Specialized pro-resolving mediators (SPMs) are bioactive lipids derived from n-3 and n-6 polyunsaturated fatty acids. SPMs promote resolution of inflammation and are reduced in Alzheimer’s disease. It is unknown whether SPMs are associated with post-stroke cognitive impairment (PSCI).
Objective:
In the present report, we aimed to study the levels of SPMs in PSCI patients in the acute phase of ischemic stroke.
Methods:
Levels of SPMs in the plasma from 36 patients with PSCI and 33 patients with post-stroke non-cognitive impairment (PSNCI) were measured by enzyme immunoassay.
Results:
We found that levels of the SPM lipoxin A4 (LXA4) were significantly reduced in PSCI patients compared with PSNCI patients. Interestingly, the LXA4 levels were positively correlated with Mini-Mental State Examination scores, but not with the National Institutes of Health Stroke Scale scores. Such alteration and correlation were not found in any of the other SPMs analyzed, i.e., including resolvin D1, resolvin D2, and maresin 1.
Conclusion:
We conclude that the plasma levels of LXA4 were reduced in PSCI patents in the acute phase of ischemic stroke and were correlated to cognitive function.
GalimbertiD, VenturelliE, FenoglioC, GuidiI, VillaC, BergamaschiniL, CortiniF, ScalabriniD, BaronP, VerganiC, BresolinN, ScarpiniE (2008) Intrathecal levels of IL-6, IL-11 and LIF in Alzheimer’s disease and frontotemporal lobar degeneration. J Neurol255, 539–544.
3.
GriffinWS, StanleyLC, LingC, WhiteL, MacLeodV, PerrotLJ, White 3rdCL, AraozC (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A86, 7611–7615.
4.
AraujoDM, LapchakPA (1994) Induction of immune system mediators in the hippocampal formation in Alzheimer’s and Parkinson’s diseases: Selective effects on specific interleukins and interleukin receptors. Neuroscience61, 745–754.
5.
RaoJS, RapoportSI, KimHW (2011) Altered neuroinflammatory, arachidonic acid cascade and synaptic markers in postmortem Alzheimer’s disease brain. Transl Psychiatry1, e31.
6.
AngelopoulosP, AgouridakiH, VaiopoulosH, SiskouE, DoutsouK, CostaV, BaloyiannisSI (2008) Cytokines in Alzheimer’s disease and vascular dementia. Int J Neurosci118, 1659–1672.
7.
BermejoP, Martin-AragonS, BenediJ, SusinC, FeliciE, GilP, RiberaJM, VillarAM (2008) Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer’s disease. Immunol Lett117, 198–202.
8.
ZulianiG, CavalieriM, GalvaniM, PassaroA, MunariMR, BosiC, ZurloA, FellinR (2008) Markers of endothelial dysfunction in older subjects with late onset Alzheimer’s disease or vascular dementia. J Neurol Sci272, 164–170.
9.
SerhanCN (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature510, 92–101.
10.
BasilMC, LevyBD (2016) Specialized pro-resolving mediators: Endogenous regulators of infection and inflammation. Nat Rev Immunol16, 51–67.
11.
ChiurchiuV, LeutiA, MaccarroneM (2018) Bioactive lipids and chronic inflammation: Managing the fire within. Front Immunol9, 38.
12.
KrashiaP, CordellaA, NobiliA, La BarberaL, FedericiM, LeutiA, CampanelliF, NataleG, MarinoG, CalabreseV, VedeleF, GhiglieriV, PicconiB, Di LazzaroG, SchirinziT, SancesarioG, CasadeiN, RiessO, BernardiniS, PisaniA, CalabresiP, ViscomiMT, SerhanCN, ChiurchiuV, D’AmelioM, MercuriNB (2019) Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease. Nat Commun10, 3945.
13.
KooijG, TrolettiCD, LeutiA, NorrisPC, RileyI, AlbaneseM, RuggieriS, LibrerosS, van der PolSMA, van Het HofB, SchellY, GuerreraG, ButtariF, MercuriNB, CentonzeD, GasperiniC, BattistiniL, de VriesHE, SerhanCN, ChiurchiuV (2020) Specialized pro-resolving lipid mediators are differentially altered in peripheral blood of patients with multiple sclerosis and attenuate monocyte and blood-brain barrier dysfunction. Haematologica105, 2056–2070.
14.
WangX, ZhuM, HjorthE, Cortes-ToroV, EyjolfsdottirH, GraffC, NennesmoI, PalmbladJ, EriksdotterM, SambamurtiK, FitzgeraldJM, SerhanCN, GranholmAC, SchultzbergM (2015) Resolution of inflammation is altered in Alzheimer’s disease. Alzheimers Dement11, 40–50.e1-2.
15.
MedeirosR, KitazawaM, PassosGF, Baglietto-VargasD, ChengD, CribbsDH, LaFerlaFM (2013) Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice. Am J Pathol182, 1780–1789.
16.
DunnHC, AgerRR, Baglietto-VargasD, ChengD, KitazawaM, CribbsDH, MedeirosR (2015) Restoration of lipoxin A4 signaling reduces Alzheimer’s disease-like pathology in the 3xTg-AD mouse model. J Alzheimers Dis43, 893–903.
17.
LukiwWJ, CuiJG, MarcheselliVL, BodkerM, BotkjaerA, GotlingerK, SerhanCN, BazanNG (2005) A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest115, 2774–2783.
18.
ArbaF, QuinnT, HankeyGJ, AliM, LeesKR, InzitariD, CollaborationV (2017) Cerebral small vessel disease, medial temporal lobe atrophy and cognitive status in patients with ischaemic stroke and transient ischaemic attack. Eur J Neurol24, 276–282.
19.
LiuR, YuX, WangJ, LiuY, LiuB, LiX, WangY, CaoT, YuanH (2020) Evaluation of the efficacy and safety of the use of acupuncture for the adjuvant treatment of patients with post-stroke cognitive impairment: Protocol for a randomized controlled trial. Trials21, 753.
20.
LeeJY, HanSH, ParkMH, BaekB, SongIS, ChoiMK, TakuwaY, RyuH, KimSH, HeX, SchuchmanEH, BaeJS, JinHK (2018) Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer’s disease. Nat Commun9, 1479.
21.
WuJ, WangA, MinZ, XiongY, YanQ, ZhangJ, XuJ, ZhangS (2011) Lipoxin A4 inhibits the production of proinflammatory cytokines induced by β-amyloid in vitro and in vivo. Biochem Biophys Res Commun408, 382–387.
HawkinsKE, DeMarsKM, AlexanderJC, de LeonLG, PachecoSC, GravesC, YangC, McCreaAO, FrankowskiJC, GarrettTJ, FeboM, Candelario-JalilE (2017) Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long-term effects on neurological recovery. Brain Behav7, e00688.
24.
SmithHK, GilCD, OlianiSM, GavinsFN (2015) Targeting formyl peptide receptor 2 reduces leukocyte-endothelial interactions in a murine model of stroke. FASEB J29, 2161–2171.
25.
HawkinsKE, DeMarsKM, SinghJ, YangC, ChoHS, FrankowskiJC, DoreS, Candelario-JalilE (2014) Neurovascular protection by post-ischemic intravenous injections of the lipoxin A4 receptor agonist, BML-111, in a rat model of ischemic stroke. J Neurochem129, 130–142.
26.
WuL, LiuZJ, MiaoS, ZouLB, CaiL, WuP, Ye duY, WuQ, LiHH (2013) Lipoxin A4 ameliorates cerebral ischaemia/reperfusion injury through upregulation of nuclear factor erythroid 2-related factor 2. Neurol Res35, 968–975.
27.
WuY, WangYP, GuoP, YeXH, WangJ, YuanSY, YaoSL, ShangY (2012) A lipoxin A4 analog ameliorates blood-brain barrier dysfunction and reduces MMP-9 expression in a rat model of focal cerebral ischemia-reperfusion injury. J Mol Neurosci46, 483–491.
28.
WuY, YeXH, GuoPP, XuSP, WangJ, YuanSY, YaoSL, ShangY (2010) Neuroprotective effect of lipoxin A4 methyl ester in a rat model of permanent focal cerebral ischemia. J Mol Neurosci42, 226–234.
29.
YeXH, WuY, GuoPP, WangJ, YuanSY, ShangY, YaoSL (2010) Lipoxin A4 analogue protects brain and reduces inflammation in a rat model of focal cerebral ischemia reperfusion. Brain Res1323, 174–183.
30.
SobradoM, PereiraMP, BallesterosI, HurtadoO, Fernandez-LopezD, PradilloJM, CasoJR, VivancosJ, NombelaF, SerenaJ, LizasoainI, MoroMA (2009) Synthesis of lipoxin A4 by 5-lipoxygenase mediates PPAR-γ-dependent, neuroprotective effects of rosiglitazone in experimental stroke. J Neurosci29, 3875–3884.
31.
ZhangX, BiX (2020) Post-stroke cognitive impairment: A review focusing on molecular biomarkers. J Mol Neurosci70, 1244–1254.
NarasimhaluK, LeeJ, LeongYL, MaL, De SilvaDA, WongMC, ChangHM, ChenC (2015) Inflammatory markers and their association with post stroke cognitive decline. Int J Stroke10, 513–518.
34.
RothenburgLS, HerrmannN, SwardfagerW, BlackSE, TennenG, KissA, GladstoneDJ, WeenJ, SnaidermanA, LanctotKL (2010) The relationship between inflammatory markers and post stroke cognitive impairment. J Geriatr Psychiatry Neurol23, 199–205.
35.
KimH, SeoJS, LeeSY, HaKT, ChoiBT, ShinYI, Ju YunY, ShinHK (2020) AIM2 inflammasome contributes to brain injury and chronic post-stroke cognitive impairment in mice. Brain Behav Immun87, 765–776.
36.
LiYQ, ChenJX, LiQW, XiaoZJ, YuanT, XieZH (2020) Targeting NLRP3 inflammasome improved the neurogenesis and post-stroke cognition in a mouse model of photothrombotic stroke. Neuroreport31, 806–813.
37.
JacksonL, DongG, AlthomaliW, SayedMA, EldahshanW, BabanB, JohnsonMH, FilosaJ, FaganSC, ErgulA (2020) Delayed administration of angiotensin II type 2 receptor (AT2R) agonist compound 21 prevents the development of post-stroke cognitive impairment in diabetes through the modulation of microglia polarization. Transl Stroke Res11, 762–775.
38.
JacksonL, DumanliS, JohnsonMH, FaganSC, ErgulA (2020) Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke. J Neuroinflammation17, 137.
39.
RingholzFC, BuchananPJ, ClarkeDT, MillarRG, McDermottM, LinnaneB, HarveyBJ, McNallyP, UrbachV (2014) Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4 ratio in children with cystic fibrosis. Eur Respir J44, 394–404.
40.
Oliveira PerucciL, Pereira SantosTA, Campi SantosP, Ribeiro TeixeiraLC, Nessralla AlpoimP, Braga GomesK, Pires SousaL, Sant’Ana DusseLM, TalvaniA (2020) Pre-eclampsia is associated with reduced resolvin D1 and maresin 1 to leukotriene B4 ratios in the plasma. Am J Reprod Immunol83, e13206.
41.
ThulS, LabatC, TemmarM, BenetosA, BackM (2017) Low salivary resolvin D1 to leukotriene B4 ratio predicts carotid intima media thickness: A novel biomarker of non-resolving vascular inflammation. Eur J Prev Cardiol24, 903–906.
42.
FredmanG, HellmannJ, ProtoJD, KuriakoseG, ColasRA, DorweilerB, ConnollyES, SolomonR, JonesDM, HeyerEJ, SpiteM, TabasI (2016) An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun7, 12859.
43.
PendleburyST, RothwellPM (2009) Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: A systematic review and meta-analysis. Lancet Neurol8, 1006–1018.
