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Neurological Sciences
Published in: Neurological Sciences 7/2017

01-07-2017 | Review Article

Pathogenic mechanisms following ischemic stroke

Authors: Seyed Esmaeil Khoshnam, William Winlow, Maryam Farzaneh, Yaghoob Farbood, Hadi Fathi Moghaddam

Published in: Neurological Sciences | Issue 7/2017

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Abstract

Stroke is the second most common cause of death and the leading cause of disability worldwide. Brain injury following stroke results from a complex series of pathophysiological events including excitotoxicity, oxidative and nitrative stress, inflammation, and apoptosis. Moreover, there is a mechanistic link between brain ischemia, innate and adaptive immune cells, intracranial atherosclerosis, and also the gut microbiota in modifying the cerebral responses to ischemic insult. There are very few treatments for stroke injuries, partly owing to an incomplete understanding of the diverse cellular and molecular changes that occur following ischemic stroke and that are responsible for neuronal death. Experimental discoveries have begun to define the cellular and molecular mechanisms involved in stroke injury, leading to the development of numerous agents that target various injury pathways. In the present article, we review the underlying pathophysiology of ischemic stroke and reveal the intertwined pathways that are promising therapeutic targets.
Literature
1.
Hossmann K-A (2006) Pathophysiology and therapy of experimental stroke. Cell Mol Neurobiol 26(7–8):1055–1081CrossRef
2.
Heron M (2007) Deaths: leading causes for 2004. Natl Vital Stat Rep 56(5):1–96PubMed
3.
Tsuchiya M, Sako K, Yura S et al (1992) Cerebral blood flow and histopathological changes following permanent bilateral carotid artery ligation in Wistar rats. Exp Brain Res 89(1):87–92PubMedCrossRef
4.
Seto S-W, Chang D, Jenkins A et al (2016) Angiogenesis in ischemic stroke and angiogenic effects of Chinese herbal medicine. Journal of clinical medicine 5(6):56PubMedCentralCrossRef
5.
Fonarow GC, Zhao X, Smith EE et al (2014) Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative. JAMA 311(16):1632–1640PubMedCrossRef
6.
Del Zoppo GJ, Saver JL, Jauch EC et al (2009) Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 40(8):2945–2948PubMedPubMedCentralCrossRef
7.
Sandercock P, Wardlaw JM, Lindley RI et al (2012) The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet (London, England) 379(9834):2352–2363CrossRef
8.
Amarenco P, Bogousslavsky J, Caplan L et al (2009) Classification of stroke subtypes. Cerebrovasc Dis 27(5):493–501PubMedCrossRef
9.
Beal CC (2010) Gender and stroke symptoms: a review of the current literature. J Neurosci Nurs 42(2):80–87PubMedCrossRef
10.
11.
Murphy TH, Li P, Betts K et al (2008) Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines. J Neurosci 28(7):1756–1772PubMedCrossRef
12.
Besancon E, Guo S, Lok J et al (2008) Beyond NMDA and AMPA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke. Trends Pharmacol Sci 29(5):268–275PubMedCrossRef
13.
Bretón RR, Rodríguez JCG (2012) Excitotoxicity and oxidative stress in acute ischemic stroke. Stroke 8:9
14.
Ouyang Y-B, Voloboueva LA, Xu L-J et al (2007) Selective dysfunction of hippocampal CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia. J Neurosci 27(16):4253–4260PubMedPubMedCentralCrossRef
15.
Xu L, Emery JF, Ouyang YB et al (2010) Astrocyte targeted overexpression of Hsp72 or SOD2 reduces neuronal vulnerability to forebrain ischemia. Glia 58(9):1042–1049PubMedPubMedCentralCrossRef
16.
Siesjö B (1992) Pathophysiology and treatment of focal cerebral ischemia. II: Mechanisms of damage and treatment. J Neurosurg 77(3):337–354PubMedCrossRef
17.
Bandera E, Botteri M, Minelli C et al (2006) Cerebral blood flow threshold of ischemic penumbra and infarct core in acute ischemic stroke a systematic review. Stroke 37(5):1334–1339PubMedCrossRef
18.
Baron J-C (1999) Mapping the ischaemic penumbra with PET: implications for acute stroke treatment. Cerebrovasc Dis 9(4):193–201PubMedCrossRef
19.
Jung S, Gilgen M, Slotboom J et al (2013) Factors that determine penumbral tissue loss in acute ischaemic stroke. Brain 136(Pt 12):3554–3560 awt246PubMedCrossRef
20.
21.
Edvinsson L, Krause DN (2002) Cerebral blood flow and metabolism. Eur J Neurol 9(5):550–550
22.
Caplan L (2000) Caplan’s stroke: a clinical approach, 3rd edn. Butterworth Heinemann, Boston
23.
24.
Lai TW, Zhang S, Wang YT (2014) Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 115:157–188PubMedCrossRef
25.
26.
Mehta SL, Manhas N, Raghubir R (2007) Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 54(1):34–66PubMedCrossRef
27.
Olney JW, Price MT, Samson L et al (1986) The role of specific ions in glutamate neurotoxicity. Neurosci Lett 65(1):65–71PubMedCrossRef
28.
Rothman SM (1985) The neurotoxicity of excitatory amino acids is produced by passive chloride influx. J Neurosci 5(6):1483–1489PubMed
29.
Choi DW (1985) Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett 58(3):293–297PubMedCrossRef
30.
Tymianski M, Charlton MP, Carlen PL et al (1993) Secondary Ca 2+ overload indicates early neuronal injury which precedes staining with viability indicators. Brain Res 607(1):319–323PubMedCrossRef
31.
Pizzi M, Fallacara C, Arrighi V et al (1993) Attenuation of excitatory amino acid toxicity by metabotropic glutamate receptor agonists and aniracetam in primary cultures of cerebellar granule cells. J Neurochem 61(2):683–689PubMedCrossRef
32.
Mosbacher J, Schöpfer R, Monyer H et al (1994) A molecular determinant for submillisecond desensitization in glutamate receptors. Science 266(5187):1059–1062PubMedCrossRef
33.
Moriyoshi K, Masu M, Ishii T et al (1991) Molecular cloning and characterization of the rat NMD receptor. Nature 354:31–37PubMedCrossRef
34.
Berdichevsky E, Riveros N, Sánchez-Armáss S et al (1983) Kainate, N-methylaspartate and other excitatory amino acids increase calcium influx into rat brain cortex cells in vitro. Neurosci Lett 36(1):75–80PubMedCrossRef
35.
Liu B, Liao M, Mielke JG et al (2006) Ischemic insults direct glutamate receptor subunit 2-lacking AMPA receptors to synaptic sites. J Neurosci 26(20):5309–5319PubMedCrossRef
36.
Peng PL, Zhong X, Tu W et al (2006) ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron 49(5):719–733PubMedCrossRef
37.
Hsu CY (1998) Ischemic stroke: from basic mechanisms to new drug development, vol 16. Karger Medical and Scientific Publishers, Basel
38.
Boscia F, Gala R, Pignataro G et al (2006) Permanent focal brain ischemia induces isoform-dependent changes in the pattern of Na+/Ca2+ exchanger gene expression in the ischemic core, periinfarct area, and intact brain regions. J Cereb Blood Flow Metab 26(4):502–517PubMedCrossRef
39.
Molinaro P, Cantile M, Cuomo O et al (2013) Neurounina-1, a novel compound that increases Na+/Ca2+ exchanger activity, effectively protects against stroke damage. Mol Pharmacol 83(1):142–156PubMedCrossRef
40.
Bano D, Young KW, Guerin CJ et al (2005) Cleavage of the plasma membrane Na+/Ca 2+ exchanger in excitotoxicity. Cell 120(2):275–285PubMedCrossRef
41.
Castilho RF, Hansson O, Ward MW et al (1998) Mitochondrial control of acute glutamate excitotoxicity in cultured cerebellar granule cells. J Neurosci 18(24):10277–10286PubMed
42.
Abramov AY, Duchen MR (2008) Mechanisms underlying the loss of mitochondrial membrane potential in glutamate excitotoxicity. Biochimica et Biophysica Acta (BBA)-Bioenergetics 1777(7):953–964CrossRef
43.
Ward MW, Rego AC, Frenguelli BG et al (2000) Mitochondrial membrane potential and glutamate excitotoxicity in cultured cerebellar granule cells. J Neurosci 20(19):7208–7219PubMed
44.
Stout AK, Raphael HM, Kanterewicz BI et al (1998) Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat Neurosci 1(5):366–373PubMedCrossRef
45.
White RJ, Reynolds IJ (1996) Mitochondrial depolarization in glutamate-stimulated neurons: an early signal specific to excitotoxin exposure. J Neurosci 16(18):5688–5697PubMed
46.
White RJ, Reynolds IJ (1997) Mitochondria accumulate Ca2+ following intense glutamate stimulation of cultured rat forebrain neurones. J Physiol 498(Pt 1):31PubMedPubMedCentralCrossRef
47.
Tymianski M, Charlton MP, Carlen PL et al (1993) Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci 13(5):2085–2104PubMed
48.
Baudry M, Greget R, Pernot F et al (2012) Roles of group I metabotropic glutamate receptors under physiological conditions and in neurodegeneration. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 1(4):523–532
49.
Rong R, Ahn J-Y, Huang H et al (2003) PI3 kinase enhancer–Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. Nat Neurosci 6(11):1153–1161PubMedCrossRef
50.
Chong ZZ, Li F, Maiese K (2006) Group I metabotropic receptor neuroprotection requires Akt and its substrates that govern FOXO3a, Bim, and β-catenin during oxidative stress. Curr Neurovasc Res 3(2):107–117PubMedPubMedCentralCrossRef
51.
Hou L, Klann E (2004) Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci 24(28):6352–6361PubMedCrossRef
52.
Bruno V, Battaglia G, Copani A et al (2001) Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. J Cereb Blood Flow Metab 21(9):1013–1033PubMedCrossRef
53.
Yang Z-B, Zhang Z, Li T-B et al (2014) Up-regulation of brain-enriched miR-107 promotes excitatory neurotoxicity through down-regulation of glutamate transporter-1 expression following ischaemic stroke. Clin Sci 127(12):679–689PubMedCrossRef
54.
Fang Q, Hu W-W, Wang X-F et al (2014) Histamine up-regulates astrocytic glutamate transporter 1 and protects neurons against ischemic injury. Neuropharmacology 77:156–166PubMedCrossRef
55.
Lee J-M, Zipfel GJ, Choi DW (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399:A7–A14PubMedCrossRef
56.
Rothman SM, Olney JW (1995) Excitotoxicity and the NMDA receptor-still lethal after eight years. Trends Neurosci 18(2):57–58PubMed
57.
58.
Collingridge GL, Peineau S, Howland JG et al (2010) Long-term depression in the CNS. Nat Rev Neurosci 11(7):459–473PubMedCrossRef
59.
Liu Y, Wong TP, Aarts M et al (2007) NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci 27(11):2846–2857PubMedCrossRef
60.
Chen M, Lu T-J, Chen X-J et al (2008) Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke 39(11):3042–3048PubMedCrossRef
61.
Ryan TJ, Emes RD, Grant SG et al (2008) Evolution of NMDA receptor cytoplasmic interaction domains: implications for organisation of synaptic signalling complexes. BMC Neurosci 9(1):6PubMedPubMedCentralCrossRef
62.
Zhou M, Baudry M (2006) Developmental changes in NMDA neurotoxicity reflect developmental changes in subunit composition of NMDA receptors. J Neurosci 26(11):2956–2963PubMedCrossRef
63.
DeRidder MN, Simon MJ, Siman R et al (2006) Traumatic mechanical injury to the hippocampus in vitro causes regional caspase-3 and calpain activation that is influenced by NMDA receptor subunit composition. Neurobiol Dis 22(1):165–176PubMedCrossRef
64.
Terasaki Y, Sasaki T, Yagita Y et al (2010) Activation of NR2A receptors induces ischemic tolerance through CREB signaling. J Cereb Blood Flow Metab 30(8):1441–1449PubMedPubMedCentralCrossRef
65.
66.
Martin HG, Wang YT (2010) Blocking the deadly effects of the NMDA receptor in stroke. Cell 140(2):174–176PubMedCrossRef
67.
Hardingham GE, Fukunaga Y, Bading H (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 5(5):405–414PubMed
68.
69.
Zhou L, Li F, Xu H-B et al (2010) Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95. Nat Med 16(12):1439–1443PubMedCrossRef
70.
Lai TW, Shyu W-C, Wang YT (2011) Stroke intervention pathways: NMDA receptors and beyond. Trends Mol Med 17(5):266–275PubMedCrossRef
71.
Aluclu MU, Arslan S, Acar A et al (2008) Evaluation of effects of memantine on cerebral ischemia in rats. Neurosciences (Riyadh) 13(2):113–116
72.
Okamoto S-I, Pouladi MA, Talantova M et al (2009) Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 15(12):1407–1413PubMedPubMedCentralCrossRef
73.
Aarts M, Liu Y, Liu L et al (2002) Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 298(5594):846–850PubMedCrossRef
74.
75.
76.
Koumura A, Nonaka Y, Hyakkoku K et al (2008) A novel calpain inhibitor,((1S)-1 ((((1S)-1-benzyl-3-cyclopropylamino-2, 3-di-oxopropyl) amino) carbonyl)-3-methylbutyl) carbamic acid 5-methoxy-3-oxapentyl ester, protects neuronal cells from cerebral ischemia-induced damage in mice. Neuroscience 157(2):309–318PubMedCrossRef
77.
López-Menéndez C, Gascón S, Sobrado M et al (2009) Kidins220/ARMS downregulation by excitotoxic activation of NMDARs reveals its involvement in neuronal survival and death pathways. J Cell Sci 122(19):3554–3565PubMedCrossRef
78.
Xu J, Kurup P, Zhang Y et al (2009) Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J Neurosci 29(29):9330–9343PubMedPubMedCentralCrossRef
79.
Taghibiglou C, Martin HG, Lai TW et al (2009) Role of NMDA receptor—dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries. Nat Med 15(12):1399–1406PubMedCrossRef
80.
81.
82.
Allen C, Bayraktutan U (2009) Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke 4(6):461–470PubMedCrossRef
83.
84.
Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21(1):2–14PubMedCrossRef
85.
Kontos HA (2001) Oxygen radicals in cerebral ischemia the 2001 Willis lecture. Stroke 32(11):2712–2716PubMedCrossRef
86.
Cherubini A, Ruggiero C, Polidori MC et al (2005) Potential markers of oxidative stress in stroke. Free Radic Biol Med 39(7):841–852PubMedCrossRef
87.
Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262(5134):689–695PubMedCrossRef
88.
Cuzzocrea S, Riley DP, Caputi AP et al (2001) Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol Rev 53(1):135–159PubMed
89.
Lafon-Cazal M, Pietri S, Culcasi M et al (1993) NMDA-dependent superoxide production and neurotoxicity. Nature 364(6437):535–537PubMedCrossRef
90.
Piantadosi CA, Zhang J (1996) Mitochondrial generation of reactive oxygen species after brain ischemia in the rat. Stroke 27(2):327–332PubMedCrossRef
91.
Sugawara T, Chan PH (2003) Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid Redox Signal 5(5):597–607PubMedCrossRef
92.
Saeed SA, Shad KF, Saleem T et al (2007) Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke. Exp Brain Res 182(1):1–10PubMedCrossRef
93.
Adibhatla RM, Hatcher JF (2010) Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 12(1):125–169PubMedCrossRef
94.
Girouard H, Wang G, Gallo EF et al (2009) NMDA receptor activation increases free radical production through nitric oxide and NOX2. J Neurosci 29(8):2545–2552PubMedPubMedCentralCrossRef
95.
Brennan AM, Suh SW, Won SJ et al (2009) NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci 12(7):857–863PubMedPubMedCentralCrossRef
96.
Nicholls DG (2008) Oxidative stress and energy crises in neuronal dysfunction. Ann N Y Acad Sci 1147(1):53–60PubMedCrossRef
97.
Abramov AY, Scorziello A, Duchen MR (2007) Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci 27(5):1129–1138PubMedCrossRef
98.
Förstermann U (2010) Nitric oxide and oxidative stress in vascular disease. Pflügers Archiv-European Journal of Physiology 459(6):923–939PubMedCrossRef
99.
Wei EP, Kontos HA, Beckman JS (1996) Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite. Am J Phys Heart Circ Phys 271(3):H1262–H1266
100.
101.
102.
Nakamura T, Lipton SA (2009) According to GOSPEL: filling in the GAP (DH) of NO-mediated neurotoxicity. Neuron 63(1):3–6PubMedCrossRef
103.
Gu Z, Kaul M, Yan B et al (2002) S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297(5584):1186–1190PubMedCrossRef
104.
Faraci FM (2006) Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol 100(2):739–743PubMedCrossRef
105.
Lipton SA (2007) Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci 8(10):803–808PubMedCrossRef
106.
107.
Gariballa S, Hutchin T, Sinclair A (2002) Antioxidant capacity after acute ischaemic stroke. QJM 95(10):685–690PubMedCrossRef
108.
Spranger M, Krempien S, Schwab S et al (1997) Superoxide dismutase activity in serum of patients with acute cerebral ischemic injury correlation with clinical course and infarct size. Stroke 28(12):2425–2428PubMedCrossRef
109.
Alfieri A, Srivastava S, Siow R et al (2011) Targeting the Nrf2–Keap1 antioxidant defence pathway for neurovascular protection in stroke. J Physiol 589(17):4125–4136PubMedPubMedCentralCrossRef
110.
Margaill I, Plotkine M, Lerouet D (2005) Antioxidant strategies in the treatment of stroke. Free Radic Biol Med 39(4):429–443PubMedCrossRef
111.
Zhang C, Shu L, Kong A-N T (2015) MicroRNAs: new players in cancer prevention targeting Nrf2, oxidative stress and inflammatory pathways. Current pharmacology reports 1(1):21–30PubMedPubMedCentralCrossRef
112.
113.
Hardingham GE, Lipton SA (2011) Regulation of neuronal oxidative and nitrosative stress by endogenous protective pathways and disease processes. Antioxid Redox Signal 14(8):1421–1424PubMedCrossRef
114.
Dang J, Brandenburg L-O, Rosen C et al (2012) Nrf2 expression by neurons, astroglia, and microglia in the cerebral cortical penumbra of ischemic rats. J Mol Neurosci 46(3):578–584PubMedCrossRef
115.
Joshi GA, Johnson J (2012) The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases. Recent patents on CNS drug discovery 7(3):218–229PubMedPubMedCentralCrossRef
116.
Jiang S, Deng C, Lv J et al (2016) Nrf2 weaves an elaborate network of neuroprotection against stroke. Mol Neurobiol 1–16
117.
Zhang M, An C, Gao Y et al (2013) Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol 100:30–47PubMedCrossRef
118.
Liou AK, Clark RS, Henshall DC et al (2003) To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways. Prog Neurobiol 69(2):103–142PubMedCrossRef
119.
120.
McColl B, Allan S, Rothwell N (2009) Systemic infection, inflammation and acute ischemic stroke. Neuroscience 158(3):1049–1061PubMedCrossRef
121.
Pan J, Palmateer J, Schallert T et al (2014) Novel humanized recombinant T cell receptor ligands protect the female brain after experimental stroke. Translational stroke research 5(5):577–585PubMedPubMedCentralCrossRef
122.
123.
Amantea D, Nappi G, Bernardi G et al (2009) Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J 276(1):13–26PubMedCrossRef
124.
Kriz J (2006) Inflammation in ischemic brain injury: timing is important. Critical reviews™ in Neurobiology 18 (1–2):
125.
Stanimirovic DB, Wong J, Shapiro A et al (1997) Increase in surface expression of ICAM-1, VCAM-1 and E-selectin in human cerebromicrovascular endothelial cells subjected to ischemia-like insults. In: Brain Edema X. Springer, Berlin Heidelberg New York, p 12–16
126.
127.
Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7(1):1CrossRef
128.
129.
Rogove A, Lu W, Tsirka S (2002) Microglial activation and recruitment, but not proliferation, suffice to mediate neurodegeneration. Cell Death Differ 9(8):801–806PubMedCrossRef
130.
131.
McKimmie CS, Roy D, Forster T et al (2006) Innate immune response gene expression profiles of N9 microglia are pathogen-type specific. J Neuroimmunol 175(1):128–141PubMedCrossRef
132.
Hoehn BD, Palmer TD, Steinberg GK (2005) Neurogenesis in rats after focal cerebral ischemia is enhanced by indomethacin. Stroke 36(12):2718–2724PubMedCrossRef
133.
Pena-Philippides JC, Yang Y, Bragina O et al (2014) Effect of pulsed electromagnetic field (PEMF) on infarct size and inflammation after cerebral ischemia in mice. Translational stroke research 5(4):491–500PubMedCrossRef
134.
135.
Mrak RE, Griffin WST (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26(3):349–354PubMedCrossRef
136.
Eikelenboom P, Rozemuller AJ, Hoozemans JJ et al (2000) Neuroinflammation and Alzheimer disease: clinical and therapeutic implications. Alzheimer Dis Assoc Disord 14(1):S54–S61PubMedCrossRef
137.
138.
Fernandes A, Miller-Fleming L, Pais TF (2014) Microglia and inflammation: conspiracy, controversy or control? Cell Mol Life Sci 71(20):3969–3985PubMedCrossRef
139.
140.
141.
Fleming JC, Norenberg MD, Ramsay DA et al (2006) The cellular inflammatory response in human spinal cords after injury. Brain 129(12):3249–3269PubMedCrossRef
142.
Ross AM, Hurn P, Perrin N et al (2007) Evidence of the peripheral inflammatory response in patients with transient ischemic attack. J Stroke Cerebrovasc Dis 16(5):203–207PubMedCrossRef
143.
Greenwood J, Heasman S, Alvarez J et al (2011) Review: leucocyte–endothelial cell crosstalk at the blood–brain barrier: a prerequisite for successful immune cell entry to the brain. Neuropathol Appl Neurobiol 37(1):24–39PubMedCrossRef
144.
Yang MS, Min KJ, Joe E (2007) Multiple mechanisms that prevent excessive brain inflammation. J Neurosci Res 85(11):2298–2305PubMedCrossRef
145.
Vincent V, Tilders F, Van Dam AM (1997) Inhibition of endotoxin-induced nitric oxide synthase production in microglial cells by the presence of astroglial cells: a role for transforming growth factor β. Glia 19(3):190–198PubMedCrossRef
146.
Pyo H, Yang M-S, Jou I et al (2003) Wortmannin enhances lipopolysaccharide-induced inducible nitric oxide synthase expression in microglia in the presence of astrocytes in rats. Neurosci Lett 346(3):141–144PubMedCrossRef
147.
Min K-J, Yang M-S, Kim S-U et al (2006) Astrocytes induce hemeoxygenase-1 expression in microglia: a feasible mechanism for preventing excessive brain inflammation. J Neurosci 26(6):1880–1887PubMedCrossRef
148.
Kim JH, Min KJ, Seol W et al (2010) Astrocytes in injury states rapidly produce anti-inflammatory factors and attenuate microglial inflammatory responses. J Neurochem 115(5):1161–1171PubMedCrossRef
149.
Kim B, Jeong H-K, Kim J-H et al (2011) Uridine 5′-diphosphate induces chemokine expression in microglia and astrocytes through activation of the P2Y6 receptor. J Immunol 186(6):3701–3709PubMedCrossRef
150.
Hoek RM, Ruuls SR, Murphy CA et al (2000) Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290(5497):1768–1771PubMedCrossRef
151.
Cardona AE, Pioro EP, Sasse ME et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924PubMedCrossRef
152.
Kim YS, Kim SS, Cho JJ et al (2005) Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. J Neurosci 25(14):3701–3711PubMedCrossRef
153.
154.
Swanson RA, Ying W, Kauppinen TM (2004) Astrocyte influences on ischemic neuronal death. Curr Mol Med 4(2):193–205PubMedCrossRef
155.
Ferrarese C, Mascarucci P, Zoia C et al (1999) Increased cytokine release from peripheral blood cells after acute stroke. J Cereb Blood Flow Metab 19(9):1004–1009PubMedCrossRef
156.
157.
Chamorro Á, Meisel A, Planas AM et al (2012) The immunology of acute stroke. Nat Rev Neurol 8(7):401–410PubMedCrossRef
158.
Gelderblom M, Leypoldt F, Steinbach K et al (2009) Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40(5):1849–1857PubMedCrossRef
159.
Hammond MD, Taylor RA, Mullen MT et al (2014) CCR2+ Ly6Chi inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage. J Neurosci 34(11):3901–3909PubMedPubMedCentralCrossRef
160.
Zhang R, Chopp M, Zhang Z et al (1998) The expression of P-and E-selectins in three models of middle cerebral artery occlusion. Brain Res 785(2):207–214PubMedCrossRef
161.
Huang J, Upadhyay UM, Tamargo RJ (2006) Inflammation in stroke and focal cerebral ischemia. Surg Neurol 66(3):232–245PubMedCrossRef
162.
163.
Liu T, Clark R, McDonnell P et al (1994) Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 25(7):1481–1488PubMedCrossRef
164.
Zhu Y, Yang G-Y, Ahlemeyer B et al (2002) Transforming growth factor-β1 increases bad phosphorylation and protects neurons against damage. J Neurosci 22(10):3898–3909PubMed
165.
Spera PA, Ellison JA, Feuerstein GZ et al (1998) IL-10 reduces rat brain injury following focal stroke. Neurosci Lett 251(3):189–192PubMedCrossRef
166.
Vila N, Castillo J, Dávalos A et al (2003) Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke 34(3):671–675PubMedCrossRef
167.
Viviani B, Bartesaghi S, Gardoni F et al (2003) Interleukin-1β enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23(25):8692–8700PubMed
168.
Bernardes-Silva M, Anthony DC, Issekutz AC et al (2001) Recruitment of Neutrophils across the blood–brain barrier: the role of E-and P-selectins. J Cereb Blood Flow Metab 21(9):1115–1124PubMedCrossRef
169.
Konsman JP, Vigues S, Mackerlova L et al (2004) Rat brain vascular distribution of interleukin-1 type-1 receptor immunoreactivity: relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli. J Comp Neurol 472(1):113–129PubMedCrossRef
170.
Mazzotta G, Sarchielli P, Caso V et al (2004) Different cytokine levels in thrombolysis patients as predictors for clinical outcome. Eur J Neurol 11(6):377–381PubMedCrossRef
171.
Bö L, Peterson JW, Mørk S et al (1996) Distribution of immunoglobulin superfamily members ICAM-1,-2,-3, and the β2 integrin LFA-1 in multiple sclerosis lesions. J Neuropathol Exp Neurol 55(10):1060–1072PubMedCrossRef
172.
Huang FP, Wang ZQ, Wu DC et al (2003) Early NFκB activation is inhibited during focal cerebral ischemia in interleukin-1β-converting enzyme deficient mice. J Neurosci Res 73(5):698–707PubMedCrossRef
173.
Ohtaki H, Takaki A, Yin L et al (2003) Suppression of oxidative stress after transient focal ischemia in interleukin-1 knock out mice. In: Brain Edema XII. Springer, Berlin Heidelberg New York, p 191–194
174.
Wang X, Yue T-L, Young PR et al (1995) Expression of interleukin-6, c-fos, and zif268 mRNAs in rat ischemic cortex. J Cereb Blood Flow Metab 15(1):166–171PubMedCrossRef
175.
Tarkowski E, Rosengren L, Blomstrand C et al (1995) Early intrathecal production of interleukin-6 predicts the size of brain lesion in stroke. Stroke 26(8):1393–1398PubMedCrossRef
176.
177.
Hakkoum D, Stoppini L, Muller D (2007) Interleukin-6 promotes sprouting and functional recovery in lesioned organotypic hippocampal slice cultures. J Neurochem 100(3):747–757PubMedCrossRef
178.
Tancredi V, D'Antuono M, Cafè C et al (2000) The inhibitory effects of interleukin-6 on synaptic plasticity in the rat hippocampus are associated with an inhibition of mitogen-activated protein kinase ERK. J Neurochem 75(2):634–643PubMedCrossRef
179.
Relton J, Martin D, Thompson R et al (1996) Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol 138(2):206–213PubMedCrossRef
180.
Azzimondi G, Bassein L, Nonino F et al (1995) Fever in acute stroke worsens prognosis: a prospective study. Stroke 26(11):2040–2043PubMedCrossRef
181.
Zaremba J, Skrobanski P, Losy J (2001) Tumour necrosis factor-alpha is increased in the cerebrospinal fluid and serum of ischaemic stroke patients and correlates with the volume of evolving brain infarct. Biomed Pharmacother 55(5):258–263PubMedCrossRef
182.
Dawson DA, Martin D, Hallenbeck JM (1996) Inhibition of tumor necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. Neurosci Lett 218(1):41–44PubMedCrossRef
183.
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):52–58PubMedCrossRef
184.
Nawashiro H, Martin D, Hallenbeck JM (1997) Inhibition of tumor necrosis factor and amelioration of brain infarction in mice. J Cereb Blood Flow Metab 17(2):229–232PubMedCrossRef
185.
Nawashiro H, Martin D, Hallenbeck JM (1997) Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res 778(2):265–271PubMedCrossRef
186.
Ooboshi H, Ibayashi S, Shichita T et al (2005) Postischemic gene transfer of interleukin-10 protects against both focal and global brain ischemia. Circulation 111(7):913–919PubMedCrossRef
187.
Liesz A, Suri-Payer E, Veltkamp C et al (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15(2):192–199PubMedCrossRef
188.
189.
McNeill H, Williams C, Guan J et al (1994) Neuronal rescue with transforming growth factor-[beta] 1 after hypoxic-ischaemic brain injury. Neuroreport 5(8):901–904PubMedCrossRef
190.
Mori E, Del Zoppo GJ, Chambers JD et al (1992) Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke 23(5):712–718PubMedCrossRef
191.
Nurmi A, Lindsberg PJ, Koistinaho M et al (2004) Nuclear factor-κB contributes to infarction after permanent focal ischemia. Stroke 35(4):987–991PubMedCrossRef
192.
193.
Ridder D, Schwaninger M (2009) NF-κB signaling in cerebral ischemia. Neuroscience 158(3):995–1006PubMedCrossRef
194.
Han H, Yenari M (2003) Cellular targets of brain inflammation in stroke. Current opinion in investigational drugs (London, England: 2000) 4(5):522–529
195.
Baeuerle P, Henkel T (1994) Dunction and activation of NF-B in the immune system. Annu Rev Immunol 12(141):79
196.
Ko HM, Koppula S, Kim B-W et al (2010) Inflexin attenuates proinflammatory responses and nuclear factor-ΚB activation in LPS-treated microglia. Eur J Pharmacol 633(1):98–106PubMedCrossRef
197.
Jin H, Zhu ZG, Yu PJ et al (2012) Myrislignan attenuates lipopolysaccharide-induced inflammation reaction in murine macrophage cells through inhibition of NF-κB signalling pathway activation. Phytother Res 26(9):1320–1326PubMedCrossRef
198.
Wang X, Hu D, Zhang L et al (2014) Gomisin A inhibits lipopolysaccharide-induced inflammatory responses in N9 microglia via blocking the NF-κB/MAPKs pathway. Food Chem Toxicol 63:119–127PubMedCrossRef
199.
Montaner J, Alvarez-Sabín J, Molina C et al (2001) Matrix metalloproteinase expression after human cardioembolic stroke temporal profile and relation to neurological impairment. Stroke 32(8):1759–1766PubMedCrossRef
200.
Danton GH, Dietrich WD (2003) Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62(2):127–136PubMedCrossRef
201.
Jin R, Yang G, Li G (2010) Molecular insights and therapeutic targets for blood–brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator. Neurobiol Dis 38(3):376–385PubMedPubMedCentralCrossRef
202.
Asahi M, Wang X, Mori T et al (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J Neurosci 21(19):7724–7732PubMed
203.
Zhao B-Q, Wang S, Kim H-Y et al (2006) Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 12(4):441–445PubMedCrossRef
204.
205.
Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11(5):373–384PubMedCrossRef
206.
Karikó K, Ni H, Capodici J et al (2004) mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem 279(13):12542–12550PubMedCrossRef
207.
Marsh BJ, Stenzel-Poore MP (2008) Toll-like receptors: novel pharmacological targets for the treatment of neurological diseases. Curr Opin Pharmacol 8(1):8–13PubMedCrossRef
208.
Brea D, Blanco M, Ramos-Cabrer P et al (2011) Toll-like receptors 2 and 4 in ischemic stroke: outcome and therapeutic values. J Cereb Blood Flow Metab 31(6):1424–1431PubMedPubMedCentralCrossRef
209.
Caso JR, Pradillo JM, Hurtado O et al (2007) Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 115(12):1599–1608PubMedCrossRef
210.
Yao L, Kan EM, Lu J et al (2013) Toll-like receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: role of TLR4 in hypoxic microglia. J Neuroinflammation 10(1):23PubMedPubMedCentralCrossRef
211.
Hyakkoku K, Hamanaka J, Tsuruma K et al (2010) Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia. Neuroscience 171(1):258–267PubMedCrossRef
212.
Lehnardt S, Lehmann S, Kaul D et al (2007) Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. J Neuroimmunol 190(1):28–33PubMedCrossRef
213.
Cao C-X, Yang Q-w, Lv F-L et al (2007) Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. Biochem Biophys Res Commun 353(2):509–514PubMedCrossRef
214.
Bohacek I, Cordeau P, Lalancette-Hébert M et al (2012) Toll-like receptor 2 deficiency leads to delayed exacerbation of ischemic injury. J Neuroinflammation 9(1):1CrossRef
215.
Akira S (2006) TLR signaling, in from innate immunity to immunological memory. Springer, Berlin Heidelberg New York, pp 1–16CrossRef
216.
217.
218.
219.
Benakis C, Garcia-Bonilla L, Iadecola C et al (2015) The role of microglia and myeloid immune cells in acute cerebral ischemia. Front Cell Neurosci 8:461PubMedPubMedCentralCrossRef
220.
Singh V, Roth S, Veltkamp R et al (2016) HMGB1 as a key mediator of immune mechanisms in ischemic stroke. Antioxid Redox Signal 24(12):635–651PubMedCrossRef
221.
Marsh BJ, Williams-Karnesky RL, Stenzel-Poore MP (2009) Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience 158(3):1007–1020PubMedCrossRef
222.
Anrather J, Iadecola C (2016) Inflammation and stroke: an overview. Neurotherapeutics 1–10
223.
Schilling M, Strecker J-K, Ringelstein EB et al (2009) The role of CC chemokine receptor 2 on microglia activation and blood-borne cell recruitment after transient focal cerebral ischemia in mice. Brain Res 1289:79–84PubMedCrossRef
224.
Konsman JP, Drukarch B, Van Dam A-M (2007) (Peri) vascular production and action of pro-inflammatory cytokines in brain pathology. Clin Sci 112(1):1–25PubMedCrossRef
225.
Mantovani A, Sica A, Locati M (2005) Macrophage polarization comes of age. Immunity 23(4):344–346PubMedCrossRef
226.
Connolly ES Jr, Winfree CJ, Springer TA et al (1996) Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke. J Clin Invest 97(1):209PubMedPubMedCentralCrossRef
227.
Connolly E, Winfree C, Prestigiacomo C et al (1997) Exacerbation of cerebral injury in mice that express the P-selectin gene. Circ Res 81(3):304–310PubMedCrossRef
228.
Soriano SG, Lipton SA, Wang YF et al (1996) Intercellular adhesion molecule-1-deficient mice are less susceptible to cerebral ischemia-reperfusion lnjury. Ann Neurol 39(5):618–624PubMedCrossRef
229.
Justicia C, Panés J, Solé S et al (2003) Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats. J Cereb Blood Flow Metab 23(12):1430–1440PubMedCrossRef
230.
231.
Felger JC, Abe T, Kaunzner UW et al (2010) Brain dendritic cells in ischemic stroke: time course, activation state, and origin. Brain Behav Immun 24(5):724–737PubMedCrossRef
232.
Kostulas N, Li H-L, Xiao B-G et al (2002) Dendritic cells are present in ischemic brain after permanent middle cerebral artery occlusion in the rat. Stroke 33(4):1129–1134PubMedCrossRef
233.
Yilmaz A, Fuchs T, Dietel B et al (2009) Transient decrease in circulating dendritic cell precursors after acute stroke: potential recruitment into the brain. Clin Sci 118(2):147–157PubMedCrossRef
234.
Saino O, Taguchi A, Nakagomi T et al (2010) Immunodeficiency reduces neural stem/progenitor cell apoptosis and enhances neurogenesis in the cerebral cortex after stroke. J Neurosci Res 88(11):2385–2397PubMed
235.
Santana M, Rosenstein Y (2003) What it takes to become an effector T cell: the process, the cells involved, and the mechanisms. J Cell Physiol 195(3):392–401PubMedCrossRef
236.
Collison LW, Workman CJ, Kuo TT et al (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450(7169):566–569PubMedCrossRef
237.
Niedbala W, Wei XQ, Cai B et al (2007) IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol 37(11):3021–3029PubMedCrossRef
238.
Shichita T, Sugiyama Y, Ooboshi H et al (2009) Pivotal role of cerebral interleukin-17–producing γδT cells in the delayed phase of ischemic brain injury. Nat Med 15(8):946–950PubMedCrossRef
239.
Liesz A, Karcher S, Veltkamp R (2013) Spectratype analysis of clonal T cell expansion in murine experimental stroke. J Neuroimmunol 257(1):46–52PubMedCrossRef
240.
Ren X, Akiyoshi K, Dziennis S et al (2011) Regulatory B cells limit CNS inflammation and neurologic deficits in murine experimental stroke. J Neurosci 31(23):8556–8563PubMedPubMedCentralCrossRef
241.
Benakis C, Brea D, Caballero S et al (2016) Commensal microbiota affects ischemic stroke outcome by regulating intestinal [gamma][delta] T cells. Nat Med 22:516–523PubMedPubMedCentralCrossRef
242.
Singh V, Roth S, Llovera G et al (2016) Microbiota dysbiosis controls the neuroinflammatory response after stroke. J Neurosci 36(28):7428–7440PubMedCrossRef
243.
244.
Yin J, Liao SX, He Y et al (2015) Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc 4(11):e002699PubMedPubMedCentralCrossRef
245.
Arpaia N, Campbell C, Fan X et al (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504(7480):451–455PubMedPubMedCentralCrossRef
246.
Zhou W, Liesz A, Bauer H et al (2013) Postischemic brain infiltration of leukocyte subpopulations differs among murine permanent and transient focal cerebral ischemia models. Brain Pathol 23(1):34–44PubMedCrossRef
247.
Vandenabeele P, Galluzzi L, Berghe TV et al (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11(10):700–714PubMedCrossRef
248.
Wei L, Ying D-J, Cui L et al (2004) Necrosis, apoptosis and hybrid death in the cortex and thalamus after barrel cortex ischemia in rats. Brain Res 1022(1):54–61PubMedCrossRef
249.
Ünal-Çevik I, Kılınç M, Can A et al (2004) Apoptotic and necrotic death mechanisms are concomitantly activated in the same cell after cerebral ischemia. Stroke 35(9):2189–2194PubMedCrossRef
250.
251.
Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87(1):99–163PubMedCrossRef
252.
Nikoletopoulou V, Markaki M, Palikaras K et al (2013) Crosstalk between apoptosis, necrosis and autophagy. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1833(12):3448–3459CrossRef
253.
Culmsee C, Zhu C, Landshamer S et al (2005) Apoptosis-inducing factor triggered by poly (ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci 25(44):10262–10272PubMedCrossRef
254.
Broughton BR, Reutens DC, Sobey CG (2009) Apoptotic mechanisms after cerebral ischemia. Stroke 40(5):e331–e339PubMedCrossRef
255.
Li H, Colbourne F, Sun P et al (2000) Caspase inhibitors reduce neuronal injury after focal but not global cerebral ischemia in rats. Stroke 31(1):176–182PubMedCrossRef
256.
Hickey EJ, You X, Kaimaktchiev V et al (2007) Lipopolysaccharide preconditioning induces robust protection against brain injury resulting from deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 133(6):1588–1596PubMedCrossRef
257.
Kroemer G, Reed JC (2000) Mitochondrial control of cell death. Nat Med 6(5)
258.
Adams JM, Cory S (2001) Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci 26(1):61–66PubMedCrossRef
259.
Antonsson B, Montessuit S, Sanchez B et al (2001) Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells. J Biol Chem 276(15):11615–11623PubMedCrossRef
260.
261.
Zoppo G, Ginis I, Hallenbeck JM et al (2000) Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 10(1):95–112PubMedCrossRef
262.
Zoppo GJ (1997) Microvascular responses to cerebral ischemia/inflammation. Ann N Y Acad Sci 823(1):132–147PubMedCrossRef
263.
Jin K, Graham SH, Mao X et al (2001) Fas (CD95) may mediate delayed cell death in hippocampal CA1 sector after global cerebral ischemia. J Cereb Blood Flow Metab 21(12):1411–1421PubMedCrossRef
264.
Namura S, Zhu J, Fink K et al (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18(10):3659–3668PubMed
265.
266.
Ferrer I, Planas AM (2003) Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J Neuropathol Exp Neurol 62(4):329–339PubMedCrossRef
267.
Seko Y, Kayagaki N, K-i S et al (2002) Role of Fas/FasL pathway in the activation of infiltrating cells in murine acute myocarditis caused by Coxsackievirus B3. J Am Coll Cardiol 39(8):1399–1403PubMedCrossRef
268.
Ma J, Endres M, Moskowitz MA (1998) Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischaemia in mice. Br J Pharmacol 124(4):756–762PubMedPubMedCentralCrossRef
269.
Graham SH, Chen J (2001) Programmed cell death in cerebral ischemia. J Cereb Blood Flow Metab 21(2):99–109PubMedCrossRef
270.
Wei N, Xiao L, Xue R et al (2015) MicroRNA-9 mediates the cell apoptosis by targeting Bcl2l11 in ischemic stroke. Mol Neurobiol 1–9
271.
272.
273.
Yin K-J, Deng Z, Huang H et al (2010) miR-497 regulates neuronal death in mouse brain after transient focal cerebral ischemia. Neurobiol Dis 38(1):17–26PubMedPubMedCentralCrossRef
274.
Moon J-M, Xu L, Giffard RG (2013) Inhibition of microRNA-181 reduces forebrain ischemia-induced neuronal loss. J Cereb Blood Flow Metab 33(12):1976–1982PubMedPubMedCentralCrossRef
275.
Huang W, Liu X, Cao J et al (2015) miR-134 regulates ischemia/reperfusion injury-induced neuronal cell death by regulating CREB signaling. J Mol Neurosci 55(4):821–829PubMedCrossRef
276.
Shinoura N, Satou R, Yoshida Y et al (2000) Adenovirus-mediated transfer of Bcl-X L protects neuronal cells from Bax-induced apoptosis. Exp Cell Res 254(2):221–231PubMedCrossRef
277.
Zhao H, Yenari MA, Cheng D et al (2003) Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. J Neurochem 85(4):1026–1036PubMedCrossRef
278.
Gonzalez R, Hirsch J, Koroshetz W et al (2007) Acute ischemic stroke: imaging and intervention. Am J Neuroradiol 28(8):1622CrossRef
279.
Guan Q-H, Pei D-S, Liu X-M et al (2006) Neuroprotection against ischemic brain injury by SP600125 via suppressing the extrinsic and intrinsic pathways of apoptosis. Brain Res 1092(1):36–46PubMedCrossRef
280.
Guan Q-H, Pei D-S, Zong Y-Y et al (2006) Neuroprotection against ischemic brain injury by a small peptide inhibitor of c-Jun N-terminal kinase (JNK) via nuclear and non-nuclear pathways. Neuroscience 139(2):609–627PubMedCrossRef
281.
Kim JS, Kim Y-J, Ahn S-H et al (2016) Location of cerebral atherosclerosis: why is there a difference between East and West? Int J Stroke
282.
Ritz K, Denswil NP, Stam OC et al (2014) Cause and mechanisms of intracranial atherosclerosis. Circulation 130(16):1407–1414PubMedCrossRef
283.
Suri MFK, Qiao Y, Ma X et al (2016) Prevalence of intracranial atherosclerotic stenosis using high-resolution magnetic resonance angiography in the general population. Stroke 47(5):1187–1193PubMedPubMedCentralCrossRef
284.
Hu X, De Silva TM, Chen J et al (2017) Cerebral vascular disease and neurovascular injury in ischemic stroke. Circ Res 120(3):449–471PubMedCrossRef
285.
Hollander W, Prusty S, Kemper T et al (1993) The effects of hypertension on cerebral atherosclerosis in the cynomolgus monkey. Stroke 24(8):1218–1226PubMedCrossRef
286.
Arvanitakis Z, Capuano AW, Leurgans SE et al (2016) Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study. The Lancet Neurology 15(9):934–943PubMedCrossRef
287.
Roher AE, Esh C, Kokjohn TA et al (2003) Circle of Willis atherosclerosis is a risk factor for sporadic Alzheimer’s disease. Arterioscler Thromb Vasc Biol 23(11):2055–2062PubMedCrossRef
288.
Gupta A, Iadecola C (2015) Impaired Aβ clearance: a potential link between atherosclerosis and Alzheimer’s disease. Front Aging Neurosci 16(7):115
289.
Ballinger SW, Patterson C, Knight-Lozano CA et al (2002) Mitochondrial integrity and function in atherogenesis. Circulation 106(5):544–549PubMedCrossRef
290.
Napoli C, Witztum JL, de Nigris F et al (1999) Intracranial arteries of human fetuses are more resistant to hypercholesterolemia-induced fatty streak formation than extracranial arteries. Circulation 99(15):2003–2010PubMedCrossRef
291.
D’armiento FP, Bianchi A, de Nigris F et al (2001) Age-related effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classic risk factors for atherosclerosis. Stroke 32(11):2472–2480PubMedCrossRef
292.
Wang Z, Roberts AB, Buffa JA et al (2015) Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163(7):1585–1595PubMedPubMedCentralCrossRef
293.
294.
295.
Shobha N, Buchan AM, Hill MD et al (2010) Thrombolysis at 3–4.5 hours after acute ischemic stroke onset–evidence from the Canadian Alteplase for Stroke Effectiveness Study (CASES) registry. Cerebrovasc Dis 31(3):223–228PubMedCrossRef
296.
Parmar S, Moore-Langston S, Fredrickson V et al (2015) Neuroprotective mechanisms of oxygen and ethanol: a potential combination therapy in stroke. Curr Med Chem 22(10):1194–1204PubMedCrossRef
297.
Geng X, Fu P, Ji X et al (2013) Synergetic neuroprotection of normobaric oxygenation and ethanol in ischemic stroke through improved oxidative mechanism. Stroke 44(5):1418–1425PubMedCrossRef
298.
Geng X, Parmar S, Li X et al (2013) Reduced apoptosis by combining normobaric oxygenation with ethanol in transient ischemic stroke. Brain Res 1531:17–24PubMedCrossRef
299.
Geng X, Sy CA, Kwiecien TD et al (2015) Reduced cerebral monocarboxylate transporters and lactate levels by ethanol and normobaric oxygen therapy in severe transient and permanent ischemic stroke. Brain Res 1603:65–75PubMedCrossRef
300.
Choi K-E, Hall CL, Sun J-M et al (2012) A novel stroke therapy of pharmacologically induced hypothermia after focal cerebral ischemia in mice. FASEB J 26(7):2799–2810PubMedPubMedCentralCrossRef
301.
Katz LM, Young AS, Frank JE et al (2004) Regulated hypothermia reduces brain oxidative stress after hypoxic-ischemia. Brain Res 1017(1):85–91PubMedCrossRef
302.
Truettner JS, Suzuki T, Dietrich WD (2005) The effect of therapeutic hypothermia on the expression of inflammatory response genes following moderate traumatic brain injury in the rat. Mol Brain Res 138(2):124–134PubMedCrossRef
303.
Lee JH, Wei L, Gu X et al (2014) Therapeutic effects of pharmacologically induced hypothermia against traumatic brain injury in mice. J Neurotrauma 31(16):1417–1430PubMedPubMedCentralCrossRef
304.
Polderman KH, Joe RTT, Peerdeman SM et al (2002) Effects of therapeutic hypothermia on intracranial pressure and outcome in patients with severe head injury. Intensive Care Med 28(11):1563–1573PubMedCrossRef
305.
Lee JH, Wei ZZ, Cao W et al (2016) Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice. Neurobiol Dis 96:248–260PubMedCrossRef
306.
Zausinger S, Schöller K, Plesnila N et al (2003) Combination drug therapy and mild hypothermia after transient focal cerebral ischemia in rats. Stroke 34(9):2246–2251PubMedCrossRef
307.
Kollmar R, Henninger N, Bardutzky J et al (2004) Combination therapy of moderate hypothermia and thrombolysis in experimental thromboembolic stroke—an MRI study. Exp Neurol 190(1):204–212PubMedCrossRef
308.
Zhao H, Shimohata T, Wang JQ et al (2005) Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. J Neurosci 25(42):9794–9806PubMedCrossRef
309.
Zhao H, Yenari MA, Sapolsky RM et al (2004) Mild postischemic hypothermia prolongs the time window for gene therapy by inhibiting cytochrome C release. Stroke 35(2):572–577PubMedCrossRef
310.
Faillace MP, Keller Sarmiento MI, Rosenstein RE (1996) Melatonin effect on [3H] glutamate uptake and release in the golden hamster retina. J Neurochem 67(2):623–628PubMedCrossRef
311.
Qian Y, Tang X, Guan T et al (2016) Neuroprotection by combined administration with maslinic acid, a natural product from Olea europaea, and MK-801 in the cerebral ischemia model. Molecules 21(8):1093CrossRef
312.
313.
314.
Bang OY, Saver JL, Buck BH et al (2008) Impact of collateral flow on tissue fate in acute ischaemic stroke. J Neurol Neurosurg Psychiatry 79(6):625–629PubMedCrossRef
315.
Lima FO, Furie KL, Silva GS et al (2010) The pattern of leptomeningeal collaterals on CT angiography is a strong predictor of long-term functional outcome in stroke patients with large vessel intracranial occlusion. Stroke 41(10):2316–2322PubMedPubMedCentralCrossRef
316.
Shuaib A, Butcher K, Mohammad AA et al (2011) Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target. The Lancet Neurology 10(10):909–921PubMedCrossRef
317.
318.
Hess DC, Hoda MN, Bhatia K (2013) Remote limb perconditioning and postconditioning. Stroke 44(4):1191–1197PubMedCrossRef
319.
320.
Pignataro G, Scorziello A, Di Renzo G et al (2009) Post-ischemic brain damage: effect of ischemic preconditioning and postconditioning and identification of potential candidates for stroke therapy. FEBS J 276(1):46–57PubMedCrossRef
321.
Zhao H, Joo S, Xie W et al (2013) Using hormetic strategies to improve ischemic preconditioning and postconditioning against stroke. Int J Physiol Pathophysiol Pharmacol 5(2):61–72PubMedPubMedCentral
322.
Meng R, Asmaro K, Meng L et al (2012) Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology 79(18):1853–1861PubMedCrossRef
323.
Stowe AM, Wacker BK, Cravens PD et al (2012) CCL2 upregulation triggers hypoxic preconditioning-induced protection from stroke. J Neuroinflammation 9(1):33PubMedPubMedCentralCrossRef
324.
Ouk T, Laprais M, Bastide M et al (2009) Withdrawal of fenofibrate treatment partially abrogates preventive neuroprotection in stroke via loss of vascular protection. Vasc Pharmacol 51(5):323–330CrossRef
325.
Khan MB, Hoda MN, Vaibhav K et al (2015) Remote ischemic postconditioning: harnessing endogenous protection in a murine model of vascular cognitive impairment. Translational stroke research 6(1):69–77PubMedCrossRef
326.
327.
Bowen KK, Naylor M, Vemuganti R (2006) Prevention of inflammation is a mechanism of preconditioning-induced neuroprotection against focal cerebral ischemia. Neurochem Int 49(2):127–135PubMedCrossRef
328.
Joo SP, Xie W, Xiong X et al (2013) Ischemic postconditioning protects against focal cerebral ischemia by inhibiting brain inflammation while attenuating peripheral lymphopenia in mice. Neuroscience 243:149–157PubMedPubMedCentralCrossRef
329.
Dai Y, Li W, Zhong M et al (2014) Preconditioning and post-treatment with cobalt chloride in rat model of perinatal hypoxic–ischemic encephalopathy. Brain and Development 36(3):228–240PubMedCrossRef
330.
Pignataro G, Meller R, Inoue K et al (2008) In vivo and in vitro characterization of a novel neuroprotective strategy for stroke: ischemic postconditioning. J Cereb Blood Flow Metab 28(2):232–241PubMedCrossRef
Metadata
Title
Pathogenic mechanisms following ischemic stroke
Authors
Seyed Esmaeil Khoshnam
William Winlow
Maryam Farzaneh
Yaghoob Farbood
Hadi Fathi Moghaddam
Publication date
01-07-2017
Publisher
Springer Milan
Published in
Neurological Sciences / Issue 7/2017
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI
https://doi.org/10.1007/s10072-017-2938-1

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