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Neuroprotective Effect of Lipoxin A4 Methyl Ester in a Rat Model of Permanent Focal Cerebral Ischemia

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Abstract

Neuroprotective effect of lipoxin A4 methyl ester (LXA4 ME) was tested in a rat model of permanent middle cerebral artery occlusion. LXA4 ME was administrated through intracerebroventricular injection immediately after middle cerebral artery was occluded. Administration of LXA4 ME ameliorated neurological deficit, reduced infarct volume, attenuated histological damage, and decreased number of apoptotic neuron induced by ischemic insult. These neuroprotective effects of LXA4 ME were associated with inhibition of neutrophil infiltration, lipid peroxidation, and astrocyte activation. In addition, LXA4 ME also attenuated proinflammatory cytokines (TNF-α and IL-1β) production. These data suggest that LXA4 ME protects neuron against permanent cerebral ischemia by inhibiting inflammatory responses.

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References

  • Bannenberg G, Moussignac RL, Gronert K et al (2004) Lipoxins and novel 15-epi-lipoxin analogs display potent anti-inflammatory actions after oral administration. Br J Pharmacol 143(1):43–52

    Article  CAS  PubMed  Google Scholar 

  • Chiang N, Fierro IM, Gronert K, Serhan CN (2000) Activation of lipoxin A(4) receptors by aspirin-triggered lipoxins and select peptides evokes ligand-specific responses in inflammation. J Exp Med 191(7):1197–1208

    Article  CAS  PubMed  Google Scholar 

  • Chiang N, Arita M, Serhan CN (2005) Anti-inflammatory circultry: lipoxin, aspirin- triggered lipoxins and their receptor ALX. Prostaglandins Leukot Essent Fat Acids 73(3–4):163–177

    Article  CAS  Google Scholar 

  • Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36(2):180–190

    Article  CAS  PubMed  Google Scholar 

  • ElKebir D, József L, Filep JG (2008) Opposing regulation of neutrophil apoptosis through the formyl peptide receptor-like 1/lipoxin A4 receptor: implications for resolution of inflammation. J Leukoc Biol 84(3):600–606

    Article  CAS  Google Scholar 

  • Fierro IM, Colgan SP, Bernasconi G et al (2003) Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit human neutrophil migration: comparisons between synthetic 15 epimers in chemotaxis and transmigration with microvessel endothelial cells and epithelial cells. J Immunol 170(5):2688–2694

    CAS  PubMed  Google Scholar 

  • Huang J, Upadhyay UM, Tamargo RJ (2006) Inflammation in stroke and focal cerebral ischemia. Surg Neurol 66(3):232–245

    Article  PubMed  Google Scholar 

  • Jin SW, Zhang L, Lian QQ et al (2007) Posttreatment with aspirin-triggered lipoxin A4 analog attenuates lipopolysaccharide-induced acute lung injury in mice: the role of heme oxygenase-1. Anesth Analg 104(2):369–377

    Article  CAS  PubMed  Google Scholar 

  • Jordán J, Segura T, Brea D et al (2008) Inflammation as therapeutic objective in stroke. Curr Pharm Des 14(33):3549–3564

    Article  PubMed  Google Scholar 

  • Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM (2007) Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther 321(3):892–901

    Article  CAS  PubMed  Google Scholar 

  • Kleinig TJ, Vink R (2009) Suppression of inflammation in ischemic and hemorrhagic stroke: therapeutic options. Curr Opin Neurol 22(3):294–301

    Article  PubMed  Google Scholar 

  • Lavine SD, Hofman FM, Zlokovic BV (1998) Circulating antibody against tumor necrosis factor-alpha protects rat brain from reperfusion injury. J Cereb Blood Flow Metab 18(1):52–58

    Article  CAS  PubMed  Google Scholar 

  • Lawrence T, Willoughby DA, Gilroy DW (2002) Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol 2(10):787–795

    Article  CAS  PubMed  Google Scholar 

  • Li JS, Zhang W, Kang ZM et al (2009) Hyperbaric oxygen preconditioning reduces ischemia-reperfusion injury by inhibition of apoptosis via mitochondrial pathway in rat brain. Neuroscience 159(4):1309–1315

    Article  CAS  PubMed  Google Scholar 

  • Maddox JF, Hachicha M, Takano T, Petasis NA, Fokin W, Serhan CN (1997) Lipoxin A4 stable analogues are potent mimetics that stimulate human monocytes and THP-1 cell via a G-protein linked lipoxin A4 receptor. J Biol Chem 272(11):6972–6978

    Article  CAS  PubMed  Google Scholar 

  • Medeiros R, Rodrigues GB, Figueiredo CP et al (2008) Molecular mechanisms of topical anti-inflammatory effects of lipoxin A(4) in endotoxin-induced uveitis. Mol Pharmacol 74(1):154–161

    Article  CAS  PubMed  Google Scholar 

  • Mitchell S, Thomas G, Harvey K et al (2002) Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo. J Am Soc Nephrol 13(10):2497–2507

    Article  CAS  PubMed  Google Scholar 

  • Nascimento-Silva V, Arruda MA, Barja-Fidalgo C, Fierro IM (2007) Aspirin-triggered lipoxin A4 blocks reactive oxygen species generation in endothelial cells: a novel antioxidative mechanism. Thromb Haemost 97(1):88–98

    CAS  PubMed  Google Scholar 

  • Parkinson JF (2006) Lipoxin and synthetic lipoxin analogs: an overview of anti-inflammatory functions and new concepts in immunomodulation. Inflamm Allergy Drug Targets 5(2):91–106

    Article  CAS  PubMed  Google Scholar 

  • Planagumà A, Kazani S, Marigowda G et al (2008) Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. Am J Respir Crit Care Med 178(6):574–582

    Article  PubMed  Google Scholar 

  • Pouliot M, Serhan CN (1999) Lipoxin A4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor-alpha-initiated neutrophil responses and trafficking: novel regulators of a cytokine-chemokine axis relevant to periodontal diseases. J Periodontal Res 34(7):370–373

    Article  CAS  PubMed  Google Scholar 

  • Shang Y, Li X, Prasad PV et al (2009a) Erythropoietin attenuates lung injury in lipopolysaccharide treated rats. J Surg Res 155(1):104–110

    Article  CAS  PubMed  Google Scholar 

  • Shang Y, Jiang YX, Xu SP et al (2009b) Reduction of pulmonary inflammatory response by erythropoietin in a rat model of endotoxaemia. Chin Med J (Engl) 122(7):834–838

    CAS  Google Scholar 

  • Serhan CN, Savill J (2005) Resolution of inflammation: the beginning programs the end. Nat Immunol 6(12):1191–1197

    Article  CAS  PubMed  Google Scholar 

  • Serhan CN, Maddox JF, Petasis NA et al (1995) Design of lipoxin A4 stable analogs that block transmigration and adhesion of human neutrophils. Biochemistry 34(44):14609–14615

    Article  CAS  PubMed  Google Scholar 

  • Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8(5):349–361

    Article  CAS  PubMed  Google Scholar 

  • Sobrado M, Pereira MP, Ballesteros I et al (2009) Synthesis of lipoxin A4 by 5-lipoxygenase mediates PPARgamma-dependent, neuroprotective effects of rosiglitazone in experimental stroke. J Neurosci 29(12):3875–3884

    Article  CAS  PubMed  Google Scholar 

  • Sodin-Semrl S, Spagnolo A, Mikus R, Barbaro B, Varga J, Fiore S (2004) Opposing regulation of interleukin-8 and NF-kappaB responses by lipoxin A4 and serum amyloid A via the common lipoxin A receptor. Int J Immunopathol Pharmacol 17(2):145–156

    CAS  PubMed  Google Scholar 

  • Souza DG, Fagundes CT, Amaral FA et al (2007) The required role of endogenously produced lipoxin A4 and annexin-1 for the production of IL-10 and inflammatory hyporesponsiveness in mice. J Immunol 179(12):8533–8543

    CAS  PubMed  Google Scholar 

  • Svensson CI, Zattoni M, Serhan CN (2007) Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing. J Exp Med 204(2):245–252

    Article  CAS  PubMed  Google Scholar 

  • Wada K, Arita M, Nakajima A et al (2006) Leukotriene B4 and lipoxin A4 are regulatory signals for neural stem cell proliferation and differentiation. FASEB J 20(11):1785–1792

    Article  CAS  PubMed  Google Scholar 

  • Wang CX, Shuaib A (2002) Involvement of inflammatory cytokines in central nervous system injury. Prog Neurobiol 67(2):161–172

    Article  CAS  PubMed  Google Scholar 

  • Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184(1–2):53–68

    Article  CAS  PubMed  Google Scholar 

  • Wu SH, Wu XH, Liao PY, Dong L (2007) Signal transduction involved in protective effects of 15(R/S)-methyl-lipoxin A(4) on mesangioproliferative nephritis in rats. Prostaglandins Leukot Essent Fat Acids 76(3):173–180

    Article  CAS  Google Scholar 

  • Xing B, Chen H, Zhang M et al (2008) Ischemic post-conditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion. J Neurochem 105(5):1737–1745

    Article  CAS  PubMed  Google Scholar 

  • Yang GY, Zhao YJ, Davidson BL, Betz AL (1997) Overexpression of interleukin-1 receptor antagonist in the mouse brain reduces ischemic brain injury. Brain Res 751(12):181–188

    Article  CAS  PubMed  Google Scholar 

  • Zhao L, Wang Y, Sun N, Liu X, Li L, Shi J (2007) Electroacupuncture regulates TRPM7 expression through the trkA/PI3K pathway after cerebral ischemia-reperfusion in rats. Life Sci 81(15):1211–1222

    Article  CAS  PubMed  Google Scholar 

  • Zheng Z, Yenari MA (2004) Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol Res 26(8):884–892

    Article  CAS  PubMed  Google Scholar 

  • Zhou XY, Wu P, Zhang L et al (2007) Effects of lipoxin A(4) on lipopolysaccharide induced proliferation and reactive oxygen species production in RAW264.7 macrophages through modulation of G-CSF secretion. Inflamm Res 56(8):324–333

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Grant from National Natural Science Foundation of China (No. 30700784).

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Correspondence to Shi-Ying Yuan or You Shang.

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Yan Wu and Xi-Hong Ye contributed equally to this work.

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Wu, Y., Ye, XH., Guo, PP. et al. Neuroprotective Effect of Lipoxin A4 Methyl Ester in a Rat Model of Permanent Focal Cerebral Ischemia. J Mol Neurosci 42, 226–234 (2010). https://doi.org/10.1007/s12031-010-9355-8

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  • DOI: https://doi.org/10.1007/s12031-010-9355-8

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