Патфиз1 -13 / 25

Inflammation as a Therapy for Stroke

their effector function, such as the release of cytokines. Cytokines released by activated T cells induce further T-cell proliferation and differentiation, APC activation and B-cell antibody production. The ability of statins to downregulate expression of MHCII may lead to decrase Th1 differentiation and activation in vivo and thus inhibit the release of proinflammatory cytokines. This suggest that statins may be useful to reduce inflammatory response after stroke [182].

10.2. Immunization and Induction of Tolerance

Pre-exposition of the brain to a short ischemic event can result in subsequent resistance to severe ischemic injury [183]. This phenomenon has been named as preconditioning, and it has been described to be present in several organs, especially heart and brain. Preconditioning proportions ischemic tolerance and it has been observed in humans in clinical practice. Indeed, less severe strokes have been described in patients with prior ipsilateral transient ischemic attacks (TIA) within a short period of time [184].

Although nature of induced protection and the underlying molecular mechanisms of preconditioning remain poorly understood, several mechanisms for the induction and maintenance of tolerance in the brain have been postulated [185]. Several works have tried to solve this question, pointing some of them to different mechanisms that involve in some extent inflammatory mediators such as NF- B [186] and their activators signals like proinflammatory cytokines, neurotrophic factors and neurotransmitters [187].

Numerous studies have also demonstrated that preconditioning of the brain with a variety of potentially harmful stimuli, induces a profound tolerance to a subsequent episode of ischemia. A brief ischemic insult can also induce ischemic tolerance in the spinal cord [188] and other organs, such as the heart [189], liver [190] or kidneys [191]. The exact molecular mechanisms underlying delayed ischemic tolerance are not well understood, but requirements for de novo protein synthesis [192], activation of the proinflammatory transcription factor NF- B [186], and induction of inflammatory cytokines such as TNF, IL-1, IL-6 and IL-8 have been demonstrated.

Since administration of lipopolysacharide (LPS) can induce ischemic tolerance [193], Karikó et al. [194] have developed an hypothetic model to explain this phenomenon. They hypothesized that tolerance is dependent on inhibition of TLR and cytokine signaling pathways, suppressing in this way the inflammatory response to ischemia. When an ischemic event takes place, the ischemic cascade involves TLR activation and cytokine expression, activating inflammation, among other mechanisms. Furthermore, TLR and cytokine signaling, trigger other pathways to increase expression of signaling inhibitors, decoy receptors and antiinflammatory cytokines. These pathways induce immune suppression and when an ischemic event occurs, inflammatory inhibitors are present, reducing inflammatory response and the subsequent secondary cell death.

Alternatively, brain preconditioning could be the consequence of immunomodulation strategies. Following stroke, novel CNS antigens are exposed to the immune system that could increase cellular damage. Therefore, strategies to re-

Current Pharmaceutical Design, 2008, Vol. 14, No. 33 3559

duce this response have been proposed. Animals can acquire tolerance to a variety of vascular antigens including myelinrelated proteins and E-selectin, before MCAO surgery is performed. These animals experience smaller infarcts than animals tolerized to an irrelevant antigen [35, 195].

Ischemic tolerance is an endogenous mechanism that evolves to protect the organism from ischemia, being consequently a good example of immunomodulation.

11. CONCLUSIONS

Cerebral ischemia triggers a very important inflammatory response, which has been associated to an increase in brain damage and poor outcome in stroke patients. Therefore, antiinflammatory therapies should be considered to reduce brain damage. However, inflammation is necessary to initiate the processes of neovascularization and regeneration. Therefore, “contained” inflammatory response might be necessary and beneficial after stroke. It is possible that optimal treatment of inflammation in stroke include an inhibition in the acute phase and activation in later phases to promote neovascularization, plasticity and regeneration.

Furthermore, the latest advances in the immunomodulation field, together with the advances on the knowledge of the ischemic tolerance phenomenon and the role of innate immunity in such phenomenon could open a possibility for the application of immunomodulatory therapies prior to a stroke insult to prepare the organism to can stand better the inflammatory response when stroke occurs.

In summary, inflammation has been associated to an increase in brain damage in stroke patients. Furthermore, inflammation is necessary to activate repairing mechanisms. Therefore, it is necessary a strict control of inflammatory response after stroke to reduce brain damage without inhibition of the repairing mechanisms.

REFERENCES

[1]Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 1747-57.

[2]Perry VH. A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation. J Neuroimmunol 1998; 90: 113-21.

[3]Kaur C, Ling EA. Blood brain barrier in hypoxic-ischemic conditions. Curr Neurovasc Res 2008; 5: 71-81.

[4]Aloisi F. Immune function of microglia. Glia 2001; 36: 165-79.

[5]Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996; 19(8): 312-8.

[6]Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. Gan WB: ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005, 8: 752-758.

[7]Ling EA, Wong WC. The origin and nature of ramified and amoeboid microglia: a historical review and current concepts. Glia 1993; 7: 9-18.

[8]Schmidtmayer J, Jacobsen C, Miksch G, Sievers J. Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocytes: membrane currents. Glia 1994; 12: 259-67.

[9]Streit WJ, Graeber MB. Heterogeneity of microglial and perivascular cell populations: insights gained from the facial nucleus paradigm. Glia 1993; 7: 68-74.

[10]Hickey WF, Kimura H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 1988; 239: 290-2.

3560 Current Pharmaceutical Design, 2008, Vol. 14, No. 33

[11]Nimmerjahn A, Kirchhoff F, Helmchen F: Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308: 1314-8.

[12]Garden GA, Moller T: Microglia biology in health and disease. J Neuroimmune Pharmacol 2006, 1: 127-37.

[13]Perry VH, Newman TA, Cunningham C: The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci 2003, 4: 103-12.

[14]Nakajima K, Kohsaka S. Microglia: activation and their significance in the central nervous system. J Biochem 2001; 130: 169-75.

[15]Banati RB, Gehrmann J, Kreutzberg GW. Early glial reactions in ischemic lesions. Adv Neurol 1996; 71: 329-36; discussion 336-7.

[16]Schroeter M, Zickler P, Denhardt DT, Hartung HP, Jander S. Increased thalamic neurodegeneration following ischaemic cortical stroke in osteopontin-deficient mice. Brain 2006; 129: 1426-37.

[17]Price CJ, Wang D, Menon DK, Guadagno JV, Cleij M, Fryer T, et al. Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke 2006; 37: 1749-53.

[18]Baron JC. How healthy is the acutely reperfused ischemic penumbra? Cerebrovasc Dis 2005; 20 Suppl 2: 25-31.

[19]Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, et al. Minocycline treatment in acute stroke: an open-label, evalua- tor-blinded study. Neurology 2007; 69(14): 1404-10.

[20]Jordan J, Fernandez-Gomez FJ, Ramos M, Ikuta I, Aguirre N, Galindo MF. Minocycline and cytoprotection: shedding new light on a shadowy controversy. Curr Drug Deliv 2007; 4: 225-31.

[21]Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cell Signal 2001; 13: 85-94.

[22]McEver RP, Cummings RD. Perspectives series: cell adhesion in vascular biology. Role of PSGL-1 binding to selectins in leukocyte recruitment. J Clin Invest 1997 Aug 1; 100(3): 485-91.

[23]Connolly ESJ, Winfree CJ, Springer TA, Naka Y, Liao H, Yan SD, et al. 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 1996; 97: 209-16.

[24]Moore KL, Eaton SF, Lyons DE, Lichenstein HS, Cummings RD, McEver RP. The P-selectin glycoprotein ligand from human neutrophils displays sialylated, fucosylated, O-linked poly-N- acetyllactosamine. J Biol Chem 1994; 269: 23318-27.

[25]Huang J, Kim LJ, Mealey R, Marsh Jr HC, Zhang Y, Tenner AJ, et al. Neuronal protection in stroke by an sLe(x)-glycosylated complement inhibitory protein. Science 1999; 285: 595-9.

[26]Stenberg PE, Shuman MA, Levine SP, Bainton DF. Redistribution of alpha-granules and their contents in thrombin-stimulated platelets. J Cell Biol 1984; 98: 748-60.

[27]Diacovo TG, Roth SJ, Buccola JM, Bainton DF, Springer TA. Neutrophil rolling, arrest, and transmigration across activated, sur- face-adherent platelets via sequential action of P-selectin and the2integrin CD11b/CD18. Blood 1996; 88: 146-57.

[28]Cha JK, Jeong MH, Kim EK, Lim YJ, Ha BR, Kim SH, et al. Surface expression of P-selectin on platelets is related with clinical worsening in acute ischemic stroke. J Korean med sci 2002; 17: 811-6.

[29]Mayadas TN, Johnson RC, Rayburn H, Hynes RO, Wagner DD. Leukocyte rolling and extravasation are severely compromised in P-selectin deficient mice. Cell 1993; 74: 541-54.

[30]Huang J, Choudhri TF, Winfree CJ, McTaggart RA, Kiss S, Mocco J, et al. Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke. Stroke 2000; 31: 3047-53

[31]Mocco J, Choudhri T, Huang J, Harfeldt E, Efros L, Klingbeil C, et al. HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circulation Research 2002; 91: 907-14.

[32]Zhang RL, Chopp M, Zhang ZG, Phillips ML, Rosenbloom CL, Cruz R, et al. E-selectin in focal cerebral ischemia and reperfusion in the rat. J Cereb Blood Flow Metab 1996; 16: 1126-36.

[33]Zhang R, Chopp M, Zhang Z, Jiang N, Powers C. The expression of P- and E-selectins in three models of middle cerebral artery occlusion. Brain Res 1998; 785: 207-14.

[34]Lehmberg J, Beck J, Baethmann A, Uhl E. Effect of P-selectin inhibition on leukocyte-endothelium interaction and survival after global cerebral ischemia. J Neurol 2006; 253: 357-63.

Jordán et al.

[35]Chen Y, Ruetzler C, Pandipati S, Spatz M, McCarron RM, Becker K, et al. Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury. Proc Natl Acad Sci USA 2003; 100: 15107-12.

[36]Yenari MA, Sun GH, Kunis DM, Onley D, Vexler V. L-selectin inhibition does not reduce injury in a rabbit model of transient focal cerebral ischemia. Neurol Res 2001; 23: 72-8.

[37]Frijns CJM, Kappell LJ. Inflammatory cell adhesion molecules in ischemic cerebrovascular disease. Stroke 2002; 33: 2115-22.

[38]Hess DC, Zhao W, Carroll J, McEachin M, Buchanan K. Increased expression of ICAM-1 during reoxygenation in brain endothelial cells. Stroke 1994; 25: 1463-8.

[39]Stanimirovic D, Shapiro A, Wong J, Hutchison J, Durkin J. The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/HCEC adhesion. Journal of Neuroimmunology 1997; 76: 193-205

[40]Zhang RL, Chopp M, Chen H, Garcia JH. Temporal profile of ischemic tissue damage, neutrophil response, and vascular plugging following permanent and transient (2H) middle cerebral artery occlusion in the rat. J Neurol Sci 1994; 125: 3-10.

[41]Shyu KG, Chang H, Lin CC. Serum levels of intercellular adhesion molecule-1 and E-selectin in patients with acute ischaemic stroke. J Neurol 1997; 244: 90-3.

[42]Bitsch A, Klene W, Murtada L, Prange H, Rieckmann P. A longitudinal prospective study of soluble adhesion molecules in acute stroke. Stroke 1998; 29: 2129-35.

[43]Lindsberg PJ, Carpe?n O, Paetau A, Karjalainen-Lindsberg ML, Kaste M. Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation 1996;

94:939-45.

[44]Endres M, Laufs U, Merz H, Kaps M. Focal expression of intercellular adhesion molecule-1 in the human carotid bifurcation. Stroke 1997; 28: 77-82.

[45]DeGraba TJ, Siren AL, Penix L, McCarron RM, Hargraves R, Sood S, et al. Increased endothelial expression of intercellular adhesion molecule-1 in symptomatic versus asymptomatic human carotid atherosclerotic plaque. Stroke 1998; 29: 1405-10.

[46]Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM, Jr., et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation 1997; 96: 4219-25.

[47]Vemuganti R, Dempsey RJ, Bowen KK. Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke 2004; 35: 179-84.

[48]Zhang RL, Chopp M, Li Y, Zaloga C, Jiang N, Jones ML, et al. Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 1994;

44:1747-51.

[49]Bowes MP, Zivin JA, Rothlein R. Monoclonal antibody to the ICAM-1 adhesion site reduces neurological damage in a rabbit cerebral embolism stroke model. Exp Neurol 1993; 119: 215-9.

[50]Zhang LH, Wei EQ. Neuroprotective effect of ONO-1078, a leukotriene receptor antagonist, on transient global cerebral ischemia in rats. Acta Pharmacol Sin 2003; 24: 1241-7.

[51]Justicia C, Martin A, Rojas S, Gironella M, Cervera A, Panes J, et al. Anti-VCAM-1 antibodies did not protect against ischemic damage either in rats or in mice. J Cereb Blood Flow Metab 2006; 26: 421-32.

[52]Haring HP, Akamine P, Habermann R, Koziol JA, Del Zoppo GJ. Distribution of integrin-like immunoreactivity on primate brain microvasculature. Journal of Neuropathology and Experimental Neurology 1996; 55: 236-45.

[53]Springer TA. Adhesion receptors of the immune system. Nature 1990; 346: 425-34.

[54]Harmon D, Lan W, Shorten G. The effect of aprotinin on hypoxia- reoxygenation-induced changes in neutrophil and endothelial function. Eur J Anaesthesiol 2004; 21: 973-9.

[55]Zhang ZG, Chopp M, Tang WX, Jiang N, Zhang RL. Postischemic treatment (2-4 h) with anti-CD11b and anti-CD18 monoclonal anti-

Inflammation as a Therapy for Stroke

bodies are neuroprotective after transient (2 h) focal cerebral ischemia in the rat. Brain Res 1995; 698: 79-85.

[56]Prestigiacomo CJ, Kim SC, Connolly ES, Jr., Liao H, Yan SF, Pinsky DJ. CD18-mediated neutrophil recruitment contributes to the pathogenesis of reperfused but not nonreperfused stroke. Stroke 1999; 30: 1110-7.

[57]Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA. Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke 2003; 34: 2543-8.

[58]Becker K, Kindrick D, Relton J, Harlan J, Winn R. Antibody to the alpha4 integrin decreases infarct size in transient focal cerebral ischemia in rats. Stroke 2001; 32: 206-11.

[59]Dinarello CA. Interleukin-1 and interleukin-1 antagonism. Blood 1991; 77: 1627-52.

[60]Dripps DJ, Brandhuber BJ, Thompson RC, Eisenberg SP. Interleu- kin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 1991;

266:10331-6.

[61]Koga S, Ogawa S, Kuwabara K, Brett J, Leavy JA, Ryan J, et al. Synthesis and release of interleukin 1 by reoxygenated human mononuclear phagocytes. J Clin Invest 1992; 90: 1007-15.

[62]Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 1992; 356: 768-74.

[63]Rothwell NJ. Functions and mechanisms of interleukin 1 in the brain. Trends Pharmacol Sci 1991; 12: 430-6.

[64]Minami M, Kuraishi Y, Satoh M. Effects of kainic acid on messenger RNA levels of IL-1 beta, IL-6, TNF alpha and LIF in the rat brain. Biochem Biophys Res Commun 1991; 176: 593-8.

[65]Buttini M, Boddeke H. Peripheral lipopolysaccharide stimulation induces interleukin-1 beta messenger RNA in rat brain microglial cells. Neuroscience 1995; 65: 523-30.

[66]Buttini M, Sauter A, Boddeke HW. Induction of interleukin-1 beta mRNA after focal cerebral ischaemia in the rat. Brain Res Mol Brain Res 1994; 23: 126-34.

[67]Davies CA, Loddick SA, Toulmond S, Stroemer RP, Hunt J, Rothwell NJ. The progression and topographic distribution of inter- leukin-1beta expression after permanent middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 1999; 19: 87-98.

[68]Haqqani AS, Nesic M, Preston E, Baumann E, Kelly J, Stanimirovic D. Characterization of vascular protein expression patterns in cerebral ischemia/reperfusion using laser capture microdissection and ICAT-nanoLC-MS/MS. FASEB J 2005; 19: 1809-21.

[69]John GR, Chen L, Rivieccio MA, Melendez-Vasquez CV, Hartley A, Brosnan CF. Interleukin-1beta induces a reactive astroglial phenotype via deactivation of the Rho GTPase-Rock axis. J Neurosci 2004; 24: 2837-45.

[70]Azzimondi G, Bassein L, Nonino F, Fiorani L, Vignatelli L, Re G, et al. Fever in acute stroke worsens prognosis. A prospective study. Stroke 1995; 26: 2040-3.

[71]Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC. Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNFalpha impart neuroprotection to an excitotoxin through distinct pathways. J Immunol 1999; 163: 3963-8.

[72]Strijbos PJ, Rothwell NJ. Interleukin-1 beta attenuates excitatory amino acid-induced neurodegeneration in vitro: involvement of nerve growth factor. J Neurosci 1995; 15: 3468-74.

[73]Yamasaki Y, Matsuura N, Shozuhara H, Onodera H, Itoyama Y, Kogure K. Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats. Stroke 1995; 26: 676-80; discussion 681.

[74]Yang GY, Zhao YJ, Davidson BL, Betz AL. Overexpression of interleukin-1 receptor antagonist in the mouse brain reduces ischemic brain injury. Brain Res 1997; 751: 181-8.

[75]Relton JK, Martin D, Thompson RC, Russell DA. Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol 1996;

138:206-13.

[76]Pinteaux E, Rothwell NJ, Boutin H. Neuroprotective actions of endogenous interleukin-1 receptor antagonist (IL-1ra) are mediated by glia. Glia 2006; 53: 551-6.

Current Pharmaceutical Design, 2008, Vol. 14, No. 33 3561

[77]Herrmann O, Tarabin V, Suzuki S, Attigah N, Coserea I, Schneider A, et al. Regulation of body temperature and neuroprotection by endogenous interleukin-6 in cerebral ischemia. J Cereb Blood Flow Metab 2003; 23: 406-15.

[78]Wang X, Yue TL, Barone FC, White RF, Gagnon RC, Feuerstein GZ. Concomitant cortical expression of TNFand IL-1 mRNAs follows early response gene expression in transient focal ischemia. Mol Chem Neuropathol 1994; 23: 103-14.

[79]Vila N, Castillo J, Davalos A, Chamorro A. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 2000; 31: 2325-9.

[80]Castillo J, Rodriguez I. Biochemical changes and inflammatory response as markers for brain ischaemia: molecular markers of diagnostic utility and prognosis in human clinical practice. Cerebrovasc Dis 2004; 17 Suppl 1: 7-18.

[81]Smith CJ, Emsley HC, Gavin CM, Georgiou RF, Vail A, Barberan EM, et al. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 2004; 4: 2

[82]Sriram K, O'Callaghan JP. Divergent roles for tumor necrosis fac- tor-alpha in the brain. J Neuroimmune Pharmacol 2007; 2: 140-53.

[83]Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, et al. Tumor necrosis factorexpression in ischemic neurons. Stroke 1994; 25: 1481-8.

[84]Buttini M, Appel K, Sauter A, Gebicke-Haerter PJ, Boddeke HW. Expression of tumor necrosis factor alpha after focal cerebral ischaemia in the rat. Neuroscience 1996; 71: 1-16.

[85]Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, Feuerstein GZ. Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke 1997; 28: 1233-44.

[86]Liu T, Mc Donnell PC, Young PR, White RF, Siren AL, Hallenbeck JM, et al. Interleukin-1 mRNA expression in ischemic rat cortex. Stroke 1993; 24: 1746-51.

[87]Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA. Correlations and interactions in the production of inter- leukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 1990; 75: 40-7.

[88]Murakami Y, Saito K, Hara A, Zhu Y, Sudo K, Niwa M, et al. Increases in tumor necrosis factor-alpha following transient global cerebral ischemia do not contribute to neuron death in mouse hippocampus. J Neurochem 2005; 93: 1616-22.

[89]Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab 2006; 26: 654-65.

[90]Tomimoto H, Akiguchi I, Wakita H, Kinoshita A, Ikemoto A, Nakamura S, et al. Glial expression of cytokines in the brains of cerebrovascular disease patients. Acta Neuropathol 1996; 92: 281- 7.

[91]Sairanen T, Carpen O, Karjalainen-Lindsberg ML, Paetau A, Turpeinen U, Kaste M, et al. Evolution of cerebral tumor necrosis fac- tor-alpha production during human ischemic stroke. Stroke 2001; 32: 1750-8.

[92]Tarkowski E, Rosengren L, Blomstrand C, Wikkelso C, Jensen C, Ekholm S, et al. Early intrathecal production of interleukin-6 predicts the size of brain lesion in stroke. Stroke 1995; 26: 1393-8.

[93]van Exel E, Gussekloo J, de Craen AJ, Bootsma-van der Wiel A, Frolich M, Westendorp RG. Inflammation and stroke: the Leiden 85-Plus Study. Stroke 2002; 33: 1135-8.

[94]Castellanos M, Castillo J, Garcia MM, Leira R, Serena J, Chamorro A, et al. Inflammation-mediated damage in progressing lacunar infarctions: a potential therapeutic target. Stroke 2002; 33: 982-7.

[95]Hallenbeck JM. The many faces of tumor necrosis factor in stroke. Nat Med 2002; 8: 1363-8.

[96]Yang GY, Gong C, Qin Z, Ye W, Mao Y, Bertz AL. Inhibition of TNFalpha attenuates infarct volume and ICAM-1 expression in ischemic mouse brain. Neuroreport 1998; 9: 2131-4.

[97]Dawson DA, Martin D, Hallenbeck JM. Inhibition of tumor necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. Neurosci Lett 1996; 218: 41-4.

3562 Current Pharmaceutical Design, 2008, Vol. 14, No. 33

[98]Lavine SD, Hofman FM, Zlokovic BV. Circulating antibody against tumor necrosis factor-alpha protects rat brain from reperfusion injury. J Cereb Blood Flow Metab 1998; 18: 52-8.

[99]Wang CX, Shuaib A. Involvement of inflammatory cytokines in central nervous system injury. Prog Neurobiol 2002; 67: 161-72.

[100]Ginis I, Jaiswal R, Klimanis D, Liu J, Greenspon J, Hallenbeck JM. TNF-alpha-induced tolerance to ischemic injury involves differential control of NF-kappaB transactivation: the role of NF-kappaB association with p300 adaptor. J Cereb Blood Flow Metab 2002;

22:142-52.

[101]Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, et al. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 1996; 2: 788-94.

[102]Dopp JM, Mackenzie-Graham A, Otero GC, Merrill JE. Differential expression, cytokine modulation, and specific functions of type-1 and type-2 tumor necrosis factor receptors in rat glia. J Neuroimmunol 1997; 75: 104-12.

[103]Nawashiro H, Tasaki K, Ruetzler CA, Hallenbeck JM. TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice. J Cereb Blood Flow Metab 1997; 17: 483-90.

[104]Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, et al. Interleukin-10 in the brain. Crit Rev Immunol 2001; 21: 427-49.

[105]Tarkowski E, Rosengren L, Blomstrand C, Wikkelso C, Jensen C, Ekholm S, et al. Intrathecal release of proand anti-inflammatory cytokines during stroke. Clin Exp Immunol 1997; 110: 492-9.

[106]Vila N, Castillo J, Davalos A, Esteve A, Planas AM, Chamorro A. Levels of anti-inflammatory cytokines and neurological worsening

in acute ischemic stroke. Stroke 2003; 34: 671-5.

[107]Grilli M, Barbieri I, Basudev H, Brusa R, Casati C, Lozza G, Ongini E. Interleukin-10 modulates neuronal threshold of vulner-

ability to ischaemic damage. Eur J Neurosci 2000; 12: 2265-72.

[108]Spera PA, Ellison JA, Feuerstein GZ, Barone FC. IL-10 reduces rat brain injury following focal stroke. Neurosci Lett 1998; 251: 189-

[109]Ooboshi H, Ibayashi S, Shichita T, Kumai Y, Takada J, Ago T, et al. Postischemic gene transfer of interleukin-10 protects against

both focal and global brain ischemia. Circulation 2005; 111: 913-9.

[110]Kim JS, Yoon SS, Kim YH, Ryu JS. Serial measurement of inter- leukin-6, transforming growth factor-beta, and S-100 protein in pa-

tients with acute stroke. Stroke 1996; 27: 1553-7.

[111]Klempt ND, Sirimanne E, Gunn AJ, Klempt M, Singh K, Williams C, et al. Hypoxia-ischemia induces transforming growth factor beta

1mRNA in the infant rat brain. Mol Brain Res 1992; 13: 93-101.

[112]Wienner C, Gehrmann J, Lindholm D, Topper R, Kreutzberg GW, Hossmann KA. Expression of transforming growth factor-beta1

and interleukin-1 beta mRNA in rat brain following transient forebrain ischemia. Acta Neuropathol 1993; 86: 439-46.

[113]Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: Induction of circulating

IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 1994; 83: 113-8.

[114]Pang L, Ye W, Che XM, Roessler BJ, Betz AL, Yang GY. Reduction of inflammatory response in the mouse brain with adenoviralmediated transforming growth factor-ss1 expression. Stroke 2001;

32:544-52.

[115]Lu YZ, Lin CH, Cheng FC, Hsueh CM. Molecular mechanisms responsible for microglia-derived protection of Sprague-Dawley rat brain cells during in vitro ischemia. Neurosci Lett 2005; 373: 159-

[116]Mori E, Del Zoppo GJ, Chambers JD, Copeland BR, Arfors KE. Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke 1992;

23:712-8.

[117]Gross CE, Bednar MM, Howard DB, Sporn MB, MacMillan V. Transforming growth factor-beta1 reduces infarct size after experimental cerebral ischemia in a rabbit model. Stroke 1993; 24: 558-62.

[118]Johnston RE, Dillon-Carter O, Freed WJ, Borlongan CV. Trophic factor secreting kidney cell lines: In vitro characterization and functional effects following transplantation in ischemic rats. Brain Res 2001; 900: 268-76.

Jordán et al.

[119]Benveniste EN. Cytokine actions in the central nervous system. Cytokine Growth Factor Rev 1998; 9: 259-75.

[120]Emsley HC, Tyrrell PJ. Inflammation and infection in clinical stroke. J Cereb Blood Flow Metab 2002; 22: 1399-419.

[121]Garau A, Bertini R, Colotta F, Casilli F, Bigini P, Cagnotto A, et al. Neuroprotection with the CXCL8 inhibitor repertaxin in transient brain ischemia. Cytokine 2005; 30: 125-31.

[122]Losy J, Zaremba J. Monocyte chemoattractant protein-1 is increased in the cerebrospinal fluid of patients with ischemic stroke. Stroke 2001; 32: 2695-6.

[123]Stamatovic SM, Shakui P, Keep RF, Moore BB, Kunkel SL, Van Rooijen N, et al. Monocyte chemoattractant protein-1 regulation of blood-brain barrier permeability. J Cereb Blood Flow Metab 2005;

25:593-606.

[124]Wang L, Li Y, Chen J, Gautam SC, Zhang Z, Lu M, et al. Ischemic cerebral tissue and MCP-1 enhance rat bone marrow stromal cell migration in interface culture. Exp Hematol 2002; 30: 831-6.

[125]Ré DB, Przedborski S. Fractalkine: moving from chemotaxis to neuroprotection. Nat Neurosci 2006; 9: 859-61.

[126]Soriano SG, Amaravadi LS, Wang YF, Zhou H, Yu GX, Tonra JR, Fairchild-Huntress V, Fang Q, Dunmore JH, Huszar D, Pan Y. Mice deficient in fractalkine are less susceptible to cerebral ische- mia-reperfusion injury. J Neuroimmunol 2002; 125: 59-65.

[127]Tarozzo G, Campanella M, Ghiani M, Bulfone A, Beltramo M. Expression of fractalkine and its receptor, CX3CR1, in response to ischaemia-reperfusion brain injury in the rat. Eur J Neurosci 2002;

15:1663-8.

[128]Lavergne E, Labreuche J, Daoudi M, Debré P, Cambien F, Deterre P, Amarenco P, Combadière C; GENIC Investigators. Adverse associations between CX3CR1 polymorphisms and risk of cardiovascular or cerebrovascular disease. Arterioscler Thromb Vasc Biol 2005; 25: 847-53.

[129]Schwab JM, Beschorner R, Meyermann R, Gozalan F, Schluesener HJ. Persistent accumulation of cyclooxygenase-1-expressing microglial cells and macrophages and transient upregulation by endothelium in human brain injury. J Neurosurg 2002; 96: 892-9.

[130]Smith WL, Marnett LJ. Prostaglandin endoperoxide synthase: structure and catalysis. Biochim Biophys Acta 1991; 1083: 1-17.

[131]Iadecola C, Sugimoto K, Niwa K, Kazama K, Ross ME. Increased susceptibility to ischemic brain injury in cyclooxygenase-1- deficient mice. J Cereb Blood Flow Metab 2001; 21: 1436-41.

[132]Candelario-Jalil E, Gonzalez-Falcon A, Garcia-Cabrera M, Alvarez D, Al-Dalain S, Martinez G, et al. Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia. J Neurochem 2003; 86: 545-55.

[133]Planas AM, Soriano MA, Rodriguez-Farre E, Ferrer I. Induction of cyclooxygenase-2 mRNA and protein following transient focal ischemia in the rat brain. Neurosci Lett 1995; 200: 187-90.

[134]Nogawa S, Zhang F, Ross ME, Iadecola C. Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 1997; 17: 2746-55.

[135]Sairanen T, Ristimaki A, Karjalainen-Lindsberg ML, Paetau A, Kaste M, Lindsberg PJ. Cyclooxygenase-2 is induced globally in infarcted human brain. Ann Neurol 1998; 43: 738-47.

[136]Sugimoto K, Iadecola C. Delayed effect of administration of COX- 2 inhibitor in mice with acute cerebral ischemia. Brain Res 2003;

960:273-6.

[137]Dore S, Otsuka T, Mito T, Sugo N, Hand T, Wu L, et al. Neuronal overexpression of cyclooxygenase-2 increases cerebral infarction. Ann Neurol 2003; 54: 155-62.

[138]Llorens S, Jordán J, Nava E. The nitric oxide pathway in the cardiovascular system. J Physiol Biochem 2002; 58: 179-88.

[139]Nathan C. Inducible nitric oxide synthase: what difference does it make? J Clin Invest 1997; 100: 2417-23.

[140]Cui J, Holmes EH, Greene TG, Liu PK. Oxidative DNA damage precedes DNA fragmentation after experimental stroke in rat brain. Faseb J 2000; 14: 955-67.

[141]Iadecola C. Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci 1997; 20: 132-9.

[142]Huang Z, Huang PL, Ma J, Meng W, Ayata C, Fishman MC, et al. Enlarged infarcts in endothelial nitric oxide synthase knockout

Inflammation as a Therapy for Stroke

mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab 1996; 16: 981-7.

[143]Iadecola C, Zhang F, Casey R, Nagayama M, Ross ME. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci 1997;

17:9157-64.

[144]Parmentier S, Bohme GA, Lerouet D, Damour D, Stutzmann JM, Margaill I, et al. Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury. Br J Pharmacol 1999; 127: 546-52.

[145]Rosenberg GA, Navratil M, Barone F, Feuerstein G. Proteolytic cascade enzymes increase in focal cerebral ischemia in rat. J Cereb Blood Flow Metab 1996; 16: 360-6.

[146]Clark AW, Krekoski CA, Bou SS, Chapman KR, Edwards DR. Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia. Neurosci Lett 1997; 238: 53-6.

[147]Castellanos M, Leira R, Serena J, Pumar JM, Lizasoain I, Castillo J, et al. Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke. Stroke 2003; 34: 40-6.

[148]Montaner J, Alvarez-Sabin J, Molina C, Angles A, Abilleira S, Arenillas J, et al. Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke 2001; 32: 1759-66.

[149]Kusano K, Miyaura C, Inada M, Tamura T, Ito A, Nagase H, et al. Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption. Endocrinology 1998; 139: 1338-45.

[150]Pfefferkorn T, Rosenberg GA. Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke 2003;

34:2025-30.

[151]Asahi M, Sumii T, Fini ME, Itohara S, Lo EH. Matrix metalloproteinase 2 gene knockout has no effect on acute brain injury after focal ischemia. Neuroreport 2001; 12: 3003-7.

[152]Zhao BQ, Wang S, Kim HY, Storrie H, Rosen BR, Mooney DJ, Wang X, Lo EH. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 2006; 12: 441-5.

[153]Gomez-Lazaro M, Fernandez-Gomez FJ, Jordán J. p53: twenty five years understanding the mechanism of genome protection. J Physiol Biochem 2004; 60: 287-307.

[154]Crumrine RC, Thomas AL, Morgan PF. Attenuation of p53 expression protects against focal ischemic damage in transgenic mice. J Cereb Blood Flow Metab 1994; 14: 887-91.

[155]Jordán J, Galindo MF, González-García C, Ceña V. Role and regulation of p53 in depolarization-induced neuronal death. Neuroscience 2003; 122(3): 707-15.

[156]O'Mahony A, Raber J, Montano M, Foehr E, Han V, Lu SM, Kwon H, LeFevour A, Chakraborty-Sett S, Greene WC. NF-kappaB/Rel regulates inhibitory and excitatory neuronal function and synaptic plasticity. Mol Cell Biol 2006; 26: 7283-98.

[157]Tureyen K, Kapadia R, Bowen KK, Satriotomo I, Liang J, Feinstein DL, Vemuganti R. Peroxisome proliferator-activated receptorgamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. J Neurochem 2007; 101: 41-56.

[158]Yenari MA, Han HS. Influence of hypothermia on post-ischemic inflammation: role of nuclear factor kappa B (NFkappaB). Neurochem Int 2006; 49: 164-9.

[159]Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol 2005; 17: 1-14.

[160]Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004; 5: 987-95.

[161]Akira S, Sato S. Toll-like receptors and their signalling mechanisms. Scand J Infect Dis 2003; 35: 555-62.

[162]Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001; 2: 67580.

[163]Medzhitov R. Toll-like receptors and innate immunity. Nat. Rev. Immunol 2001; 1: 135-45.

Current Pharmaceutical Design, 2008, Vol. 14, No. 33 3563

[164]Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003; 21: 335-76.

[165]Nguyen KB. Critical role for STAT4 activation by type 1 interferons in the interferon-[gamma] response to viral infection. Science 2002; 297: 2063-6.

[166]Ziegler G, Harhausen D, Schepers C, Hoffmann O, Rohr C, Prinz V, et al. TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochem Biophys Res Commun 2007; 359: 574-9.

[167]Cao CX, Yang QW, Lv FL, Cui J, Fu HB, Wang JZ. Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. Biochem Biophys Res Commun 2007; 353: 509-14.

[168]Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 2007; 115: 1599-608.

[169]Caso JR, Pradillo JM, Hurtado O, Leza JC, Moro MA, Lizasoain I. Toll-Like Receptor 4 Is Involved in Subacute Stress-Induced Neuroinflammation and in the Worsening of Experimental Stroke. Stroke 2008.

[170]Zhang Z, Schluesener HJ. Mammalian toll-like receptors: from endogenous ligands to tissue regeneration. Cellular and Molecular Life Sciences (CMLS) 2006; V63: 2901-7.

[171]Prass K, Meisel C, Hoflich C, Braun J, Halle E, Wolf T, et al. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med 2003; 198: 725-36.

[172]Hendrix S, Nitsch R. The role of T helper cells in neuroprotection and regeneration. J Neuroimmunol 2007; 184: 100-12.

[173]Dirnagl U, Klehmet J, Braun JS, Harms H, Meisel C, Ziemssen T, et al. Stroke-induced immunodepression: experimental evidence and clinical relevance. Stroke 2007; 38: 770-3.

[174]Chamorro A, Urra X, Planas AM. Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Stroke 2007; 38: 1097-103.

[175]Klangsinsirikul P, Russell NH. Peripheral blood stem cell harvests from G-CSF-stimulated donors contain a skewed Th2 CD4 phenotype and a predominance of type 2 dendritic cells. Exp Hematol 2002; 30: 495-501.

[176]Agnello D, Mascagni P, Bertini R, Villa P, Senaldi G, Ghezzi P. Granulocyte colony-stimulating factor decreases tumor necrosis factor production in whole blood: role of interleukin-10 and prostaglandin E(2). Eur Cytokine Netw 2004; 15: 323-6.

[177]Rutella S, Pierelli L, Bonanno G, Sica S, Ameglio F, Capoluongo E, et al. Role for granulocyte colony-stimulating factor in the generation of human T regulatory type 1 cells. Blood 2002; 100: 256271.

[178]Pan L, Delmonte J, Jr., Jalonen CK, Ferrara JL. Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood 1995; 86: 4422-9.

[179]Hirayama Y, Sakamaki S, Matsunaga T, Kuroda H, Kusakabe T, Akiyama T, et al. Granulocyte-colony stimulating factor enhances the expression of transforming growth factor-beta mRNA in CD4positive peripheral blood lymphocytes in the donors for allogeneic peripheral blood stem cell transplantation. Am J Hematol 2002; 69: 138-40.

[180]Zou L, Barnett B, Safah H, Larussa VF, Evdemon-Hogan M, Mottram P, et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res 2004; 64: 8451-5.

[181]Xiao BG, Lu CZ, Link H. Cell biology and clinical promise of G- CSF: immunomodulation and neuroprotection. J Cell Mol Med 2007; 11: 1272-90.

[182]Palinski W. Immunomodulation: a new role for statins? Nat Med 2000; 6: 1311-2.

[183]Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, et al. 'Ischemic tolerance' phenomenon found in the brain. Brain Res 1990; 528: 21-4.

[184]Weih M, Kallenberg K, Bergk A, Dirnagl U, Harms L, Wernecke KD, et al. Attenuated stroke severity after prodromal TIA: a role for ischemic tolerance in the brain? Stroke 1999; 30: 1851-4.

3564 Current Pharmaceutical Design, 2008, Vol. 14, No. 33

[185]Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 2003; 26: 248-54.

[186]Blondeau N, Widmann C, Lazdunski M, Heurteaux C. Activation of the nuclear factor-kappaB is a key event in brain tolerance. J Neurosci 2001; 21: 4668-77.

[187]Mattson MP, Culmsee C, Yu Z, Camandola S. Roles of nuclear factor kappaB in neuronal survival and plasticity. J Neurochem 2000; 74: 443-56.

[188]Zvara DA, Colonna DM, Deal DD, Vernon JC, Gowda M, Lundell JC. Ischemic preconditioning reduces neurologic injury in a rat model of spinal cord ischemia. Ann Thorac Surg 1999; 68: 874-80.

[189]Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74: 1124-36.

[190]Tsuyama H, Shimizu K, Yoshimoto K, Nezuka H, Ito H, Yamamoto S, et al. Protective effect of ischemic preconditioning on hepatic ischemia-reperfusion injury in mice. Transplant Proc 2000; 32: 2310-3.

Jordán et al.

[191]Toosy N, McMorris EL, Grace PA, Mathie RT. Ischaemic preconditioning protects the rat kidney from reperfusion injury. BJU Int 1999; 84: 489-94.

[192]Currie RW, Ellison JA, White RF, Feuerstein GZ, Wang X, Barone FC. Benign focal ischemic preconditioning induces neuronal Hsp70 and prolonged astrogliosis with expression of Hsp27. Brain Res 2000; 863: 169-81.

[193]Tasaki K, Ruetzler CA, Ohtsuki T, Martin D, Nawashiro H, Hallenbeck JM. Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats. Brain Res 1997; 748: 267-70.

[194]Kariko K, Weissman D, Welsh FA. Inhibition of toll-like receptor and cytokine signaling--a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab 2004; 24: 1288-304.

[195]Becker KJ, McCarron RM, Ruetzler C, Laban O, Sternberg E, Flanders KC, et al. Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia. Proc Natl Acad Sci USA 1997; 94: 10873-8.