Login Register Cart 0
Generic placeholder image

Current Neurovascular Research

Editor-in-Chief

ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Simvastatin Upregulates Lipoxin A4 and Accelerates Neuroinflammation Resolution After Intracerebral Hemorrhage

Author(s): Jianbo Zhang, Na Hao, Wei Li, Qianwei Chen, Zhi Chen, Hua Feng, Yao Wu* and Xia Shi*

Volume 19, Issue 3, 2022

Published on: 18 October, 2022

Page: [321 - 332] Pages: 12

DOI: 10.2174/1567202619666220913124627

Price: $65

Abstract

Background: Previous studies have demonstrated that statins can relieve inflammatory brain injury after intracerebral hemorrhage (ICH), but the mechanisms remain poorly characterized. This study aims to test whether simvastatin exerts an anti-inflammatory effect by regulating the proresolving mediators.

Methods: First, male Sprague–Dawley rats had an injection of 200 μL autologous blood. Then, rats were randomly divided into groups treated with simvastatin (i.p. 2 mg/kg) or vehicle. Next, all rats underwent pro-resolving mediator lipoxin A4 (LXA4) level detection, flow cytometric, immunofluorescence, brain edema measurement, neurological scoring and western blot analysis.

Results: We found that simvastatin significantly increased the plasma level of LXA4, an endogenous formyl-peptide receptor 2 (FPR2) agonist, in the early stage of ICH. Consistent with the effect of simvastatin, exogenous LXA4 administration also promoted apoptosis of the circulating neutrophils, reduced neutrophils brain infiltration, and ameliorated inflammatory brain injury after ICH. In addition, similar to simvastatin, exogenous LXA4 markedly decreased the level of phosphorylated p38 mitogen-activated protein kinase (MAPK) and the apoptosis-related proteins myeloid cell leukemia 1(Mcl-1)/Bax ratio (a decreased ratio represents the induction of apoptosis) in circulating neutrophils isolated from ICH rats. Notably, all of the aforementioned effects of simvastatin on ICH were significantly abolished by Boc-2, a selective antagonist of FPR2. Moreover, simvastatin led to a similar Mcl-1/Bax ratio reduction as SB203580 (a p38 MAPK inhibitor), but it was abolished by P79350 (a p38 MAPK agonist).

Conclusion: Collectively, these results suggest that simvastatin ameliorates ICH-mediated inflammatory brain injury, possibly by upregulating the level of pro-resolving mediator LXA4 and further stimulating the FPR2/p38 MAPK signaling pathway.

Keywords: Intracerebral hemorrhage, Statins, Neutrophils, Apoptosis, Lipoxin A4, Formyl-peptide receptor 2, Inflammation

« Previous Next »
[1]
Cordonnier C, Demchuk A, Ziai W, Anderson CS. Intracerebral haemorrhage: Current approaches to acute management. Lancet 2018; 392(10154): 1257-68.
[http://dx.doi.org/10.1016/S0140-6736(18)31878-6] [PMID: 30319113]
[2]
Xi G, Strahle J, Hua Y, Keep RF. Progress in translational research on intracerebral hemorrhage: Is there an end in sight? Prog Neurobiol 2014; 115: 45-63.
[http://dx.doi.org/10.1016/j.pneurobio.2013.09.007] [PMID: 24139872]
[3]
Zhou Y, Wang Y, Wang J, Anne Stetler R, Yang QW. Inflammation in intracerebral hemorrhage: From mechanisms to clinical translation. Prog Neurobiol 2014; 115: 25-44.
[http://dx.doi.org/10.1016/j.pneurobio.2013.11.003] [PMID: 24291544]
[4]
Otto CM. Statins for primary prevention of cardiovascular disease. BMJ 2016; 355: i6334.
[http://dx.doi.org/10.1136/bmj.i6334] [PMID: 27884825]
[5]
Chen Q, Shi X, Tan Q, et al. Simvastatin promotes hematoma absorption and reduces hydrocephalus following intraventricular hemorrhage in part by upregulating CD36. Transl Stroke Res 2017; 8(4): 362-73.
[http://dx.doi.org/10.1007/s12975-017-0521-y] [PMID: 28102508]
[6]
Flint AC, Conell C, Rao VA, et al. Effect of statin use during hospitalization for intracerebral hemorrhage on mortality and discharge disposition. JAMA Neurol 2014; 71(11): 1364-71.
[http://dx.doi.org/10.1001/jamaneurol.2014.2124] [PMID: 25244578]
[7]
Witsch J, Al-Mufti F, Connolly ES, et al. Statins and perihemorrhagic edema in patients with spontaneous intracerebral hemorrhage. Neurology 2019; 92(18): e2145-49.
[http://dx.doi.org/10.1212/WNL.0000000000006931] [PMID: 30728307]
[8]
Chen PS, Cheng CL, Chang YC, Kao YYH, Yeh PS, Li YH. Early statin therapy in patients with acute intracerebral hemorrhage without prior statin use. Eur J Neurol 2015; 22(5): 773-80.
[http://dx.doi.org/10.1111/ene.12649] [PMID: 25623473]
[9]
Pan YS, Jing J, Wang YL, et al. Use of statin during hospitalization improves the outcome after intracerebral hemorrhage. CNS Neurosci Ther 2014; 20(6): 548-55.
[http://dx.doi.org/10.1111/cns.12274] [PMID: 24750990]
[10]
Chung CM, Lin MS, Liu CH, et al. Discontinuing or continuing statin following intracerebral hemorrhage from the view of a national cohort study. Atherosclerosis 2018; 278: 15-22.
[http://dx.doi.org/10.1016/j.atherosclerosis.2018.08.049] [PMID: 30236866]
[11]
Lattanzi S, Cagnetti C, Provinciali L, Silvestrini M. Neutrophil-to-lymphocyte ratio predicts the outcome of acute intracerebral hemorrhage. Stroke 2016; 47(6): 1654-7.
[http://dx.doi.org/10.1161/STROKEAHA.116.013627] [PMID: 27165957]
[12]
Gusdon AM, Gialdini G, Kone G, et al. Neutrophil–lymphocyte ratio and perihematomal edema growth in intracerebral hemorrhage. Stroke 2017; 48(9): 2589-92.
[http://dx.doi.org/10.1161/STROKEAHA.117.018120] [PMID: 28698256]
[13]
Morotti A, Phuah CL, Anderson CD, et al. Leukocyte count and intracerebral hemorrhage expansion. Stroke 2016; 47(6): 1473-8.
[http://dx.doi.org/10.1161/STROKEAHA.116.013176] [PMID: 27103016]
[14]
Wang Z, Gong Q, Guo C, Luo Y, Chen L. Neutrophil-to-lymphocyte ratio predicts hematoma growth in intracerebral hemorrhage. J Int Med Res 2019; 47(7): 2970-5.
[http://dx.doi.org/10.1177/0300060519847866] [PMID: 31122126]
[15]
Zhang J, Shi X, Hao N, et al. Simvastatin reduces neutrophils infiltration into brain parenchyma after intracerebral hemorrhage via regulating peripheral neutrophils apoptosis. Front Neurosci 2018; 12: 977.
[http://dx.doi.org/10.3389/fnins.2018.00977] [PMID: 30631264]
[16]
Spite M, Serhan CN. Novel lipid mediators promote resolution of acute inflammation: Impact of aspirin and statins. Circ Res 2010; 107(10): 1170-84.
[http://dx.doi.org/10.1161/CIRCRESAHA.110.223883] [PMID: 21071715]
[17]
Futokoro R, Hijioka M, Arata M, Kitamura Y. Lipoxin A4 Receptor stimulation attenuates neuroinflammation in a mouse model of intracerebral hemorrhage. Brain Sci 2022; 12(2): 162.
[http://dx.doi.org/10.3390/brainsci12020162] [PMID: 35203926]
[18]
Guo Z, Hu Q, Xu L, et al. Lipoxin A4 reduces inflammation through formyl peptide receptor 2/p38 MAPK signaling pathway in subarachnoid hemorrhage rats. Stroke 2016; 47(2): 490-7.
[http://dx.doi.org/10.1161/STROKEAHA.115.011223] [PMID: 26732571]
[19]
Ye XH, Wu Y, Guo PP, et al. Lipoxin A4 analogue protects brain and reduces inflammation in a rat model of focal cerebral ischemia reperfusion. Brain Res 2010; 1323: 174-83.
[http://dx.doi.org/10.1016/j.brainres.2010.01.079] [PMID: 20138164]
[20]
Wu R, Zhou W, Chen S, et al. Lipoxin A 4 suppresses the development of endometriosis in an ALX receptor-dependent manner via the p38 MAPK pathway. Br J Pharmacol 2014; 171(21): 4927-40.
[http://dx.doi.org/10.1111/bph.12816] [PMID: 24923883]
[21]
González HF, Cramer A, Pimentel P, et al. Simvastatin attenuates endothelial activation through 15-Epi-lipoxin A4 production in murine chronic chagas cardiomyopathy. Antimicrob Agents Chemother 2017; 61(3): e02137-16.
[http://dx.doi.org/10.1128/AAC.02137-16] [PMID: 27993857]
[22]
El Kebir D, József L, Pan W, et al. 15-epi-lipoxin A4 inhibits myeloperoxidase signaling and enhances resolution of acute lung injury. Am J Respir Crit Care Med 2009; 180(4): 311-9.
[http://dx.doi.org/10.1164/rccm.200810-1601OC] [PMID: 19483113]
[23]
Tan Q, Chen Q, Niu Y, et al. Urokinase, a promising candidate for fibrinolytic therapy for intracerebral hemorrhage. J Neurosurg 2017; 126(2): 548-57.
[http://dx.doi.org/10.3171/2016.1.JNS152287] [PMID: 27104852]
[24]
Liew HK, Pang CY, Hsu CW, et al. Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation in rats. J Neuroinflammation 2012; 9(1): 13.
[http://dx.doi.org/10.1186/1742-2094-9-13] [PMID: 22257737]
[25]
Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G. Behavioral tests after intracerebral hemorrhage in the rat. Stroke 2002; 33(10): 2478-84.
[http://dx.doi.org/10.1161/01.STR.0000032302.91894.0F] [PMID: 12364741]
[26]
Chen Q, Tang J, Tan L, et al. Intracerebral hematoma contributes to hydrocephalus after intraventricular hemorrhage via aggravating iron accumulation. Stroke 2015; 46(10): 2902-8.
[http://dx.doi.org/10.1161/STROKEAHA.115.009713] [PMID: 26265129]
[27]
Amarenco P, Bogousslavsky J, Callahan AIII, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355(6): 549-59.
[http://dx.doi.org/10.1056/NEJMoa061894] [PMID: 16899775]
[28]
Chen Q, Zhang J, Feng H, Chen Z. An update on statins: Pleiotropic effect performed in intracerebral hemorrhage. Atherosclerosis 2019; 284: 264-5.
[http://dx.doi.org/10.1016/j.atherosclerosis.2019.01.020] [PMID: 30712828]
[29]
Van Der Most PJ, Dolga AM, Nijholt IM, Luiten PGM, Eisel ULM. Statins: Mechanisms of neuroprotection. Prog Neurobiol 2009; 88(1): 64-75.
[http://dx.doi.org/10.1016/j.pneurobio.2009.02.002] [PMID: 19428962]
[30]
Fu T, Mohan M, Brennan EP, et al. Therapeutic potential of lipoxin A 4 in chronic inflammation: Focus on cardiometabolic disease. ACS Pharmacol Transl Sci 2020; 3(1): 43-55.
[http://dx.doi.org/10.1021/acsptsci.9b00097] [PMID: 32259087]
[31]
Lv W, Lv C, Yu S, et al. Lipoxin A4 attenuation of endothelial inflammation response mimicking pancreatitis-induced lung injury. Exp Biol Med 2013; 238(12): 1388-95.
[http://dx.doi.org/10.1177/1535370213502611] [PMID: 24000382]
[32]
Li QQ, Ding DH, Wang XY, Sun YY, Wu J. Lipoxin A4 regulates microglial M1/M2 polarization after cerebral ischemia-reperfusion injury via the Notch signaling pathway. Exp Neurol 2021; 339: 113645.
[http://dx.doi.org/10.1016/j.expneurol.2021.113645] [PMID: 33600815]
[33]
Li Y, Wang N, Ma Z, et al. Lipoxin A4 protects against paraquat induced acute lung injury by inhibiting the TLR4/MyD88 mediated activation of the NF κB and PI3K/AKT pathways. Int J Mol Med 2021; 47(5): 86.
[http://dx.doi.org/10.3892/ijmm.2021.4919] [PMID: 33760150]
[34]
Wei N, Lu T, Yang L, Dong Y, Liu X. Lipoxin A4 protects primary spinal cord neurons from Erastin‐induced ferroptosis by activating the Akt/Nrf2/HO‐1 signaling pathway. FEBS Open Bio 2021; 11(8): 2118-26.
[http://dx.doi.org/10.1002/2211-5463.13203] [PMID: 34048148]
[35]
Yuan J, Lin F, Chen L, et al. Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2–IRF pathway. Inflammopharmacology 2022; 30(2): 487-98.
[http://dx.doi.org/10.1007/s10787-022-00942-y] [PMID: 35235107]
[36]
Adhyaru BB, Jacobson TA. Safety and efficacy of statin therapy. Nat Rev Cardiol 2018; 15(12): 757-69.
[http://dx.doi.org/10.1038/s41569-018-0098-5] [PMID: 30375494]
[37]
Seo WW, Seo SI, Kim Y, et al. Impact of pitavastatin on new-onset diabetes mellitus compared to atorvastatin and rosuvastatin: A distributed network analysis of 10 real-world databases. Cardiovasc Diabetol 2022; 21(1): 82.
[http://dx.doi.org/10.1186/s12933-022-01524-6] [PMID: 35606846]
[38]
Xian M, Zhan S, Zheng K, et al. Neuroprotective effect and mechanism of daidzein in oxygen-glucose deprivation/reperfusion injury based on experimental approaches and network pharmacology. Tradit Med Res 2021; 6(5): 41.
[http://dx.doi.org/10.53388/TMR20210812240]
[39]
Zhang Z, Hu C, Dai F, Tang F, Tang CL. Mechanisms and status of research on the protective effects of traditional Chinese medicine against ischemic brain injury. Tradit Med Res 2022; 7(1): 6.
[http://dx.doi.org/10.53388/TMR20211021250]

Rights & Permissions Print Cite
Article Metrics
1
© 2024 Bentham Science Publishers | Privacy Policy