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BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2019

Open Access 01-12-2019 | Research article

Qingkailing injection ameliorates cerebral ischemia-reperfusion injury and modulates the AMPK/NLRP3 Inflammasome Signalling pathway

Authors: Chongyang Ma, Xueqian Wang, Tian Xu, Xue Yu, Shuang Zhang, Shuling Liu, Yushan Gao, Shuning Fan, Changxiang Li, Changming Zhai, Fafeng Cheng, Qingguo Wang

Published in: BMC Complementary Medicine and Therapies | Issue 1/2019

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Abstract

Background

Cerebral ischemia is the second-leading cause of death and the main cause of permanent adult disabilities worldwide. Qingkailing (QKL) injection, a patented Chinese medicine approved by the China Food and Drug Administration, has been widely used in clinical practice to treat cerebral ischemia in China. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is activated in cerebral ischemia and thus, is an effective therapeutic target. AMP-activated protein kinase (AMPK) is an important regulator inhibiting NLRP3 inflammasome activation.

Methods

We investigated the potential of QKL injection to provide neuroprotection after cerebral ischemia in a rat model of middle cerebral artery occlusion (MCAO). Adult male Sprague-Dawley rats (210–230 g) were randomly divided into three groups which consist of sham, MCAO and 3 ml/kg QKL. Rats in the QKL group received intraperitoneal injections of 3 ml/kg QKL, while rats in other groups were given saline in the same volumes. After 90 min ischemia and 24 h reperfusion, neurological function, laser speckle imaging, brain infarction, brain water content and brain blood barrier permeability were examined and cell apoptosis at prefrontal cortex were evaluated 24 h after MCAO, and western blot and real-time quantitative polymerase chain reaction was also researched, respectively.

Results

Intraperitoneal administration of QKL alleviated neurological deficiencies, cerebral infarction, blood-brain barrier permeability, brain oedema and brain cell apoptosis after MCAO induction. QKL decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, and increased anti-inflammatory cytokines, IL-4 and IL-10. Furthermore, QKL activated phosphorylated AMPK, decreased oxidative stress and decreased NLRP3 inflammasome activation.

Conclusions

QKL relieved cerebral ischemia reperfusion injury and suppressed the inflammatory response by inhibiting AMPK-mediated activation of the NLRP3 inflammasome. These results suggest that QKL might have potential in treating brain inflammatory response and attenuating the cerebral ischemia-reperfusion injury.
Literature
1.
Feigin VL, Krishnamurthi RV, Parmar P, Norrving B, Mensah GA, Bennett DA, Barker-Collo S, Moran AE, Sacco RL, Truelsen T. Update on the global burden of ischemic and hemorrhagic stroke in 1990-2013: the GBD 2013 study. Neuroepidemiology. 2015;45(3):161–76.CrossRef
2.
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, Floyd J, Fornage M, Gillespie C, Isasi C. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146–603.CrossRef
3.
Powers W, Rabinstein A, Ackerson T, Adeoye O, Bambakidis N, Becker K, Biller J, Brown M, Demaerschalk B, Hoh B. 2018 guidelines for the early management of patients with acute ischemic stroke. Stroke. 2018;49(3):e46-e97.
4.
Huang J, Wang T, Yu D, Fang X, Fan H, Liu Q, Yi G, Yi X, Liu Q. l-Homocarnosine attenuates inflammation in cerebral ischemia–reperfusion injury through inhibition of nod-like receptor protein 3 inflammasome. Int J Biol Macromol. 2018;118:357-64.
5.
Cai W, Zhang K, Li P, Zhu L, Xu J, Yang B, Hu X, Lu Z, Chen J. Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: an aging effect. Ageing Res Rev. 2017;34:77–87.CrossRef
6.
Hoseini Z, Sepahvand F, Rashidi B, Sahebkar A, Masoudifar A, Mirzaei H. NLRP3 inflammasome: its regulation and involvement in atherosclerosis. J Cell Physiol. 2018;233(3):2116-32.
7.
Elliott EI, Sutterwala FS. Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol Rev. 2015;265(1):35–52.CrossRef
8.
Kanneganti T-D. Inflammatory bowel disease and the NLRP3 Inflammasome. N Engl J Med. 2017;377(7):694–6.CrossRef
9.
Fann DY-W, Lee S, Manzanero S, Tang S, Gelderblom M, Chunduri P, Bernreuther C, Glatzel M, Cheng Y, Thundyil J. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 2013;4(9):e790.CrossRef
10.
Dong Y, Fan C, Hu W, Jiang S, Ma Z, Yan X, Deng C, Di S, Xin Z, Wu G. Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling. J Pineal Res. 2016;60(3):253–62.CrossRef
11.
Yang F, Wang Z, Wei X, Han H, Meng X, Zhang Y, Shi W, Li F, Xin T, Pang Q. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J Cereb Blood Flow Metab. 2014;34(4):660–7.CrossRef
12.
Day E A, Ford R J, Steinberg G R. AMPK as a therapeutic target for treating metabolic diseases[J]. Trends in Endocrinol Metab. 2017;28(8):545-60.
13.
Cordero MD, Williams MR, Ryffel B. AMP-activated protein kinase regulation of the NLRP3 inflammasome during aging[J]. Trends inEndocrinol Metab. 2018;29(1):8-17.
14.
Shen P, Hou S, Zhu M, Zhao M, Ouyang Y, Feng J. Cortical spreading depression preconditioning mediates neuroprotection against ischemic stroke byinducing AMP-activated protein kinase-dependent autophagy in a rat cerebral ischemic/reperfusion injury model. J Neurochem. 2017;140(5):799-813.
15.
Medicine BUoC: The study of novel dosage form of an Gong Niu Huang wan. J New Med 1975, 8(12):12–13.
16.
Sun Liangming CF, Xueqian W, Qingguo W. A systematic review and Meta -analysis of Qingkailing injection on acute stroke. Zhongguo Zhongyi Jizheng. 2016;25(5):772–6.
17.
Cheng F, Wang X, Lu Y, Zhong X, Zhao Y, Wang Q. Chinese medicine injection qingkailing for treatment of acute ischemia stroke: a systematicreview of randomized controlled trials[J]. Evid Based Complement Alternat Med. 2012;2012, Article ID 213172:7.
18.
Wang G, Xie Y, Wang L, Wang Q, Jia P, Feng B. Analysis of drug combination characteristics of Qingkailing injection for treating abnormal inflammatory factors in real world. China J Chinese Materia Medica. 2017;42(10):1984–90.
19.
Mana L, Wang S, Zhu H, Xing Y, Lou L, Wu A, Dong B, Sun Y, Yang S, Wang L. Qingkailing Suppresses the Activation of BV2 Microglial Cells by Inhibiting Hypoxia/Reoxygenation-Induced Inflammatory Responses. Evidence-Based Complementray Alternative Med. 2014;2014(1):696218.
20.
Zheng Y, Hou J, Liu J, Yao M, Li L, Zhang B, Zhu H, Wang Z. Inhibition of autophagy contributes to melatonin-mediated neuroprotection against transient focal cerebral ischemia in rats. J Pharmacol Sci. 2014;124(3):354–64.CrossRef
21.
Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989;20(1):84–91.CrossRef
22.
Beker MC, Caglayan AB, Kelestemur T, Caglayan B, Yalcin E, Yulug B, Kilic U, Hermann DM, Kilic E. Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation. Oncotarget. 2015;6(31):30604–14.CrossRef
23.
Wang W, Ma X, Han J, Zhou M, Ren H, Pan Q, Zheng C, Zheng Q. Neuroprotective effect of Scutellarin on ischemic cerebral injury by Down-regulating the expression of angiotensin-converting enzyme and AT1 receptor. PLoS One. 2016;11(1):e0146197.CrossRef
24.
Chen B, Wang G, Li W, Liu W, Lin R, Tao J, Jiang M, Chen L, Wang Y. Memantine attenuates cell apoptosis by suppressing the Calpain-Caspase-3 pathway in an experimental model of ischemic stroke. Exp Cell Res. 2017;351(2):163–72.CrossRef
25.
Cheng F, Zhong X, Lu Y, Wang X, Song W, Guo S, Wang X, Liu D, Wang Q. Refined Qingkailing protects MCAO mice from endoplasmic reticulum stress-induced apoptosis with a broad time window. Evid Based Complement Alternat Med. 2012;2012 Article ID567872:12.
26.
Poinsatte K, Selvaraj UM, Ortega SB, Plautz EJ, Kong X, Gidday JM, Stowe AM. Quantification of neurovascular protection following repetitive hypoxic preconditioning and transient middle cerebral artery occlusion in mice. J Vis Exp Jove. 2015;379(99):e52675.
27.
Oh TW, Park KH, Jung HW, Park YK. Neuroprotective effect of the hairy root extract of Angelica gigas NAKAI on transient focal cerebral ischemia in rats through the regulation of angiogenesis. BMC Complement Altern Med. 2015;15(1):1–11.CrossRef
28.
Liu MW, Wei R, Su MX, Li H, Fang TW, Zhang W. Effects of Panax notoginseng saponins on severe acute pancreatitis through the regulation of mTOR/Akt and caspase-3 signaling pathway by upregulating miR-181b expression in rats. BMC Complement Altern Med. 2018;18(1):51.CrossRef
29.
Xu S, Zhong A, Ma H, Li D, Hu Y, Xu Y, Zhang J. Neuroprotective effect of salvianolic acid B against cerebral ischemic injury in rats via the CD40/NF-ΰB pathway associated with suppression of platelets activation and neuroinflammation. Brain Res. 2017:1661, 37–48.
30.
Cheng F, Ma C, Wang X, Zhai C, Wang G, Xu X, Mu J, Li C, Wang Z, Zhang X. Effect of traditional Chinese medicine formula Sinisan on chronic restraint stress-induced nonalcoholic fatty liver disease: a rat study. BMC Complement Alternat Med. 2017;17(1):203.CrossRef
31.
Zhang Z, Qin L, Peng L, Zhang Q, Wang Q, Lu Z, Song Y, Gao X. Pharmacokinetic-pharmacodynamic modeling to study the antipyretic effect of Qingkailing injection on pyrexia model rats. Molecules. 2016;21(3):317.CrossRef
32.
Ismael S, Zhao L, Nasoohi S, Ishrat T. Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke. Sci Rep. 2018;8(1):5971.CrossRef
33.
Kim MJ, Kim EH, Pun NT, Chang J-H, Kim J, Jeong J-H, Choi DY, Kim S-H, Park P-H. Globular adiponectin inhibits lipopolysaccharide-primed inflammasomes activation in macrophages via autophagy induction: the critical role of AMPK signaling. Int J Mol Sci. 2017;18(6):1275.CrossRef
34.
Jiang S, Li T, Ji T, Yi W, Gu C. AMPK: potential therapeutic target for ischemic stroke. Theranostics. 2018;8(16):4535–51.CrossRef
35.
Bullón P, Alcocer-Gómez E, Carrión AM, Marín-Aguilar F, Garrido-Maraver J, Román-Malo L, Ruiz-Cabello J, Culic O, Ryffel B, Apetoh L. AMPK phosphorylation modulates pain by activation of NLRP3 Inflammasome. Antioxid Redox Signal. 2016;24(3):157.CrossRef
36.
Qiu J, Wang M, Zhang J, Cai Q, Lu D, Li Y, Dong Y, Zhao T, Chen H. The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling. Int Immunopharmacol. 2016;40:492–500.CrossRef
37.
Nguyen H, Zarriello S, Rajani M, Tuazon J, Napoli E, Borlongan CV. Understanding the role of dysfunctional and healthy mitochondria in strokepathology and its treatment. Int J Mol Sci. 2018;19(7):2127.
38.
Garrido-Maraver J, Paz MV, Cordero MD, Bautista-Lorite J, Oropesa-Ávila M, de la Mata M, Pavón AD, De LI, Alcocer-Gómez E, Galán F: Critical role of AMP-activated protein kinase in the balance between mitophagy and mitochondrial biogenesis in MELAS disease. Biochim Biophys Acta 2015, 1852(11):2535–2553.
39.
Heid ME, Keyel PA, Kamga C, Shiva S, Watkins SC, Salter RD. Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation. J Immunol. 2013;191(10):5230–8.CrossRef
40.
Yang SJ, Shao GF, Chen JL, Gong J. The NLRP3 inflammasome: an important driver of neuroinflammation in hemorrhagic stroke. Cell Mol Neurobiol. 2018;38(3):595-603.
41.
Liu Q, Lv H, Wen Z, Ci X, Peng L. Isoliquiritigenin activates nuclear factor Erythroid-2 related factor 2 to suppress the NOD-like receptor protein 3 Inflammasome and inhibits the NF-κB pathway in macrophages and in acute lung injury. Front Immunol. 2017;8:1518.CrossRef
42.
Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, Zheng M, Zhang X, Xia D, Ke Y. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity. 2016;45(4):802–16.CrossRef
43.
Li S, Sun X, Xu L, Sun R, Ma Z, Deng X, Liu B, Fu Q, Qu R, Ma S. Baicalin attenuates in vivo and in vitro hyperglycemia-exacerbated ischemia/reperfusion injury by regulating mitochondrial function in a manner dependent on AMPK. Eur J Pharmacol. 2017;815:118-126.
44.
Li CG, Yan L, Mai FY, Shi ZJ, Xu LH, Jing YY, Zha QB, Ouyang DY, He XH. Baicalin inhibits NOD-like receptor family, Pyrin containing domain 3 Inflammasome activation in murine macrophages by augmenting protein kinase a signaling. Front Immunol. 2017;8:1409.
Metadata
Title
Qingkailing injection ameliorates cerebral ischemia-reperfusion injury and modulates the AMPK/NLRP3 Inflammasome Signalling pathway
Authors
Chongyang Ma
Xueqian Wang
Tian Xu
Xue Yu
Shuang Zhang
Shuling Liu
Yushan Gao
Shuning Fan
Changxiang Li
Changming Zhai
Fafeng Cheng
Qingguo Wang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2019
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-019-2703-5

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