,2
1. Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China;
2. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
Abstract:
Cerebral malaria (CM) is the deadliest complication of Plasmodium falciparum infection and even with effective anti-malarial treatment the mortality of children can be as high as 18%; up to one-third of CM survivors are left with neurological and cognitive deficits. The pathophysiology of CM is not completely understood, but mechanical obstruction and immunopathology are its mainstream theories. Adjuvant therapy aims to improve clinical outcomes and/or reduce mortality, as well as preventing long-term neurocognitive deficits. Improving survival and reducing neurological damage to survivors are new goals for new antimalarials and adjuvant therapies. Herein, we discussed what is known about the disease mechanism of CM and systematically summarize the progress of adjuvant therapy research in protecting the vascular endothelium, reducing adhesion formation, regulating immune balance, interfering with malarial metabolism, protecting nerves, improving nitric oxide bioavailability, improving energy metabolism and alleviating inflammation, with the aim of exploiting this understanding to reduce the neurological damage to children with CM. This work also highlights some preclinical studies which may be candidate strategies in future clinical trials.
Key words:    cerebral malaria    pathogenesis    neurological sequelae    adjuvant therapy    new strategy   
收稿日期: 2019-08-26
DOI: 10.16438/j.0513-4870.2019-0677
基金项目: 中国中医科学院十三五重点领域项目(Z2017021);国家重大新药创制科技重大专项(2017ZX09101002-001-001-3);国家自然科学基金特别资助项目(81641002);中央级公益性科研院所基本科研业务费专项资金资助(L2017001).
通讯作者: 李玉洁,Tel:13552220109,E-mail:yjli@icmm.ac.cn;陈利娜,Tel:13716370875,E-mail:lnchen@icmm.ac.cn
Email: yjli@icmm.ac.cn;lnchen@icmm.ac.cn
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参考文献:
[1] World Health Organization. World malaria report 2018[R]. WHO, 2018.
[2] Bruneel F. Human cerebral malaria:2019 mini review[J]. Rev Neurol (Paris), 2019, 175:445-450.
[3] Abdallah TM, Elmardi KA, Elhassan AH, et al. Comparison of artesunate and quinine in the treatment of severe Plasmodium falciparum malaria at Kassala hospital, Sudan[J]. J Infect Dev Ctries, 2014, 8:611-615.
[4] Varo R, Crowley VM, Sitoe A, et al. Adjunctive therapy for severe malaria:a review and critical appraisal[J]. Malar J, 2018, 17:47-65.
[5] Pais TF, Penha-Goncalves C. Brain endothelium:the "innate immunity response hypothesis" in cerebral malaria pathogenesis[J]. Front Immunol, 2018, 9:3100-3108.
[6] Hora R, Kapoor P, Thind KK, et al. Cerebral malaria——clinical manifestations and pathogenesis[J]. Metab Brain Dis, 2016, 31:225-237.
[7] Luzolo AL, Ngoyi DM. Cerebral malaria[J]. Brain Res Bull, 2019, 145:53-58.
[8] Mohanty S, Patel DK, Pati SS, et al. Adjuvant therapy in cerebral malaria[J]. Indian J Med Res, 2006, 124:245-260.
[9] John CC, Kutamba E, Mugarura K, et al. Adjunctive therapy for cerebral malaria and other severe forms of Plasmodium falciparum malaria[J]. Expert Rev Anti Infect Ther, 2010, 8:997-1008.
[10] White NJ, Turner GD, Medana IM, et al. The murine cerebral malaria phenomenon[J]. Trends Parasitol, 2010, 26:11-15.
[11] Riggle BA, Miller LH, Pierce SK. Do we know enough to find an adjunctive therapy for cerebral malaria in African children[J]. F 1000Res, 2017, 6:2039-2047.
[12] Medana IM, Day NP, Hien TT, et al. Axonal injury in cerebral malaria[J]. Am J Pathol, 2002, 160:655-666.
[13] Strangward P, Haley MJ, Shaw TN, et al. A quantitative brain map of experimental cerebral malaria pathology[J]. PLoS Pathog, 2017, 13:e1006267.
[14] Shabani E, Hanisch B, Opoka RO, et al. Plasmodium falciparum EPCR-binding PfEMP1 expression increases with malaria disease severity and is elevated in retinopathy negative cerebral malaria[J]. BMC Med, 2017, 15:183-197.
[15] Elphinstone RE, Riley F, Lin T, et al. Dysregulation of the haem-haemopexin axis is associated with severe malaria in a case-control study of Ugandan children[J]. Malar J, 2015, 14:511-521.
[16] Sierro F, Grau GER. The ins and outs of cerebral malaria pathogenesis:immunopathology, extracellular vesicles, immunometabolism, and trained immunity[J]. Front Immunol, 2019, 10:830-841.
[17] Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features, and neurological outcome of cerebral malaria[J]. Lancet Neurol, 2005, 4:827-840.
[18] van der Heyde HC, Nolan J, Combes V, et al. A unified hypothesis for the genesis of cerebral malaria:sequestration, inflammation and hemostasis leading to microcirculatory dysfunction[J]. Trends Parasitol, 2006, 22:503-508.
[19] Bruneel F. Human cerebral malaria:2019 mini review[J]. Rev Neurol (Paris), 2019, 175:445-450.
[20] Reyburn H. New WHO guidelines for the treatment of malaria[J]. BMJ, 2010, 340:c2637.
[21] Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)[J]. Autophagy, 2016, 12:1-222.
[22] Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria[J]. N Engl J Med, 2009, 361:455-467.
[23] Vreden SG, Bansie RD, Jitan JK, et al. Assessing parasite clearance during uncomplicated Plasmodium falciparum infection treated with artesunate monotherapy in Suriname[J]. Infect Drug Resist, 2016, 9:261-267.
[24] Kayano A, Dos-Santos JCK, Bastos MF, et al. Pathophysiological mechanisms in gaseous therapies for severe malaria[J]. Infect Immun, 2016, 84:874-882.
[25] Mohanty S, Benjamin LA, Majhi M, et al. Magnetic resonance imaging of cerebral malaria patients reveals distinct pathogenetic processes in different parts of the brain[J]. mSphere, 2017, 2:e00193-17.
[26] Gordon EB, Hart GT, Tran TM, et al. Targeting glutamine metabolism rescues mice from late-stage cerebral malaria[J]. Proc Natl Acad Sci U S A, 2015, 112:13075-13080.
[27] Riggle BA,Sinharay S, Schreiber-Stainthorp W, et al. MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice[J]. Proc Natl Acad Sci U S A, 2018, 115:e12024-e12033.
[28] Higgins SJ, Purcell LA, Silver KL, et al. Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria[J]. Sci Transl Med, 2016, 8:358ra128.
[29] Gallego-Delgado J, Basu-Roy U, Ty M, et al. Angiotensin receptors and beta-catenin regulate brain endothelial integrity in malaria[J]. J Clin Invest, 2016, 126:4016-4029.
[30] Liu M, Solomon W, Cespedes JC, et al. Neuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signaling[J]. J Neuroinflammation, 2018, 15:104-119.
[31] Kume A, Kasai S, Furuya H, et al. Alpha-tocopheryl succinate-suppressed development of cerebral malaria in mice[J]. Parasitol Res, 2018, 117:3177-3182.
[32] Becker BF, Jacob M, Leipert S, et al. Degradation of the endothelial glycocalyx in clinical settings:searching for the sheddases[J]. Br J Clin Pharmacol, 2015, 80:389-402.
[33] Hempel C, Sporring J, Kurtzhals JAL. Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx[J]. FASEB J, 2019, 33:2058-2071.
[34] Gillrie MR, Renaux B, Russell-Goldman E, et al. Thrombin cleavage of Plasmodium falciparum erythrocyte membrane protein 1 inhibits cytoadherence[J]. mBio, 2016, 7:e01120-16.
[35] Saiwaew S, Sritabal J, Piaraksa N, et al. Effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum infected erythrocytes[J]. PLoS One, 2017, 12:e0172718.
[36] Leitgeb AM, Charunwatthana P, Rueangveerayut R, et al. Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria[J]. PLoS One, 2017, 12:e0188754.
[37] Maude RJ, Silamut K, Plewes K, et al. Randomized controlled trial of levamisole hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia[J]. J Infect Dis, 2014, 209:120-129.
[38] Wilson KD, Ochoa LF, Solomon OD, et al. Elimination of intravascular thrombi prevents early mortality and reduces gliosis in hyper-inflammatory experimental cerebral malaria[J]. J Neuroinflamm, 2018, 15:173-190.
[39] Remer I, Pierre-Destine LF, Tay D, et al. In vivo noninvasive visualization of retinal perfusion dysfunction in murine cerebral malaria by camera-phone laser speckle imaging[J]. J Biophotonics, 2019, 12:e201800098.
[40] Potchen MJ, Kampondeni SD, Seydel KB, et al. 1.5 Tesla magnetic resonance imaging to investigate potential etiologies of brain swelling in pediatric cerebral malaria[J]. Am J Trop Med Hyg, 2018, 98:497-504.
[41] O'Brien NF, Mutatshi Taty T, Moore-Clingenpeel M, et al. Transcranial Doppler ultrasonography provides insights into neurovascular changes in children with cerebral malaria[J]. J Pediatr, 2018, 203:116-124.
[42] Eisenhut M. The evidence for a role of vasospasm in the pathogenesis of cerebral malaria[J]. Malar J, 2015, 14:405-414.
[43] Wu B, Du Y, Feng Y, et al. Oral administration of vitamin D and importance in prevention of cerebral malaria[J]. Int Immunopharmacol, 2018, 64:356-363.
[44] Wang J, Li Y, Shen Y, et al. PDL1 fusion protein protects against experimental cerebral malaria via repressing over-reactive CD8(+) T cell responses[J]. Front Immunol, 2018, 9:3157-3160.
[45] Liby KT, Sporn MB. Synthetic oleanane triterpenoids:multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease[J]. Pharmacol Rev, 2012, 64:972-1003.
[46] Crowley VM, Ayi K, Lu Z, et al. Synthetic oleanane triterpenoids enhance blood brain barrier integrity and improve survival in experimental cerebral malaria[J]. Malar J, 2017, 16:463-474.
[47] Schmidt KE, Kuepper JM, Schumak B, et al. Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators[J]. PLoS One, 2018, 13:e0192717.
[48] Weichhart T, Hengstschlager M, Linke M. Regulation of innate immune cell function by mTOR[J]. Nat Rev Immunol, 2015, 15:599-614.
[49] Donnelly S, Huston WM, Johnson M, et al. Targeting the master regulator mTOR:a new approach to prevent the neurological of consequences of parasitic infections?[J]. Parasit Vectors, 2017, 10:581-587.
[50] Gordon EB, Hart GT, Tran TM, et al. Inhibiting the mammalian target of rapamycin blocks the development of experimental cerebral malaria[J]. mBio, 2015, 6:e00725-15.
[51] Mejia P, Trevino-Villarreal JH, Reynolds JS, et al. A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration[J]. Malar J, 2017, 16:455-467.
[52] Niewold P, Cohen A, van Vreden C, et al. Experimental severe malaria is resolved by targeting newly-identified monocyte subsets using immune-modifying particles combined with artesunate[J]. Commun Biol, 2018, 1:227-240.
[53] Raza M, Bharti H, Singal A, et al. Long circulatory liposomal maduramicin inhibits the growth of Plasmodium falciparum blood stages in culture and cures murine models of experimental malaria[J]. Nanoscale, 2018, 10:13773-13791.
[54] Golenser J, Buchholz V, Bagheri A, et al. Controlled release of artemisone for the treatment of experimental cerebral malaria[J]. Parasit Vectors, 2017, 10:117-127.
[55] Rehman K, Sauerzopf U, Veletzky L, et al. Effect of mild medical hypothermia on in vitro growth of Plasmodium falciparum and the activity of anti-malarial drugs[J]. Malar J, 2016, 15:162-166.
[56] Maiese K. Erythropoietin and diabetes mellitus[J]. World J Diabetes, 2015, 6:1259-1273.
[57] Wei X, Li Y, Sun X, et al. Erythropoietin protects against murine cerebral malaria through actions on host cellular immunity[J]. Infect Immun, 2014, 82:165-173.
[58] Du Y, Chen G, Zhang X, et al. Artesunate and erythropoietin synergistically improve the outcome of experimental cerebral malaria[J]. Int Immunopharmacol, 2017, 48:219-230.
[59] Dalko E, Tchitchek N, Pays L, et al. Erythropoietin levels increase during cerebral malaria and correlate with heme, interleukin-10 and tumor necrosis factor-alpha in India[J]. PLoS One, 2016, 11:e0158420.
[60] Serghides L, McDonald CR, Lu Z, et al. PPARgamma agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria[J]. PLoS Pathog, 2014, 10:e1003980.
[61] Kapadia R, Yi JH, Vemuganti R. Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists[J]. Front Biosci, 2008, 13:1813-1826.
[62] Martin HL, Mounsey RB, Mustafa S, et al. Pharmacological manipulation of peroxisome proliferator-activated receptor gamma (PPARgamma) reveals a role for anti-oxidant protection in a model of Parkinson's disease[J]. Exp Neurol, 2012, 235:528-538.
[63] Varo R, Crowley VM, Sitoe A, et al. Safety and tolerability of adjunctive rosiglitazone treatment for children with uncomplicated malaria[J]. Malar J, 2017, 16:215-223.
[64] Cariaco Y, Lima WR, Sousa R, et al. Ethanolic extract of the fungus Trichoderma stromaticum decreases inflammation and ameliorates experimental cerebral malaria in C57BL/6 mice[J]. Sci Rep, 2018, 8:1547-1562.
[65] Yeo TW, Lampah DA, Gitawati R, et al. Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria[J]. J Exp Med, 2007, 204:2693-2704.
[66] De Caterina R, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines[J]. J Clin Invest, 1995, 96:60-68.
[67] Martins YC, Zanini GM, Frangos JA, et al. Efficacy of different nitric oxide-based strategies in preventing experimental cerebral malaria by Plasmodium berghei ANKA[J]. PLoS One, 2012, 7:e32048.
[68] Mwanga-Amumpaire J, Carroll RW, Baudin E, et al. Inhaled nitric oxide as an adjunctive treatment for cerebral malaria in children:a phase ii randomized open-label clinical trial[J]. Open Forum Infect Dis, 2015, 2:ofv111.
[69] Hawkes MT, Conroy AL, Opoka RO, et al. Inhaled nitric oxide as adjunctive therapy for severe malaria:a randomized controlled trial[J]. Malar J, 2015, 14:421-438.
[70] Orjuela-Sanchez P, Ong PK, Zanini GM, et al. Transdermal glyceryl trinitrate as an effective adjunctive treatment with artemether for late-stage experimental cerebral malaria[J]. Antimicrob Agents Chemother, 2013, 57:5462-5471.
[71] Gramaglia I, Velez J, Chang YS, et al. Citrulline protects mice from experimental cerebral malaria by ameliorating hypoargininemia, urea cycle changes and vascular leak[J]. PLoS One, 2019, 14:e0213428.
[72] Ong PK, Moreira AS, Daniel-Ribeiro CT, et al. Reversal of cerebrovascular constriction in experimental cerebral malaria by L-arginine[J]. Sci Rep, 2018, 8:15957-15968.
[73] Wang A, Huen SC, Luan HH, et al. Glucose metabolism mediates disease tolerance in cerebral malaria[J]. Proc Natl Acad Sci U S A, 2018, 115:11042-11047.
[74] Apoorv TS, Karthik C, Babu PP. AMP-activated protein kinase (AMPK) is decreased in the mouse brain during experimental cerebral malaria[J]. Neurosci Lett, 2018, 662:290-294.
[75] Cusick SE, Opoka RO, Ssemata AS, et al. Comparison of iron status 28 d after provision of antimalarial treatment with iron therapy compared with antimalarial treatment alone in Ugandan children with severe malaria[J]. Am J Clin Nutr, 2016, 103:919-925.
[76] Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, et al. Curcumin and health[J]. Molecules, 2016, 21:264-286.
[77] Reddy RC, Vatsala PG, Keshamouni VG, et al. Curcumin for malaria therapy[J]. Biochem Biophys Res Commun, 2005, 326:472-474.
[78] Dende C, Meena J, Nagarajan P, et al. Simultaneously targeting inflammatory response and parasite sequestration in brain to treat experimental cerebral malaria[J]. Sci Rep, 2015, 5:12671-12685.
[79] Freeman BD, Martins YC, Akide-Ndunge OB, et al. Endothelin-1 mediates brain microvascular dysfunction leading to long-term cognitive impairment in a model of experimental cerebral malaria[J]. PLoS Pathog, 2016, 12:e1005477.
[80] Rodriguez AAM, Carvalho LJM, Kimura EA, et al. Perillyl alcohol exhibits in vitro inhibitory activity against Plasmodium falciparum and protects against experimental cerebral malaria[J]. Int J Antimicrob Agents, 2018, 51:370-377.
[81] Bastos MF, Kayano A, Silva-Filho JL, et al. Inhibition of hypoxia-associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria[J]. FASEB J, 2018, 32:4470-4481.
[82] Hoffmann A, Pfeil J, Mueller AK, et al. MRI of iron oxide nanoparticles and myeloperoxidase activity links inflammation to brain edema in experimental cerebral malaria[J]. Radiology, 2019, 290:359-367.
[83] Genstler JT, Abdipour A. Red blood cell exchange in treatment of severe cerebral P. falciparum malaria:a case report[J]. J Clin Apher, 2019, 34:61-63.
[84] Anani WQ, Smith GP, Irani M, et al. A report of cerebral malaria treated with automated red blood cell exchange[J]. Transfusion, 2017, 57:985-988.
[85] Ou TY, Chuang CY, Chen CD, et al. Therapeutic plasma exchange in the treatment of complicated Plasmodium falciparum malaria:a case report[J]. J Clin Apher, 2018, 33:419-422.
[86] Dongare HC, Khatib KI. Exchange transfusion in severe falciparum malaria[J]. J Clin Diagn Res, 2016, 10:OD05.
[87] Calvo-Cano A, Gomez-Junyent J, Lozano M, et al. The role of red blood cell exchange for severe imported malaria in the artesunate era:a retrospective cohort study in a referral centre[J]. Malar J, 2016, 15:216-223.