Age-related brain injuries including stroke are a leading cause of morbidity and mental disability worldwide. Most patients who survive stroke experience some degree of recovery. The restoration of lost functions can be explained by neuronal plasticity, understood as brain ability to reorganize and remodel itself in response to changed environmental requirements. However, stroke triggers a cascade of events which may prevent the normal development of the plastic changes. One of them may be inflammatory response initiated immediately after stroke, which has been found to contribute to neuronal injury. Some recent evidence though has suggested that inflammatory reaction can be also neuroprotective. This paper attempts to discuss the influence of poststroke inflammatory response on brain plasticity and stroke outcome. We also describe the recent anti-inflammatory strategies that have been effective for recovery in experimental stroke. 1. Introduction Ischemic stroke results from two main pathological processes: a loss of oxygen and an interruption of glucose supply to a particular brain region. The collapse of energy provision leads to the dysfunction of ionic pumps, loss of membrane potential, and uncontrolled release of neurotransmitters. The consequence of those processes is the increase of intracellular calcium concentrations that, among many deleterious effects, result in the generation of free radicals, leading to disintegration of cell membranes and subsequent neuronal death in the core of infarction [1]. Necrosis in the center of infarction can start a few minutes after stroke and is followed by peri-infarct depolarizations, excitotoxicity, edema, and oxidative stress [2]. The more delayed processes accompanying stroke are inflammation and apoptosis. They are initiated several hours after ischemic attack and can persist even for several weeks [3]. Although a great progress has been made in understanding the cellular and molecular mechanisms of ischemic tissue damage, the only approved therapy is still thrombolysis achieved by intravenous administration of recombinant tissue plasminogen activator (tPA). Unfortunately, short therapeutic window for this therapy strongly limits the fraction of patient that can benefit from the treatment. Moreover, stroke induces a complex cascade of inflammatory response which contributes to the postischemic damage. The complex nature of phenomena after ischemic event hampers a successful design of effective therapeutic strategies (Figure 1). Figure 1: Acute cerebral ischemia, neuroinflammation, and plasticity.
References
[1]
U. Dirnagl, C. Iadecola, and M. A. Moskowitz, “Pathobiology of ischaemic stroke: an integrated view,” Trends in Neurosciences, vol. 22, no. 9, pp. 391–397, 1999.
[2]
E. H. Lo, T. Dalkara, and M. A. Moskowitz, “Mechanisms, challenges and opportunities in stroke,” Nature Reviews Neuroscience, vol. 4, no. 5, pp. 399–415, 2003.
[3]
E. Candelario-Jalil, “Injury and repair mechanisms in ischemic stroke: considerations for the development of novel neurotherapeutics,” Current Opinion in Investigational Drugs, vol. 10, no. 7, pp. 644–654, 2009.
[4]
B. B. Johansson, “Brain plasticity and stroke rehabilitation: the Willis lecture,” Stroke, vol. 31, no. 1, pp. 223–230, 2000.
[5]
S. T. Carmichael, “Plasticity of cortical projections after stroke,” Neuroscientist, vol. 9, no. 1, pp. 64–75, 2003.
[6]
P. W. Duncan, H. S. Jorgensen, and D. T. Wade, “Outcome measures in acute stroke trials: a systematic review and some recommendations to improve practice,” Stroke, vol. 31, no. 6, pp. 1429–1438, 2000.
[7]
P. W. Duncan, “Stroke recovery and rehabilitation research,” Journal of Rehabilitation Research and Development, vol. 39, pp. ix–xi, 2002.
[8]
S. Studenski, P. W. Duncan, S. Perera, D. Reker, S. M. Lai, and L. Richards, “Daily functioning and quality of life in a randomized controlled trial of therapeutic exercise for subacute stroke survivors,” Stroke, vol. 36, no. 8, pp. 1764–1770, 2005.
[9]
J. A. Jablonka, K. Burnat, O. W. Witte, and M. Kossut, “Remapping of the somatosensory cortex after a photothrombotic stroke: dynamics of the compensatory reorganization,” Neuroscience, vol. 165, no. 1, pp. 90–100, 2010.
[10]
T. Wieloch and K. Nikolich, “Mechanisms of neural plasticity following brain injury,” Current Opinion in Neurobiology, vol. 16, no. 3, pp. 258–264, 2006.
[11]
R. J. Nudo, B. M. Wise, F. SiFuentes, and G. W. Milliken, “Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct,” Science, vol. 272, no. 5269, pp. 1791–1794, 1996.
[12]
C. M. Bütefisch, “Plasticity in the human cerebral cortex: lessons from the normal brain and from stroke,” Neuroscientist, vol. 10, no. 2, pp. 163–173, 2004.
[13]
T. H. Murphy and D. Corbett, “Plasticity during stroke recovery: from synapse to behaviour,” Nature Reviews Neuroscience, vol. 10, no. 12, pp. 861–872, 2009.
[14]
S. T. Carmichael, L. Wei, C. M. Rovainen, and T. A. Woolsey, “New patterns of intracortical projections after focal cortical stroke,” Neurobiology of Disease, vol. 8, no. 5, pp. 910–922, 2001.
[15]
S. Li, J. J. Overman, D. Katsman et al., “An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke,” Nature Neuroscience, vol. 13, no. 12, pp. 1496–1506, 2010.
[16]
S. T. Carmichael, “Rodent models of focal stroke: size, mechanism, and purpose,” NeuroRx, vol. 2, no. 3, pp. 396–409, 2005.
[17]
C. E. Brown, C. Wong, and T. H. Murphy, “Rapid morphologic plasticity of peri-infarct dendritic spines after focal ischemic stroke,” Stroke, vol. 39, no. 4, pp. 1286–1291, 2008.
[18]
S. C. Cramer, “Stroke recovery: how the computer reprograms itself. Neuronal plasticity: the key to stroke recovery. Kananskis, Alberta, Canada, 19-22 March 2000,” Molecular Medicine Today, vol. 6, no. 8, pp. 301–303, 2000.
[19]
R. Mostany, T. G. Chowdhury, D. G. Johnston, S. A. Portonovo, S. T. Carmichael, and C. Portera-Cailliau, “Local hemodynamics dictate long-term dendritic plasticity in peri-infarct cortex,” Journal of Neuroscience, vol. 30, no. 42, pp. 14116–14126, 2010.
[20]
C. E. Brown, K. Aminoltejari, H. Erb, I. R. Winship, and T. H. Murphy, “In vivo voltage-sensitive dye imaging in adult mice reveals that somatosensory maps lost to stroke are replaced over weeks by new structural and functional circuits with prolonged modes of activation within both the peri-infarct zone and distant sites,” Journal of Neuroscience, vol. 29, no. 6, pp. 1719–1734, 2009.
[21]
R. D. Jones, I. M. Donaldson, and P. J. Parkin, “Impairment and recovery of ipsilateral sensory-motor function following unilateral cerebral infarction,” Brain, vol. 112, no. 1, pp. 113–132, 1989.
[22]
O. W. Witte, “Lesion-induced plasticity as a potential mechanism for recovery and rehabilitative training,” Current Opinion in Neurology, vol. 11, no. 6, pp. 655–662, 1998.
[23]
T. A. Jones, C. J. Chu, L. A. Grande, and A. D. Gregory, “Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats,” Journal of Neuroscience, vol. 19, no. 22, pp. 10153–10163, 1999.
[24]
S. T. Carmichael, “Cellular and molecular mechanisms of neural repair after stroke: making waves,” Annals of Neurology, vol. 59, no. 5, pp. 735–742, 2006.
[25]
M. P. van Meer, W. M. Otte, K. van der Marel et al., “Extent of bilateral neuronal network reorganization and functional recovery in relation to stroke severity,” The Journal of Neuroscience, vol. 32, pp. 4495–4507, 2012.
[26]
A. Sterr, Shan Shen, A. J. Szameitat, and K. A. Herron, “The role of corticospinal tract damage in chronic motor recovery and neurorehabilitation: a pilot study,” Neurorehabilitation and Neural Repair, vol. 24, no. 5, pp. 413–419, 2010.
[27]
M. Qiu, W. G. Darling, R. J. Morecraft, C. C. Ni, J. Rajendra, and A. J. Butler, “White matter integrity is a stronger predictor of motor function than BOLD response in patients with stroke,” Neurorehabilitation and Neural Repair, vol. 25, no. 3, pp. 275–284, 2011.
[28]
M. R. Borich, C. Mang, and L. A. Boyd, “Both projection and commissural pathways are disrupted in individuals with chronic stroke: investigating microstructural white matter correlates of motor recovery,” BMC Neuroscience, vol. 13, p. 107, 2012.
[29]
G. Schlaug, S. Marchina, and A. Norton, “Evidence for plasticity in white-matter tracts of patients with chronic broca's aphasia undergoing intense intonation-based speech therapy,” Annals of the New York Academy of Sciences, vol. 1169, pp. 385–394, 2009.
[30]
T. G. Bush, N. Puvanachandra, C. H. Horner et al., “Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice,” Neuron, vol. 23, no. 2, pp. 297–308, 1999.
[31]
M. Karetko-Sysa, J. Skangiel-Kramska, and D. Nowicka, “Disturbance of perineuronal nets in the perilesional area after photothrombosis is not associated with neuronal death,” Experimental Neurology, vol. 231, no. 1, pp. 113–126, 2011.
[32]
W. D. Dietrich, O. Alonso, R. Busto, and M. D. Ginsberg, “Widespread metabolic depression and reduced somatosensory circuit activation following traumatic brain injury in rats,” Journal of Neurotrauma, vol. 11, no. 6, pp. 629–640, 1994.
[33]
M. J. Passineau, W. Zhao, R. Busto et al., “Chronic metabolic sequelae of traumatic brain injury: prolonged suppression of somatosensory activation,” American Journal of Physiology, vol. 279, no. 3, pp. H924–H931, 2000.
[34]
J. Jablonka and M. Kossut, “Focal stroke in the barrel cortex of rats enhances ipsilateral response to vibrissal input,” Acta Neurobiologiae Experimentalis, vol. 66, no. 3, pp. 261–266, 2006.
[35]
J. A. Jablonka, M. Kossut, O. W. Witte, and M. Liguz-Lecznar, “Experience-dependent brain plasticity after stroke: effect of ibuprofen and poststroke delay,” European Journal of Neuroscience, vol. 36, pp. 2632–2639, 2012.
[36]
F. Greifzu, S. Schmidt, K. F. Schmidt, K. Kreikemeier, and O. W. Witte, “Global impairment and therapeutic restoration of visual plasticity mechanisms after a localized cortical stroke,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, pp. 15450–15455, 2011.
[37]
S. C. Cramer and R. J. Seitz, “Imaging functional recovery from stroke,” Handbook of Clinical Neurology, vol. 94, pp. 1097–1117, 2008.
[38]
M. Que, K. Schiene, O. W. Witte, and K. Zilles, “Widespread up-regulation of N-methyl-D-aspartate receptors after focal photothrombotic lesion in rat brain,” Neuroscience Letters, vol. 273, no. 2, pp. 77–80, 1999.
[39]
T. Neumann-Haefelin and O. W. Witte, “Periinfarct and remote excitability changes after transient middle cerebral artery occlusion,” Journal of Cerebral Blood Flow and Metabolism, vol. 20, no. 1, pp. 45–52, 2000.
[40]
G. Hagemann, C. Redecker, T. Neumann-Haefelin, H. J. Freund, and O. W. Witte, “Increased long-term potentiation in the surround of experimentally induced focal cortical infarction,” Annals of Neurology, vol. 44, no. 2, pp. 255–258, 1998.
[41]
K. A. Hossmann, “The hypoxic brain: insights from ischemia research,” Advances in Experimental Medicine and Biology, vol. 474, pp. 155–169, 2000.
[42]
R. Hata, K. Maeda, D. Hermann, G. Mies, and K. A. Hossmann, “Evolution of brain infarction after transient focal cerebral ischemia in mice,” Journal of Cerebral Blood Flow and Metabolism, vol. 20, no. 6, pp. 937–946, 2000.
[43]
J. L. Cheatwood, A. J. Emerick, M. E. Schwab, and G. L. Kartje, “Nogo-A expression after focal ischemic stroke in the adult rat,” Stroke, vol. 39, no. 7, pp. 2091–2098, 2008.
[44]
S. Li and S. T. Carmichael, “Growth-associated gene and protein expression in the region of axonal sprouting in the aged brain after stroke,” Neurobiology of Disease, vol. 23, no. 2, pp. 362–373, 2006.
[45]
L. Kaczmarek, “MMP-9 inhibitors in the brain: can old bullets shoot new targets?” Current Pharmaceutical Designs, vol. 19, no. 6, pp. 1085–1089, 2012.
[46]
A. Cybulska-Klosowicz, M. Liguz-Lecznar, D. Nowicka, M. Ziemka-Nalecz, M. Kossut, and J. Skangiel-Kramska, “Matrix metalloproteinase inhibition counteracts impairment of cortical experience-dependent plasticity after photothrombotic stroke,” European Journal of Neuroscience, vol. 33, pp. 2238–2246, 2011.
[47]
J. Kriz, “Inflammation in ischemic brain injury: timing is important,” Critical Reviews in Neurobiology, vol. 18, no. 1-2, pp. 145–157, 2006.
[48]
R. Macrez, C. Ali, O. Toutirais et al., “Stroke and the immune system: from pathophysiology to new therapeutic strategies,” The Lancet Neurology, vol. 10, pp. 471–480, 2011.
[49]
Q. Wang, X. N. Tang, and M. A. Yenari, “The inflammatory response in stroke,” Journal of Neuroimmunology, vol. 184, no. 1-2, pp. 53–68, 2007.
[50]
S. Liebigt, N. Schlegel, J. Oberland, O. W. Witte, C. Redecker, and S. Keiner, “Effects of rehabilitative training and anti-inflammatory treatment on functional recovery and cellular reorganization following stroke,” Experimental Neurology, vol. 233, pp. 776–782, 2012.
[51]
N. Morimoto, M. Shimazawa, T. Yamashima, H. Nagai, and H. Hara, “Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage,” Brain Research, vol. 1044, no. 1, pp. 8–15, 2005.
[52]
Y. C. Weng and J. Kriz, “Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia,” Experimental Neurology, vol. 204, no. 1, pp. 433–442, 2007.
[53]
H. C. A. Emsley, C. J. Smith, P. J. Tyrrell, and S. J. Hopkins, “Inflammation in acute ischemic stroke and its relevance to stroke critical care,” Neurocritical Care, vol. 9, no. 1, pp. 125–138, 2008.
[54]
M. V. Padma Srivastava, A. Bhasin, R. Bhatia et al., “Efficacy of minocycline in acute ischemic stroke: a single-blinded, placebo-controlled trial,” Neurology India, vol. 60, pp. 23–28, 2012.
[55]
S. C. Fagan, L. E. Cronic, and D. C. Hess, “Minocycline development for acute ischemic stroke,” Translational Stroke Research, vol. 2, no. 2, pp. 202–208, 2011.
[56]
S. C. Fagan, J. L. Waller, F. T. Nichols et al., “Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study,” Stroke, vol. 41, no. 10, pp. 2283–2287, 2010.
[57]
Y. Hasegawa, H. Suzuki, T. Sozen, W. Rolland, and J. H. Zhang, “Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats,” Stroke, vol. 41, no. 2, pp. 368–374, 2010.
[58]
T. V. Arumugam, S. C. Tang, J. D. Lathia et al., “Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 35, pp. 14104–14109, 2007.
[59]
T. V. Arumugam, T. M. Woodruff, J. D. Lathia, P. K. Selvaraj, M. P. Mattson, and S. M. Taylor, “Neuroprotection in stroke by complement inhibition and immunoglobulin therapy,” Neuroscience, vol. 158, no. 3, pp. 1074–1089, 2009.
[60]
N. B. Beamer, B. M. Coull, W. M. Clark, J. S. Hazel, and J. R. Silberger, “Interleukin-6 and interleukin-1 receptor antagonist in acute stroke,” Annals of Neurology, vol. 37, no. 6, pp. 800–804, 1995.
[61]
N. Vila, J. Castillo, A. Dávalos, and A. Chamorro, “Proinflammatory cytokines and early neurological worsening in ischemic stroke,” Stroke, vol. 31, no. 10, pp. 2325–2329, 2000.
[62]
F. C. Barone, B. Arvin, R. F. White et al., “Tumor necrosis factor-α: a mediator of focal ischemic brain injury,” Stroke, vol. 28, no. 6, pp. 1233–1244, 1997.
[63]
A. Denes, E. Pinteaux, N. J. Rothwell, and S. M. Allan, “Interleukin-1 and stroke: biomarker, harbinger of damage, and therapeutic target,” Cerebrovascular Diseases, vol. 32, pp. 517–527, 2011.
[64]
S. A. Loddick and N. J. Rothwell, “Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat,” Journal of Cerebral Blood Flow and Metabolism, vol. 16, no. 5, pp. 932–940, 1996.
[65]
Z. S. Vexler, X. N. Tang, and M. A. Yenari, “Inflammation in adult and neonatal stroke,” Clinical Neuroscience Research, vol. 6, no. 5, pp. 293–313, 2006.
[66]
A. D. Greenhalgh, J. Galea, A. Dénes, P. J. Tyrrell, and N. J. Rothwell, “Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection,” British Journal of Pharmacology, vol. 160, no. 1, pp. 153–159, 2010.
[67]
S. M. Lucas, N. J. Rothwell, and R. M. Gibson, “The role of inflammation in CNS injury and disease,” British Journal of Pharmacology, vol. 147, no. 1, pp. S232–S240, 2006.
[68]
A. Martin-Villalba, M. Hahne, S. Kleber et al., “Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke,” Cell Death and Differentiation, vol. 8, no. 7, pp. 679–686, 2001.
[69]
A. L. Sirén, R. McCarron, L. Wang et al., “Proinflammatory cytokine expression contributes to brain injury provoked by chronic monocyte activation,” Molecular Medicine, vol. 7, no. 4, pp. 219–229, 2001.
[70]
S. Suzuki, K. Tanaka, and N. Suzuki, “Ambivalent aspects of interleukin-6 in cerebral ischemia: inflammatory versus neurotrophic aspects,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 3, pp. 464–479, 2009.
[71]
C. J. Smith, H. C. A. Emsley, C. M. Gavin 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 Neurology, vol. 4, article 2, 2004.
[72]
U. Waje-Andreassen, J. Kr？kenes, E. Ulvestad et al., “IL-6: an early marker for outcome in acute ischemic stroke,” Acta Neurologica Scandinavica, vol. 111, no. 6, pp. 360–365, 2005.
[73]
M. Krams, K. R. Lees, W. Hacke, A. P. Grieve, J. M. Orgogozo, and G. A. Ford, “Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke,” Stroke, vol. 34, no. 11, pp. 2543–2548, 2003.
[74]
A. J. Bruce, W. Boling, M. S. Kindy et al., “Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors,” Nature Medicine, vol. 2, no. 7, pp. 788–794, 1996.
[75]
H. Nawashiro, D. Martin, and J. M. Hallenbeck, “Neuroprotective effects of TNF binding protein in focal cerebral ischemia,” Brain Research, vol. 778, no. 2, pp. 265–271, 1997.
[76]
W. Zhang and D. Stanimirovic, “Current and future therapeutic strategies to target inflammation in stroke,” Curr Drug Targets Inflamm Allergy, vol. 1, no. 2, pp. 151–166, 2002.
[77]
T. Yamashita, K. Sawamoto, S. Suzuki et al., “Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons,” Journal of Neurochemistry, vol. 94, no. 2, pp. 459–468, 2005.
[78]
L. Xu, S. C. Fagan, J. L. Waller et al., “Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats,” BMC Neurology, vol. 4, article 7, 2004.
[79]
E. Figueroa, L. E. Gordon, P. W. Feldhoff, and H. A. Lassiter, “The administration of cobra venom factor reduces post-ischemic cerebral injury in adult and neonatal rats,” Neuroscience Letters, vol. 380, no. 1-2, pp. 48–53, 2005.
[80]
U. S. Vasthare, F. C. Barone, H. M. Sarau et al., “Complement depletion improves neurological function in cerebral ischemia,” Brain Research Bulletin, vol. 45, no. 4, pp. 413–419, 1998.
[81]
N. Heydenreich, M. W. Nolte, E. Gob et al., “C1-inhibitor protects from brain ischemia-reperfusion injury by combined antiinflammatory and antithrombotic mechanisms,” Stroke, vol. 43, pp. 2457–2467, 2012.
[82]
A. F. Ducruet, B. G. Hassid, W. J. MacK et al., “C3a receptor modulation of granulocyte infiltration after murine focal cerebral ischemia is reperfusion dependent,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 5, pp. 1048–1058, 2008.
[83]
J. Mocco, W. J. Mack, A. F. Ducruet et al., “Complement component C3 mediates inflammatory injury following focal cerebral ischemia,” Circulation Research, vol. 99, no. 2, pp. 209–217, 2006.
[84]
N. Jiang, M. Chopp, and S. Chahwala, “Neutrophil inhibitory factor treatment of focal cerebral ischemia in the rat,” Brain Research, vol. 788, no. 1-2, pp. 25–34, 1998.
[85]
N. Jiang, M. Moyle, H. R. Soule, W. E. Rote, and M. Chopp, “Neutrophil inhibitory factor is neuroprotective after focal ischemia in rats,” Annals of Neurology, vol. 38, no. 6, pp. 935–942, 1995.
[86]
B. Czech, W. Pfeilschifter, N. Mazaheri-Omrani et al., “The immunomodulatory sphingosine 1-phosphate analog FTY720 reduces lesion size and improves neurological outcome in a mouse model of cerebral ischemia,” Biochemical and Biophysical Research Communications, vol. 389, no. 2, pp. 251–256, 2009.
[87]
Y. Wei, M. Yemisci, H. H. Kim et al., “Fingolimod provides long-term protection in rodent models of cerebral ischemia,” Annals of Neurology, vol. 69, pp. 119–129, 2011.
[88]
C. Iadecola, K. Niwa, S. Nogawa et al., “Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 3, pp. 1294–1299, 2001.
[89]
H. Boutin, R. A. LeFeuvre, R. Horai, M. Asano, Y. Iwakura, and N. J. Rothwell, “Role of IL-1α and IL-1β in ischemic brain damage,” Journal of Neuroscience, vol. 21, no. 15, pp. 5528–5534, 2001.
[90]
O. Touzani, H. Boutin, R. Lefeuvre et al., “Interleukin-1 influences ischemic brain damage in the mouse independently of the interleukin-1 type I receptor,” Journal of Neuroscience, vol. 22, no. 1, pp. 38–43, 2002.
[91]
A. Basu, J. Lazovic, J. K. Krady et al., “Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury,” Journal of Cerebral Blood Flow and Metabolism, vol. 25, no. 1, pp. 17–29, 2005.
[92]
G. Y. Yang, C. Gong, Z. Qin, W. Ye, Y. Mao, and A. L. Bertz, “Inhibition of TNFα attenuates infarct volume and ICAM-1 expression in ischemic mouse brain,” NeuroReport, vol. 9, no. 9, pp. 2131–2134, 1998.
[93]
M. Yepes, S. A. N. Brown, E. G. Moore, E. P. Smith, D. A. Lawrence, and J. A. Winkles, “A soluble Fn14-Fc decoy receptor reduces infarct volume in a murine model of cerebral ischemia,” American Journal of Pathology, vol. 166, no. 2, pp. 511–520, 2005.
[94]
R. K. Sumbria, R. J. Boado, and W. M. Pardridge, “Brain protection from stroke with intravenous TNFα decoy receptor-Trojan horse fusion protein,” Journal of Cerebral Blood Flow & Metabolism, vol. 32, no. 10, pp. 1933–1938, 2012.
