Fish Hydrolysate Supplementation Containing n-3 Long Chain Polyunsaturated Fatty Acids and Peptides Prevents LPS-Induced Neuroinflammation

Nutrients - Tập 13 Số 3 - Trang 824
Mathilde Chataigner1,2, Marie Martin2, Céline Lucas3, Véronique Pallet2, Sophie Layé2, Elodie Bouvret1, Anne‐Laure Dinel3,2, Corinne Joffre2
1Abyss Ingredients, 56850 Caudan, France
2Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 146 rue Léo Saignat, 33076 Bordeaux, France
3NutriBrain Research and Technology Transfer, NutriNeuro, 146 rue Léo Saignat, 33076 Bordeaux, France

Tóm tắt

Neuroinflammation constitutes a normal part of the brain immune response orchestrated by microglial cells. However, a sustained and uncontrolled production of proinflammatory factors together with microglial activation contribute to the onset of a chronic low-grade inflammation, leading to neuronal damage and cognitive as well as behavioral impairments. Hence, limiting brain inflammatory response and improving the resolution of inflammation could be particularly of interest to prevent these alterations. Dietary n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides are good candidates because of their immunomodulatory and proresolutive properties. These compounds are present in a fish hydrolysate derived from marine-derived byproducts. In this study, we compared the effect of an 18-day supplementation with this fish hydrolysate to a supplementation with docosahexaenoic acid (DHA) on lipopolysaccharide (LPS)-induced inflammation in mice. In response to peripherally injected LPS, the fish hydrolysate supplementation decreased the hippocampal mRNA expression of the proinflammatory cytokines IL-6 (p < 0.001), IL-1β (p = 0.0008) and TNF-α (p < 0.0001), whereas the DHA supplementation reduced only the expression of IL-6 (p = 0.004). This decline in proinflammatory cytokine expressions was associated with an increase in the protein expression of IκB (p = 0.014 and p = 0.0054 as compared to the DHA supplementation and control groups, respectively) and to a modulation of microglial activation markers in the hippocampus. The beneficial effects of the fish hydrolysate could be due in part to the switch of the hippocampal oxylipin profile towards a more anti-inflammatory profile as compared to the DHA supplementation. Thus, the valorization of fish byproducts seems very attractive to prevent and counteract neuroinflammation.

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Tài liệu tham khảo

Calder, 2009, Inflammatory Disease Processes and Interactions with Nutrition, Br. J. Nutr., 101, S1, 10.1017/S0007114509377867

Calder, 2013, Long Chain Fatty Acids and Gene Expression in Inflammation and Immunity, Curr. Opin. Clin. Nutr. Metab. Care, 16, 425, 10.1097/MCO.0b013e3283620616

Aloisi, 2001, Immune Function of Microglia, Glia, 36, 165, 10.1002/glia.1106

Dantzer, 2008, From Inflammation to Sickness and Depression: When the Immune System Subjugates the Brain, Nat. Rev. Neurosci., 9, 46, 10.1038/nrn2297

Dinel, 2014, Lipopolysaccharide-Induced Brain Activation of the Indoleamine 2,3-Dioxygenase and Depressive-like Behavior Are Impaired in a Mouse Model of Metabolic Syndrome, Psychoneuroendocrinology, 40, 48, 10.1016/j.psyneuen.2013.10.014

Heneka, 2015, Neuroinflammation in Alzheimer’s Disease, Lancet Neurol., 14, 388, 10.1016/S1474-4422(15)70016-5

Parnet, 1994, Peripheral Administration of Lipopolysaccharide Induces the Expression of Cytokine Transcripts in the Brain and Pituitary of Mice, Brain Res. Mol. Brain Res., 27, 157, 10.1016/0169-328X(94)90197-X

Nimmerjahn, 2005, Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo, Science, 308, 1314, 10.1126/science.1110647

2010, Polyunsaturated Fatty Acids, Neuroinflammation and Well Being, Prostaglandins Leukot. Essent. Fatty Acids, 82, 295, 10.1016/j.plefa.2010.02.006

Rothwell, 2000, Interleukin 1 in the Brain: Biology, Pathology and Therapeutic Target, Trends Neurosci., 23, 618, 10.1016/S0166-2236(00)01661-1

Venters, 2000, A New Concept in Neurodegeneration: TNFalpha Is a Silencer of Survival Signals, Trends Neurosci., 23, 175, 10.1016/S0166-2236(99)01533-7

Fullerton, 2016, Resolution of Inflammation: A New Therapeutic Frontier, Nat. Rev. Drug Discov., 15, 551, 10.1038/nrd.2016.39

Capuron, 2003, Cytokines and Depression: The Need for a New Paradigm, Brain Behav. Immun., 17, S119, 10.1016/S0889-1591(02)00078-8

Calder, 2005, Polyunsaturated Fatty Acids and Inflammation, Biochem. Soc. Trans., 33, 423, 10.1042/BST0330423

Joffre, C., Rey, C., and Layé, S. (2019). N-3 Polyunsaturated Fatty Acids and the Resolution of Neuroinflammation. Front. Pharmacol., 10.

Nadjar, 2018, Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology, Pharmacol. Rev., 70, 12, 10.1124/pr.117.014092

Hong, 2003, Novel Docosatrienes and 17S-Resolvins Generated from Docosahexaenoic Acid in Murine Brain, Human Blood, and Glial Cells. Autacoids in Anti-Inflammation, J. Biol. Chem., 278, 14677, 10.1074/jbc.M300218200

Levy, 2001, Lipid Mediator Class Switching during Acute Inflammation: Signals in Resolution, Nat. Immunol., 2, 612, 10.1038/89759

Rey, 2016, Resolvin D1 and E1 Promote Resolution of Inflammation in Microglial Cells in Vitro, Brain Behav. Immun., 55, 249, 10.1016/j.bbi.2015.12.013

Rey, 2019, Dietary N-3 Long Chain PUFA Supplementation Promotes a pro-Resolving Oxylipin Profile in the Brain, Brain Behav. Immun., 76, 17, 10.1016/j.bbi.2018.07.025

Serhan, 2000, Novel Functional Sets of Lipid-Derived Mediators with Antiinflammatory Actions Generated from Omega-3 Fatty Acids via Cyclooxygenase 2–Nonsteroidal Antiinflammatory Drugs and Transcellular Processing, J. Exp. Med., 192, 1197, 10.1084/jem.192.8.1197

Serhan, 2015, Protectins and Maresins: New pro-Resolving Families of Mediators in Acute Inflammation and Resolution Bioactive Metabolome, Biochim. Biophys. Acta, 1851, 397, 10.1016/j.bbalip.2014.08.006

Balvers, 2012, Fish Oil and Inflammatory Status Alter the N-3 to n-6 Balance of the Endocannabinoid and Oxylipin Metabolomes in Mouse Plasma and Tissues, Metabolomics, 8, 1130, 10.1007/s11306-012-0421-9

Hashimoto, 2015, N-3 Fatty Acids Effectively Improve the Reference Memory-Related Learning Ability Associated with Increased Brain Docosahexaenoic Acid-Derived Docosanoids in Aged Rats, Biochim. Biophys. Acta BBA Mol. Cell Biol. Lipids, 1851, 203

Balvers, 2012, Time-Dependent Effect of in Vivo Inflammation on Eicosanoid and Endocannabinoid Levels in Plasma, Liver, Ileum and Adipose Tissue in C57BL/6 Mice Fed a Fish-Oil Diet, Int. Immunopharmacol., 13, 204, 10.1016/j.intimp.2012.03.022

Birnie, M., Morrison, R., Camara, R., and Strauss, K.I. (2013). Temporal Changes of Cytochrome P450 (Cyp) and Eicosanoid-Related Gene Expression in the Rat Brain after Traumatic Brain Injury. BMC Genom., 14.

Rosenberger, 2004, Rat Brain Arachidonic Acid Metabolism Is Increased by a 6-Day Intracerebral Ventricular Infusion of Bacterial Lipopolysaccharide, J. Neurochem., 88, 1168, 10.1046/j.1471-4159.2003.02246.x

Taha, 2017, Dietary Linoleic Acid Lowering Reduces Lipopolysaccharide-Induced Increase in Brain Arachidonic Acid Metabolism, Mol. Neurobiol., 54, 4303, 10.1007/s12035-016-9968-1

Willenberg, 2016, Characterization of Changes in Plasma and Tissue Oxylipin Levels in LPS and CLP Induced Murine Sepsis, Inflamm. Res., 65, 133, 10.1007/s00011-015-0897-7

Kim, 2011, Dietary N-6 PUFA Deprivation Downregulates Arachidonate but Upregulates Docosahexaenoate Metabolizing Enzymes in Rat Brain, Biochim. Biophys. Acta BBA Mol. Cell Biol. Lipids, 1811, 111

Leng, 2018, Dietary ALA, EPA and DHA Have Distinct Effects on Oxylipin Profiles in Female and Male Rat Kidney, Liver and Serum, J. Nutr. Biochem., 57, 228, 10.1016/j.jnutbio.2018.04.002

Rao, 2007, Dietary N-3 PUFA Deprivation Alters Expression of Enzymes of the Arachidonic and Docosahexaenoic Acid Cascades in Rat Frontal Cortex, Mol. Psychiatry, 12, 151, 10.1038/sj.mp.4001887

Lee, 2019, Mechanisms of Neuroprotective Effects of Peptides Derived from Natural Materials and Their Production and Assessment, Compr. Rev. Food Sci. Food Saf., 18, 923, 10.1111/1541-4337.12451

Majumder, 2016, The Potential of Food Protein-Derived Anti-Inflammatory Peptides against Various Chronic Inflammatory Diseases, J. Sci. Food Agric., 96, 2303, 10.1002/jsfa.7600

Aihara, 2009, Casein-Derived Tripeptide, Val-Pro-Pro (VPP), Modulates Monocyte Adhesion to Vascular Endothelium, J. Atheroscler. Thromb., 16, 594, 10.5551/jat.729

Majumder, 2013, Structure and Activity Study of Egg Protein Ovotransferrin Derived Peptides (IRW and IQW) on Endothelial Inflammatory Response and Oxidative Stress, J. Agric. Food Chem., 61, 2120, 10.1021/jf3046076

Nakamura, 2013, Milk-Derived Peptides, Val-Pro-Pro and Ile-Pro-Pro, Attenuate Atherosclerosis Development in Apolipoprotein E–Deficient Mice: A Preliminary Study, J. Med. Food, 16, 396, 10.1089/jmf.2012.2541

Zhang, 2015, γ-Glutamyl Cysteine and γ-Glutamyl Valine Inhibit TNF-α Signaling in Intestinal Epithelial Cells and Reduce Inflammation in a Mouse Model of Colitis via Allosteric Activation of the Calcium-Sensing Receptor, Biochim. Biophys. Acta BBA Mol. Basis Dis., 1852, 792, 10.1016/j.bbadis.2014.12.023

Min, L.-J., Kobayashi, Y., Mogi, M., Tsukuda, K., Yamada, A., Yamauchi, K., Abe, F., Iwanami, J., Xiao, J.-Z., and Horiuchi, M. (2017). Administration of Bovine Casein-Derived Peptide Prevents Cognitive Decline in Alzheimer Disease Model Mice. PLoS ONE, 12.

Chai, 2016, Peptides from Hydrolysate of Lantern Fish (Benthosema Pterotum) Proved Neuroprotective In Vitro and In Vivo, J. Funct. Foods, 24, 438, 10.1016/j.jff.2016.04.009

Ahn, 2015, Purification and Anti-Inflammatory Action of Tripeptide from Salmon Pectoral Fin Byproduct Protein Hydrolysate, Food Chem., 168, 151, 10.1016/j.foodchem.2014.05.112

Toscano, 2019, GPETAFLR, an Octapeptide Isolated from Lupinus Angustifolius L. Protein Hydrolysate, Promotes the Skewing to the M2 Phenotype in Human Primary Monocytes, Food Funct., 10, 3303, 10.1039/C9FO00115H

Zhang, 2012, The PepT1-Transportable Soy Tripeptide VPY Reduces Intestinal Inflammation, Biochim. Biophys. Acta BBA Gen. Subj., 1820, 1753, 10.1016/j.bbagen.2012.07.007

Chataigner, 2020, Dietary Fish Hydrolysate Supplementation Containing N-3 LC-PUFAs and Peptides Prevents Short-Term Memory and Stress Response Deficits in Aged Mice, Brain Behav. Immun., 91, 716, 10.1016/j.bbi.2020.09.022

Belhaj, 2013, Anxiolytic-like Effect of a Salmon Phospholipopeptidic Complex Composed of Polyunsaturated Fatty Acids and Bioactive Peptides, Mar. Drugs, 11, 4294, 10.3390/md11114294

2010, Effets Sur Les Fonctions Cognitives et Mnésiques de Sujets Sains d’un Hydrolysat de Protéines Xde Poisson (FPHD!Àà): Étude Comparative Avec Le Ginkgo Biloba (EGB 761®), Méd. Longév., 2, 57, 10.1016/j.mlong.2010.04.004

Mingam, 2008, Uncoupling of Interleukin-6 from Its Signalling Pathway by Dietary n-3-Polyunsaturated Fatty Acid Deprivation Alters Sickness Behaviour in Mice, Eur. J. Neurosci., 28, 1877, 10.1111/j.1460-9568.2008.06470.x

Simões, A.E., Pereira, D.M., Amaral, J.D., Nunes, A.F., Gomes, S.E., Rodrigues, P.M., Lo, A.C., D’Hooge, R., Steer, C.J., and Thibodeau, S.N. (2013). Efficient Recovery of Proteins from Multiple Source Samples after Trizol® or Trizol®LS RNA Extraction and Long-Term Storage. BMC Genom., 14.

Labrousse, V.F., Nadjar, A., Joffre, C., Costes, L., Aubert, A., Grégoire, S., Bretillon, L., and Layé, S. (2012). Short-Term Long Chain Omega3 Diet Protects from Neuroinflammatory Processes and Memory Impairment in Aged Mice. PLoS ONE, 7.

Lafourcade, 2011, Nutritional Omega-3 Deficiency Abolishes Endocannabinoid-Mediated Neuronal Functions, Nat. Neurosci., 14, 345, 10.1038/nn.2736

Larrieu, 2012, Nutritional N-3 Polyunsaturated Fatty Acids Deficiency Alters Cannabinoid Receptor Signaling Pathway in the Brain and Associated Anxiety-like Behavior in Mice, J. Physiol. Biochem., 68, 671, 10.1007/s13105-012-0179-6

Baillif, 2013, LC-MS/MS Method for Rapid and Concomitant Quantification of pro-Inflammatory and pro-Resolving Polyunsaturated Fatty Acid Metabolites, J. Chromatogr. B Anal. Technol. Biomed. Life Sci., 932, 123, 10.1016/j.jchromb.2013.06.014

Bara, O., Day, J., and Djouadi, S.M. (2013, January 10–13). Nonlinear State Estimation for Complex Immune Responses. Proceedings of the 52nd IEEE Conference on Decision and Control, Florence, Italy.

Serhan, 2014, Pro-Resolving Lipid Mediators Are Leads for Resolution Physiology, Nature, 510, 92, 10.1038/nature13479

Serhan, 2005, Resolution of Inflammation: The Beginning Programs the End, Nat. Immunol., 6, 1191, 10.1038/ni1276

Barnig, 2019, Activation of Resolution Pathways to Prevent and Fight Chronic Inflammation: Lessons from Asthma and Inflammatory Bowel Disease, Front. Immunol., 10, 1699, 10.3389/fimmu.2019.01699

Doyle, 2006, Toll-like Receptors: From the Discovery of NFkappaB to New Insights into Transcriptional Regulations in Innate Immunity, Biochem. Pharmacol., 72, 1102, 10.1016/j.bcp.2006.07.010

Butovsky, 2018, Microglial Signatures and Their Role in Health and Disease, Nat. Rev. Neurosci., 19, 622, 10.1038/s41583-018-0057-5

Cherry, 2014, Neuroinflammation and M2 Microglia: The Good, the Bad, and the Inflamed, J. Neuroinflamm., 11, 98, 10.1186/1742-2094-11-98

Hanisch, 2013, Functional Diversity of Microglia—How Heterogeneous Are They to Begin With?, Front. Cell Neurosci., 7, 65, 10.3389/fncel.2013.00065

Czapski, 2010, Systemic Administration of Lipopolysaccharide Induces Molecular and Morphological Alterations in the Hippocampus, Brain Res., 1356, 85, 10.1016/j.brainres.2010.07.096

Farooqui, 2007, Modulation of Inflammation in Brain: A Matter of Fat, J. Neurochem., 101, 577, 10.1111/j.1471-4159.2006.04371.x

Nadjar, 2005, NFkappaB Activates in Vivo the Synthesis of Inducible Cox-2 in the Brain, J. Cereb. Blood Flow Metab., 25, 1047, 10.1038/sj.jcbfm.9600106

Rivest, 1999, Activation of the Nuclear Factor Kappa B (NF-KappaB) and Cyclooxygenase-2 (COX-2) Genes in Cerebral Blood Vessels in Response to Systemic Inflammation, Mol. Psychiatry, 4, 500, 10.1038/sj.mp.4000679

Yamamoto, 1998, Transcriptional Regulation of Fatty Acid Cyclooxygenases-1 and -2, Int. J. Tissue React., 20, 17

Delpech, 2015, Dietary N-3 PUFAs Deficiency Increases Vulnerability to Inflammation-Induced Spatial Memory Impairment, Neuropsychopharmacology, 40, 2774, 10.1038/npp.2015.127

Marcheselli, 2003, Novel Docosanoids Inhibit Brain Ischemia-Reperfusion-Mediated Leukocyte Infiltration and Pro-Inflammatory Gene Expression, J. Biol. Chem., 278, 43807, 10.1074/jbc.M305841200

Orr, 2013, Unesterified Docosahexaenoic Acid Is Protective in Neuroinflammation, J. Neurochem., 127, 378, 10.1111/jnc.12392

Shi, 2017, Fish Oil Prevents Lipopolysaccharide-Induced Depressive-Like Behavior by Inhibiting Neuroinflammation, Mol. Neurobiol., 54, 7327, 10.1007/s12035-016-0212-9

Desai, 2016, Reduced Acute Neuroinflammation and Improved Functional Recovery after Traumatic Brain Injury by α-Linolenic Acid Supplementation in Mice, J. Neuroinflamm., 13, 253, 10.1186/s12974-016-0714-4

Salvatori, 2012, Docosahexaenoic Acid Modulates Inflammatory and Antineurogenic Functions of Activated Microglial Cells, J. Neurosci. Res., 90, 575, 10.1002/jnr.22783

Chang, 2015, Docosahexaenoic Acid (DHA): A Modulator of Microglia Activity and Dendritic Spine Morphology, J. Neuroinflamm., 12, 34, 10.1186/s12974-015-0244-5

Chen, 2017, Polyunsaturated Fatty Acids Ameliorate Aging via Redox-Telomere-Antioncogene Axis, Oncotarget, 8, 7301, 10.18632/oncotarget.14236

Sargueil, 2008, Docosahexaenoic Acid Prevents Lipopolysaccharide-Induced Cytokine Production in Microglial Cells by Inhibiting Lipopolysaccharide Receptor Presentation but Not Its Membrane Subdomain Localization, J. Neurochem., 105, 296, 10.1111/j.1471-4159.2007.05129.x

Lu, 2013, Spinal Injection of Docosahexaenoic Acid Attenuates Carrageenan-Induced Inflammatory Pain through Inhibition of Microglia-Mediated Neuroinflammation in the Spinal Cord, Neuroscience, 241, 22, 10.1016/j.neuroscience.2013.03.003

Ma, 2009, Beta-Amyloid Oligomers Induce Phosphorylation of Tau and Inactivation of Insulin Receptor Substrate via c-Jun N-Terminal Kinase Signaling: Suppression by Omega-3 Fatty Acids and Curcumin, J. Neurosci., 29, 9078, 10.1523/JNEUROSCI.1071-09.2009

Belayev, 2011, Docosahexaenoic Acid Therapy of Experimental Ischemic Stroke, Transl. Stroke Res., 2, 33, 10.1007/s12975-010-0046-0

Chang, 2013, Docosahexaenoic Acid Reduces Cellular Inflammatory Response Following Permanent Focal Cerebral Ischemia in Rats, J. Nutr. Biochem., 24, 2127, 10.1016/j.jnutbio.2013.08.004

Chen, 2014, N-3 PUFA Supplementation Benefits Microglial Responses to Myelin Pathology, Sci. Rep., 4, 7458, 10.1038/srep07458

Eady, T.N., Belayev, L., Khoutorova, L., Atkins, K.D., Zhang, C., and Bazan, N.G. (2012). Docosahexaenoic Acid Signaling Modulates Cell Survival in Experimental Ischemic Stroke Penumbra and Initiates Long-Term Repair in Young and Aged Rats. PLoS ONE, 7.

Eady, 2012, Docosahexaenoic Acid Complexed to Human Albumin in Experimental Stroke: Neuroprotective Efficacy with a Wide Therapeutic Window, Exp. Transl. Stroke Med., 4, 19, 10.1186/2040-7378-4-19

Hjorth, 2013, Omega-3 Fatty Acids Enhance Phagocytosis of Alzheimer’s Disease-Related Amyloid-β 42 by Human Microglia and Decrease Inflammatory Markers, J. Alzheimer’s Dis., 35, 697, 10.3233/JAD-130131

Manzhulo, 2018, Docosahexaenoic Acid Induces Changes in Microglia/Macrophage Polarization after Spinal Cord Injury in Rats, Acta Histochem., 120, 741, 10.1016/j.acthis.2018.08.005

Serhan, 2002, Resolvins: A Family of Bioactive Products of Omega-3 Fatty Acid Transformation Circuits Initiated by Aspirin Treatment that Counter Proinflammation Signals, J. Exp. Med., 196, 1025, 10.1084/jem.20020760

Serhan, 2008, Anti-Inflammatory and Proresolving Lipid Mediators, Annu. Rev. Pathol., 3, 279, 10.1146/annurev.pathmechdis.3.121806.151409

Lukiw, 2005, A Role for Docosahexaenoic Acid-Derived Neuroprotectin D1 in Neural Cell Survival and Alzheimer Disease, J. Clin. Investig., 115, 2774, 10.1172/JCI25420

Orr, 2008, The Emerging Role of Docosahexaenoic Acid in Neuroinflammation, Curr. Opin. Investig. Drugs, 9, 735

Dalli, 2013, The Novel 13S,14S-Epoxy-Maresin Is Converted by Human Macrophages to Maresin 1 (MaR1), Inhibits Leukotriene A4 Hydrolase (LTA4H), and Shifts Macrophage Phenotype, FASEB J., 27, 2573, 10.1096/fj.13-227728

Serhan, 2009, Maresins: Novel Macrophage Mediators with Potent Antiinflammatory and Proresolving Actions, J. Exp. Med., 206, 15, 10.1084/jem.20081880

Gronert, 2017, Maresin 1 Promotes Inflammatory Resolution, Neuroprotection, and Functional Neurological Recovery After Spinal Cord Injury, J. Neurosci., 37, 11731, 10.1523/JNEUROSCI.1395-17.2017

Xian, 2016, The Pro-Resolving Lipid Mediator Maresin 1 Protects against Cerebral Ischemia/Reperfusion Injury by Attenuating the pro-Inflammatory Response, Biochem. Biophys. Res. Commun., 472, 175, 10.1016/j.bbrc.2016.02.090

Xian, 2019, Maresin 1 Attenuates the Inflammatory Response and Mitochondrial Damage in Mice with Cerebral Ischemia/Reperfusion in a SIRT1-Dependent Manner, Brain Res., 1711, 83, 10.1016/j.brainres.2019.01.013

Zhao, Y., Calon, F., Julien, C., Winkler, J.W., Petasis, N.A., Lukiw, W.J., and Bazan, N.G. (2011). Docosahexaenoic Acid-Derived Neuroprotectin D1 Induces Neuronal Survival via Secretase- and PPARγ-Mediated Mechanisms in Alzheimer’s Disease Models. PLoS ONE, 6.

Abdelmoaty, S., Wigerblad, G., Bas, D.B., Codeluppi, S., Fernandez-Zafra, T., El-Awady, E.-S., Moustafa, Y., Abdelhamid, A.E.S., Brodin, E., and Svensson, C.I. (2013). Spinal Actions of Lipoxin A4 and 17(R)-Resolvin D1 Attenuate Inflammation-Induced Mechanical Hypersensitivity and Spinal TNF Release. PLoS ONE, 8.

Luo, 2013, Lipoxin A4 Attenuates Brain Damage and Downregulates the Production of Pro-Inflammatory Cytokines and Phosphorylated Mitogen-Activated Protein Kinases in a Mouse Model of Traumatic Brain Injury, Brain Res., 1502, 1, 10.1016/j.brainres.2013.01.037

Medeiros, 2013, Aspirin-Triggered Lipoxin A4 Stimulates Alternative Activation of Microglia and Reduces Alzheimer Disease-Like Pathology in Mice, Am. J. Pathol., 182, 1780, 10.1016/j.ajpath.2013.01.051

Walker, 2011, Lipoxin A4 Increases Survival by Decreasing Systemic Inflammation and Bacterial Load in Sepsis, Shock, 36, 410, 10.1097/SHK.0b013e31822798c1

Guo, 2016, Lipoxin A4 Reduces Inflammation through Formyl Peptide Receptor 2/P38 MAPK Signaling Pathway in Subarachnoid Hemorrhage Rats, Stroke, 47, 490, 10.1161/STROKEAHA.115.011223

Martini, 2016, Lipoxin A4 Inhibits Microglial Activation and Reduces Neuroinflammation and Neuropathic Pain after Spinal Cord Hemisection, J. Neuroinflamm., 13, 75, 10.1186/s12974-016-0540-8

Wang, 2011, Aspirin-Triggered Lipoxin A4 Attenuates LPS-Induced pro-Inflammatory Responses by Inhibiting Activation of NF-ΚB and MAPKs in BV-2 Microglial Cells, J. Neuroinflamm., 8, 95, 10.1186/1742-2094-8-95

Hampson, 2002, 12-Hydroxyeicosatetrenoate (12-HETE) Attenuates AMPA Receptor-Mediated Neurotoxicity: Evidence for a G-Protein-Coupled HETE Receptor, J. Neurosci., 22, 257, 10.1523/JNEUROSCI.22-01-00257.2002

Sun, 2015, 12/15-Lipoxygenase Metabolites of Arachidonic Acid Activate PPARγ: A Possible Neuroprotective Effect in Ischemic Brain, J. Lipid Res., 56, 502, 10.1194/jlr.M053058