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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2011

Open Access 01-12-2011 | Research

Mild hypothermia causes differential, time-dependent changes in cytokine expression and gliosis following endothelin-1-induced transient focal cerebral ischemia

Authors: An-Gaëlle Ceulemans, Tine Zgavc, Ron Kooijman, Said Hachimi-Idrissi, Sophie Sarre, Yvette Michotte

Published in: Journal of Neuroinflammation | Issue 1/2011

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Abstract

Background

Stroke is an important cause of morbidity and mortality and few therapies exist thus far. Mild hypothermia (33°C) is a promising neuroprotective strategy to improve outcome after ischemic stroke. However, its complete mechanism of action has not yet been fully elaborated. This study is the first to investigate whether this neuroprotection occurs through modulation of the neuroinflammatory response after stroke in a time-dependent manner.

Methods

The Endothelin-1 (Et-1) model was used to elicit a transient focal cerebral ischemia in male Wistar rats. In this model, the core and penumbra of the insult are represented by the striatum and the cortex respectively. We assessed the effects of 2 hours of hypothermia, started 20 minutes after Et-1 injection on neurological outcome and infarct volume. Furthermore, pro- and anti-inflammatory cytokine expression was determined using ELISA. Microgliosis and astrogliosis were investigated using CD-68 and GFAP staining respectively. All parameters were determined 8, 24, 72 hours and 1 week after the administration of Et-1.

Results

Et-1 infusion caused neurological deficit and a reproducible infarct size which increased up to 3 days after the insult. Both parameters were significantly reduced by hypothermia. The strongest reduction in infarct volume with hypothermia, at 3 days, corresponded with increased microglial activation. Reducing the brain temperature affected the stroke induced increase in interleukin-1β and tumor necrosis factor α in the striatum, 8 hours after its induction, but not at later time points. Transforming growth factor β increased as a function of time after the Et-1-induced insult and was not influenced by cooling. Hypothermia reduced astrogliosis at 1 and 3 days after stroke onset.

Conclusions

The beneficial effects of hypothermia after stroke on infarct volume and functional outcome coincide with a time-dependent modulation of the cytokine expression and gliosis.
Appendix
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Literature
1.
Durukan A, Tatlisumak T: Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav. 2007, 87: 179-197. 10.1016/j.pbb.2007.04.015.CrossRefPubMed
2.
3.
Candelario-Jalil E: Injury and repair mechanisms in ischemic stroke: considerations for the development of novel neurotherapeutics. Curr Opin Investig Drugs. 2009, 10: 644-654.PubMed
4.
Zhao H, Steinberg GK, Sapolsky RM: General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage. J Cereb Blood Flow Metab. 2007, 27: 1879-1894. 10.1038/sj.jcbfm.9600540.CrossRefPubMed
5.
Tang XN, Liu L, Yenari MA: Combination therapy with hypothermia for treatment of cerebral ischemia. J Neurotrauma. 2009, 26: 325-331. 10.1089/neu.2008.0594.PubMedCentralCrossRefPubMed
6.
Bogaert L, Scheller D, Moonen J, Sarre S, Smolders I, Ebinger G, Michotte Y: Neurochemical changes and laser Doppler flowmetry in the endothelin-1 rat model for focal cerebral ischemia. Brain Res. 2000, 887: 266-275. 10.1016/S0006-8993(00)02959-0.CrossRefPubMed
7.
Maier CM, Ahern K, Cheng ML, Lee JE, Yenari MA, Steinberg GK: Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke. 1998, 29: 2171-2180.CrossRefPubMed
8.
Van Hemelrijck A, Vermijlen D, Hachimi-Idrissi S, Sarre S, Ebinger G, Michotte Y: Effect of resuscitative mild hypothermia on glutamate and dopamine release, apoptosis and ischaemic brain damage in the endothelin-1 rat model for focal cerebral ischaemia. J Neurochem. 2003, 87: 66-75. 10.1046/j.1471-4159.2003.01977.x.CrossRefPubMed
9.
Van Hemelrijck A, Hachimi-Idrissi S, Sarre S, Ebinger G, Michotte Y: Post-ischaemic mild hypothermia inhibits apoptosis in the penumbral region by reducing neuronal nitric oxide synthase activity and thereby preventing endothelin-1-induced hydroxyl radical formation. Eur J Neurosci. 2005, 22: 1327-1337. 10.1111/j.1460-9568.2005.04331.x.CrossRefPubMed
10.
Simi A, Tsakiri N, Wang P, Rothwell NJ: Interleukin-1 and inflammatory neurodegeneration. Biochem Soc Trans. 2007, 35: 1122-1126. 10.1042/BST0351122.CrossRefPubMed
11.
Sriram K, O'Callaghan JP: Divergent roles for tumor necrosis factor-alpha in the brain. J Neuroimmune Pharmacol. 2007, 2: 140-153. 10.1007/s11481-007-9070-6.CrossRefPubMed
12.
Ceulemans AG, Zgavc T, Kooijman R, Hachimi-Idrissi S, Sarre S, Michotte Y: The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia. J Neuroinflammation. 2010, 7: 74-10.1186/1742-2094-7-74.PubMedCentralCrossRefPubMed
13.
Vitkovic L, Maeda S, Sternberg E: Anti-inflammatory cytokines: expression and action in the brain. Neuroimmunomodulation. 2001, 9: 295-312. 10.1159/000059387.CrossRefPubMed
14.
Rothwell NJ, Luheshi GN: Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci. 2000, 23: 618-625. 10.1016/S0166-2236(00)01661-1.CrossRefPubMed
15.
Gregersen R, Lambertsen K, Finsen B: Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab. 2000, 20: 53-65. 10.1097/00004647-200001000-00009.CrossRefPubMed
16.
17.
Doyle KP, Cekanaviciute E, Mamer LE, Buckwalter MS: TGFbeta signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke. J Neuroinflammation. 2010, 7: 62-10.1186/1742-2094-7-62.PubMedCentralCrossRefPubMed
18.
Clausen BH, Lambertsen KL, Babcock AA, Holm TH, Dagnaes-Hansen F, Finsen B: Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice. J Neuroinflammation. 2008, 5: 46-10.1186/1742-2094-5-46.PubMedCentralCrossRefPubMed
19.
Nilupul Perera M, Ma HK, Arakawa S, Howells DW, Markus R, Rowe CC, Donnan GA: Inflammation following stroke. J Clin Neurosci. 2006, 13: 1-8. 10.1016/j.jocn.2005.07.005.CrossRefPubMed
20.
Yenari MA, Han HS: Influence of hypothermia on post-ischemic inflammation: role of nuclear factor kappa B (NFkappaB). Neurochem Int. 2006, 49: 164-169. 10.1016/j.neuint.2006.03.016.CrossRefPubMed
21.
Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT: Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. Febs J. 2009, 276: 13-26. 10.1111/j.1742-4658.2008.06766.x.CrossRefPubMed
22.
Paxinos G, Watson G, Eds: The rat brain in stereotaxic coordinates. 1986, New York: Academic Press
23.
Hachimi-Idrissi S, Van Hemelrijck A, Michotte A, Smolders I, Sarre S, Ebinger G, Huyghens L, Michotte Y: Postischemic mild hypothermia reduces neurotransmitter release and astroglial cell proliferation during reperfusion after asphyxial cardiac arrest in rats. Brain Res. 2004, 1019: 217-225. 10.1016/j.brainres.2004.06.013.CrossRefPubMed
24.
Garcia JH, Wagner S, Liu KF, Hu XJ: Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke. 1995, 26: 627-634. discussion 635CrossRefPubMed
25.
Weston RM, Jones NM, Jarrott B, Callaway JK: Inflammatory cell infiltration after endothelin-1-induced cerebral ischemia: histochemical and myeloperoxidase correlation with temporal changes in brain injury. J Cereb Blood Flow Metab. 2007, 27: 100-114. 10.1038/sj.jcbfm.9600324.CrossRefPubMed
26.
Kraig RP, Dong LM, Thisted R, Jaeger CB: Spreading depression increases immunohistochemical staining of glial fibrillary acidic protein. J Neurosci. 1991, 11: 2187-2198.PubMedCentralPubMed
27.
Chen Y, Willcockson HH, Valtschanoff JG: Influence of the vanilloid receptor TRPV1 on the activation of spinal cord glia in mouse models of pain. Exp Neurol. 2009, 220: 383-390. 10.1016/j.expneurol.2009.09.030.PubMedCentralCrossRefPubMed
28.
Wang GJ, Deng HY, Maier CM, Sun GH, Yenari MA: Mild hypothermia reduces ICAM-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. Neuroscience. 2002, 114: 1081-1090.CrossRefPubMed
29.
Deng H, Han HS, Cheng D, Sun GH, Yenari MA: Mild hypothermia inhibits inflammation after experimental stroke and brain inflammation. Stroke. 2003, 34: 2495-2501. 10.1161/01.STR.0000091269.67384.E7.CrossRefPubMed
30.
Windle V, Szymanska A, Granter-Button S, White C, Buist R, Peeling J, Corbett D: An analysis of four different methods of producing focal cerebral ischemia with endothelin-1 in the rat. Exp Neurol. 2006, 201: 324-334. 10.1016/j.expneurol.2006.04.012.CrossRefPubMed
31.
Zhang Z, Chopp M, Powers C: Temporal profile of microglial response following transient (2 h) middle cerebral artery occlusion. Brain Res. 1997, 744: 189-198. 10.1016/S0006-8993(96)01085-2.CrossRefPubMed
32.
Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J: Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci. 2007, 27: 2596-2605. 10.1523/JNEUROSCI.5360-06.2007.CrossRefPubMed
33.
Narantuya D, Nagai A, Sheikh AM, Masuda J, Kobayashi S, Yamaguchi S, Kim SU: Human microglia transplanted in rat focal ischemia brain induce neuroprotection and behavioral improvement. PLoS One. 2010, 5: e11746-10.1371/journal.pone.0011746.PubMedCentralCrossRefPubMed
34.
Lambertsen KL, Clausen BH, Babcock AA, Gregersen R, Fenger C, Nielsen HH, Haugaard LS, Wirenfeldt M, Nielsen M, Dagnaes-Hansen F, Bluethmann H, Faergeman NJ, Meldgaard M, Deierborg T, Finsen B: Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J Neurosci. 2009, 29: 1319-1330. 10.1523/JNEUROSCI.5505-08.2009.CrossRefPubMed
35.
Gary DS, Bruce-Keller AJ, Kindy MS, Mattson MP: Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor. J Cereb Blood Flow Metab. 1998, 18: 1283-1287.CrossRefPubMed
36.
Legos JJ, Whitmore RG, Erhardt JA, Parsons AA, Tuma RF, Barone FC: Quantitative changes in interleukin proteins following focal stroke in the rat. Neurosci Lett. 2000, 282: 189-192. 10.1016/S0304-3940(00)00907-1.CrossRefPubMed
37.
Zhu Y, Roth-Eichhorn S, Braun N, Culmsee C, Rami A, Krieglstein J: The expression of transforming growth factor-beta1 (TGF-beta1) in hippocampal neurons: a temporary upregulated protein level after transient forebrain ischemia in the rat. Brain Res. 2000, 866: 286-298. 10.1016/S0006-8993(00)02240-X.CrossRefPubMed
38.
Schubert P, Morino T, Miyazaki H, Ogata T, Nakamura Y, Marchini C, Ferroni S: Cascading glia reactions: a common pathomechanism and its differentiated control by cyclic nucleotide signaling. Ann N Y Acad Sci. 2000, 903: 24-33. 10.1111/j.1749-6632.2000.tb06346.x.CrossRefPubMed
39.
Nowicka D, Rogozinska K, Aleksy M, Witte OW, Skangiel-Kramska J: Spatiotemporal dynamics of astroglial and microglial responses after photothrombotic stroke in the rat brain. Acta Neurobiol Exp (Wars). 2008, 68: 155-168.
40.
Inamasu J, Suga S, Sato S, Horiguchi T, Akaji K, Mayanagi K, Kawase T: Post-ischemic hypothermia delayed neutrophil accumulation and microglial activation following transient focal ischemia in rats. J Neuroimmunol. 2000, 109: 66-74. 10.1016/S0165-5728(00)00211-3.CrossRefPubMed
41.
Lyden PD, Krieger D, Yenari M, Dietrich WD: Therapeutic hypothermia for acute stroke. Int J Stroke. 2006, 1: 9-19. 10.1111/j.1747-4949.2005.00011.x.CrossRefPubMed
42.
Zoli M, Grimaldi R, Ferrari R, Zini I, Agnati LF: Short- and long-term changes in striatal neurons and astroglia after transient forebrain ischemia in rats. Stroke. 1997, 28: 1049-1058. discussion 1059CrossRefPubMed
43.
Nawashiro H, Martin D, Hallenbeck JM: Inhibition of tumor necrosis factor and amelioration of brain infarction in mice. J Cereb Blood Flow Metab. 1997, 17: 229-232.CrossRefPubMed
44.
Lotocki G, de Rivero Vaccari JP, Perez ER, Alonso OF, Curbelo K, Keane RW, Dietrich WD: Therapeutic hypothermia modulates TNFR1 signaling in the traumatized brain via early transient activation of the JNK pathway and suppression of XIAP cleavage. Eur J Neurosci. 2006, 24: 2283-2290. 10.1111/j.1460-9568.2006.05123.x.CrossRefPubMed
45.
Kawai N, Okauchi M, Morisaki K, Nagao S: Effects of delayed intraischemic and postischemic hypothermia on a focal model of transient cerebral ischemia in rats. Stroke. 2000, 31: 1982-1989. discussion 1989CrossRefPubMed
46.
Kawamura N, Schmeichel AM, Wang Y, Schmelzer JD, Low PA: Multiple effects of hypothermia on inflammatory response following ischemia-reperfusion injury in experimental ischemic neuropathy. Exp Neurol. 2006, 202: 487-496. 10.1016/j.expneurol.2006.07.012.CrossRefPubMed
47.
Maier CM, Sun GH, Kunis D, Yenari MA, Steinberg GK: Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size. J Neurosurg. 2001, 94: 90-96. 10.3171/jns.2001.94.1.0090.CrossRefPubMed
48.
Ma M, Ma Y, Yi X, Guo R, Zhu W, Fan X, Xu G, Frey WH, Liu X: Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone. BMC Neurosci. 2008, 9: 117-10.1186/1471-2202-9-117.PubMedCentralCrossRefPubMed
49.
Pang L, Ye W, Che XM, Roessler BJ, Betz AL, Yang GY: Reduction of inflammatory response in the mouse brain with adenoviral-mediated transforming growth factor-ss1 expression. Stroke. 2001, 32: 544-552.CrossRefPubMed
50.
Meisel C, Prass K, Braun J, Victorov I, Wolf T, Megow D, Halle E, Volk HD, Dirnagl U, Meisel A: Preventive antibacterial treatment improves the general medical and neurological outcome in a mouse model of stroke. Stroke. 2004, 35: 2-6.CrossRefPubMed
51.
Shen J, Zhang H, Lin H, Su H, Xing D, Du L: Brazilein protects the brain against focal cerebral ischemia reperfusion injury correlating to inflammatory response suppression. Eur J Pharmacol. 2007, 558: 88-95. 10.1016/j.ejphar.2006.11.059.CrossRefPubMed
Metadata
Title
Mild hypothermia causes differential, time-dependent changes in cytokine expression and gliosis following endothelin-1-induced transient focal cerebral ischemia
Authors
An-Gaëlle Ceulemans
Tine Zgavc
Ron Kooijman
Said Hachimi-Idrissi
Sophie Sarre
Yvette Michotte
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2011
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-8-60

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