Object. Ibuprofen is an antiinflammatory drug that disrupts leukocyte—endothelial cell interactions by limiting expression of endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), also known as CD54. The authors hypothesized that ibuprofen could reduce the size of the infarct associated with transient focal ischemia by inhibition of ICAM-1 expression, and they evaluated its effects in rats treated with middle cerebral artery (MCA) occlusion. Ibuprofen treatment was compared with mild systemic hypothermia, which is known to be neuroprotective and is commonly used during neurosurgical procedures.
Methods. The maximum ibuprofen dose (240 mg/kg/day) that could be tolerated with no systemic toxicity was established in the initial experiments. In the efficacy experiment, rats were pretreated with vehicle, ibuprofen, or hypothermia (33°C) prior to 2 hours of MCA occlusion; then their brains were harvested at 24 hours of reperfusion for histological studies. End-ischemic cerebral blood flow (CBF) was evaluated using [14C]iodoantipyrine autoradiography in additional cohorts. Expression of ICAM-1 within ischemic compared with nonischemic caudate nucleus and putamen (striatum) or cortex was evaluated using immunohistochemical studies. Compared with vehicle treatment, ibuprofen produced a 46.2% reduction (p = 0.01) in striatal infarcts, which was comparable to hypothermia (48.7% reduction, p = 0.02). Ibuprofen did not alter end-ischemic CBF in any region studied, and the ibuprofen treatment group had the lowest proportion of animals with marked ICAM-1 staining.
Conclusions. Ibuprofen given in maximum tolerated doses reduces the striatal infarct size after focal cerebral ischemia. The neuroprotective mechanism does not work through preservation of intraischemic CBF and is consistent with inhibition of ICAM-1 expression; however, at the doses used in this study, other effects of ibuprofen on platelet and endothelial function are possible.
Alkayed NJ, , Harukuni I, & Kimes AS, et al: Gender-linked brain injury in experimental stroke. Stroke 29:159–166, 1998 Alkayed NJ, Harukuni I, Kimes AS, et al: Gender-linked brain injury in experimental stroke. Stroke 29:159–166, 1998
Alkayed NJ, , Murphy SJ, & Traystman RJ, et al: Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. Stroke 31:161–168, 2000 Alkayed NJ, Murphy SJ, Traystman RJ, et al: Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. Stroke 31:161–168, 2000
Austyn JM, & Wood KJ: Principles of Cellular and Molecular Immunology. Oxford: Oxford University Press, 1993 Austyn JM, Wood KJ: Principles of Cellular and Molecular Immunology. Oxford: Oxford University Press, 1993
Baker HJ, , Lindsey JR, & Weisbroth SH (eds): The Laboratory Rat. New York: Academic Press, 1979, Vol1 Baker HJ, Lindsey JR, Weisbroth SH (eds): The Laboratory Rat. New York: Academic Press, 1979, Vol 1
Baker KZ, , Young WL, & Stone JG, et al: Deliberate mild intraoperative hypothermia for craniotomy. Anesthesiology 81:361–367, 1994 Baker KZ, Young WL, Stone JG, et al: Deliberate mild intraoperative hypothermia for craniotomy. Anesthesiology 81:361–367, 1994
Barone FC, , Schmidt DB, & Hillegass LM, et al: Reperfusion increases neutrophils and leukotriene B4 receptor binding in rat focal ischemia. Stroke 23:1337–1348, 1992 Barone FC, Schmidt DB, Hillegass LM, et al: Reperfusion increases neutrophils and leukotriene B4 receptor binding in rat focal ischemia. Stroke 23:1337–1348, 1992
Bederson JB, , Pitts LH, & Germano SM, et al: Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke 17:1304–1308, 1986 Bederson JB, Pitts LH, Germano SM, et al: Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke 17:1304–1308, 1986
Belayev L, , Alonso OF, & Busto R, et al: Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke 27:1616–1623, 1996 Belayev L, Alonso OF, Busto R, et al: Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke 27:1616–1623, 1996
Bitsch A, , Klene W, & Murtada L, et al: A longitudinal prospective study of soluble adhesion molecules in acute stroke. Stroke 29:2129–2135, 1998 Bitsch A, Klene W, Murtada L, et al: A longitudinal prospective study of soluble adhesion molecules in acute stroke. Stroke 29:2129–2135, 1998
Chen H, , Chopp M, & Zhang RL, et al: Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 35:458–463, 1994 Chen H, Chopp M, Zhang RL, et al: Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 35:458–463, 1994
Chen H, , Chopp M, & Zhang ZG, et al: The effect of hypothermia on transient middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 12:621–628, 1992 Chen H, Chopp M, Zhang ZG, et al: The effect of hypothermia on transient middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 12:621–628, 1992
Chopp M, , Zhang RL, & Chen H, et al: Postischemic administration of an anti-mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke 25:869–876, 1994 Chopp M, Zhang RL, Chen H, et al: Postischemic administration of an anti-mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke 25:869–876, 1994
Cole DJ, , Patel PM, & Reynolds L, et al: Temporary focal cerebral ischemia in spontaneously hypertensive rats: the effect of ibuprofen on infarct volume. J Pharmacol Exp Ther 266:1713–1717, 1993 Cole DJ, Patel PM, Reynolds L, et al: Temporary focal cerebral ischemia in spontaneously hypertensive rats: the effect of ibuprofen on infarct volume. J Pharmacol Exp Ther 266:1713–1717, 1993
Connolly ES Jr, , Winfree CJ, & Springer TA, 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 Inv 97:209–216, 1996 Connolly ES Jr, Winfree CJ, Springer TA, 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 Inv 97:209–216, 1996
del Zoppo GJ, , Schmid-Schonbein GW, & Mori E, et al: Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22:1276–1283, 1991 del Zoppo GJ, Schmid-Schonbein GW, Mori E, et al: Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22:1276–1283, 1991
Diaz-Gonzalez F, & Sanchez-Madrid F: Inhibition of leukocyte adhesion: an alternative mechanism for anti-inflammatory drugs. Immunol Today 19:169–172, 1998 Diaz-Gonzalez F, Sanchez-Madrid F: Inhibition of leukocyte adhesion: an alternative mechanism for anti-inflammatory drugs. Immunol Today 19:169–172, 1998
Enlimomab Acute Stroke Trial Investigators: Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 57:1428–1434, 2001 Enlimomab Acute Stroke Trial Investigators: Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 57:1428–1434, 2001
Fiszer U, , Korczak-Kowalska G, & Palasik W, et al: Increased expression of adhesion molecule CD 18 (LFA-1β) on the leukocytes of peripheral blood in patients with acute ischemic stroke. Acta Neurol Scand 97:221–224, 1998 Fiszer U, Korczak-Kowalska G, Palasik W, et al: Increased expression of adhesion molecule CD 18 (LFA-1β) on the leukocytes of peripheral blood in patients with acute ischemic stroke. Acta Neurol Scand 97:221–224, 1998
Garcia JH, & Kamijyo Y: Cerebral infarction. Evolution of histopathological changes after occlusion of a middle cerebral artery in primates. J Neuropathol Exp Neurol 33:408–421, 1974 Garcia JH, Kamijyo Y: Cerebral infarction. Evolution of histopathological changes after occlusion of a middle cerebral artery in primates. J Neuropathol Exp Neurol 33:408–421, 1974
Garcia JH, , Liu KF, & Ho KL: Neuronal necrosis after middle cerebral artery occlusion in Wistar rats progresses at different time intervals in the caudoputamen and the cortex. Stroke 26:636–643, 1995 Garcia JH, Liu KF, Ho KL: Neuronal necrosis after middle cerebral artery occlusion in Wistar rats progresses at different time intervals in the caudoputamen and the cortex. Stroke 26:636–643, 1995
Garcia JH, , Liu KF, & Yoshida Y, et al: Influx of leukocytes and platelets in an evolving brain infarct (wistar rat). Am J Pathol 144:188–199, 1994 Garcia JH, Liu KF, Yoshida Y, et al: Influx of leukocytes and platelets in an evolving brain infarct (wistar rat). Am J Pathol 144:188–199, 1994
Goldlust EJ, , Paczynski RP, & He YY, et al: Automated measurement of infarct size with scanned images of triphenyltetrazolium chloride-stained rat brains. Stroke 27:1657–1662, 1996 Goldlust EJ, Paczynski RP, He YY, et al: Automated measurement of infarct size with scanned images of triphenyltetrazolium chloride-stained rat brains. Stroke 27:1657–1662, 1996
Grice SC, , Chappell ET, & Prough DS, et al: Ibuprofen improves cerebral blood flow after global cerebral ischemia in dogs. Stroke 18:787–791, 1987 Grice SC, Chappell ET, Prough DS, et al: Ibuprofen improves cerebral blood flow after global cerebral ischemia in dogs. Stroke 18:787–791, 1987
Hallenbeck JM: Inflammatory reactions at the blood-endothelial interface in acute stroke. Adv Neurol 71:281–300, 1996 Hallenbeck JM: Inflammatory reactions at the blood-endothelial interface in acute stroke. Adv Neurol 71:281–300, 1996
Hindman BJ, , Todd MM, & Gelb AW, et al: Mild hypothermia as a protective therapy during intracranial aneurysm surgery: a randomized prospective pilot trial. Neurosurgery 44:23–33, 1999 Hindman BJ, Todd MM, Gelb AW, et al: Mild hypothermia as a protective therapy during intracranial aneurysm surgery: a randomized prospective pilot trial. Neurosurgery 44:23–33, 1999
Ishikawa M, , Sekizuka E, & Sato S, et al: Effects of moderate hypothermia on leukocyte-endothelium interaction in the rat pial microvasculature after transient middle cerebral artery occlusion. Stroke 30:1679–1686, 1999 Ishikawa M, Sekizuka E, Sato S, et al: Effects of moderate hypothermia on leukocyte-endothelium interaction in the rat pial microvasculature after transient middle cerebral artery occlusion. Stroke 30:1679–1686, 1999
Kapiotis S, , Sengoelge G, & Sperr WR, et al: Ibuprofen inhibits pyrogen-dependent expression of VCAM-1 and ICAM-1 on human endothelial cells. Life Sci 58:2167–2181, 1996 Kapiotis S, Sengoelge G, Sperr WR, et al: Ibuprofen inhibits pyrogen-dependent expression of VCAM-1 and ICAM-1 on human endothelial cells. Life Sci 58:2167–2181, 1996
Kawai N, , Okauchi M, & Morisaki K, et al: Effects of delayed intraischemic and postischemic hypothermia on a focal model of transient cerebral ischemia in rats. Stroke 31:1982–1989, 2000 Kawai N, Okauchi M, Morisaki K, et al: Effects of delayed intraischemic and postischemic hypothermia on a focal model of transient cerebral ischemia in rats. Stroke 31:1982–1989, 2000
Kawamura S, , Li Y, & Shirasawa M, et al: Reversible middle cerebral artery occlusion in rats using an intraluminal thread technique. Surg Neurol 41:368–373, 1994 Kawamura S, Li Y, Shirasawa M, et al: Reversible middle cerebral artery occlusion in rats using an intraluminal thread technique. Surg Neurol 41:368–373, 1994
Kim JS, , Chopp M, & Chen H, et al: Adhesive glycoproteins CD11a and CD18 are upregulated in the leukocytes from patients with ischemic stroke and transient ischemic attacks. J Neurol Sci 128:45–50, 1995 Kim JS, Chopp M, Chen H, et al: Adhesive glycoproteins CD11a and CD18 are upregulated in the leukocytes from patients with ischemic stroke and transient ischemic attacks. J Neurol Sci 128:45–50, 1995
Koizumi J, , Yoshida Y, & Nakazawa T, et al: [Experimental studies of ischemic brain edema, I: a new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area.] Jpn J Stroke 8:1–7, 1986 (Jpn) Koizumi J, Yoshida Y, Nakazawa T, et al: [Experimental studies of ischemic brain edema, I: a new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area.] Jpn J Stroke 8:1–7, 1986 (Jpn)
Lehrmann E, , Christensen T, & Zimmer J, et al: Microglial and macrophage reactions mark progressive changes and define the penumbra in the rat neocortex and striatum after transient middle cerebral artery occlusion. J Comp Neurol 386:461–476, 1997 Lehrmann E, Christensen T, Zimmer J, et al: Microglial and macrophage reactions mark progressive changes and define the penumbra in the rat neocortex and striatum after transient middle cerebral artery occlusion. J Comp Neurol 386:461–476, 1997
Lindsberg PJ, , Carpen O, & Paetau A, et al: Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation 94:939–945, 1996 Lindsberg PJ, Carpen O, Paetau A, et al: Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation 94:939–945, 1996
Liszczak TM, , Hedley-Whyte ET, & Adams JF, et al: Limitations of tetrazolium salts in delineating infarcted brain. Acta Neuropathol 65:150–157, 1984 Liszczak TM, Hedley-Whyte ET, Adams JF, et al: Limitations of tetrazolium salts in delineating infarcted brain. Acta Neuropathol 65:150–157, 1984
Longa EZ, , Weinstein PR, & Carlson S, et al: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91, 1989 Longa EZ, Weinstein PR, Carlson S, et al: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91, 1989
Mabuchi T, , Kitagawa K, & Ohtsuki T, et al: Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats. Stroke 31:1735–1743, 2000 Mabuchi T, Kitagawa K, Ohtsuki T, et al: Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats. Stroke 31:1735–1743, 2000
Maier CM, , Ahern K, & Cheng ML, et al: 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 29:2171–2180, 1998 Maier CM, Ahern K, Cheng ML, et al: 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 29:2171–2180, 1998
Matsuo Y, , Onodera H, & Shiga Y, et al: Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat. Brain Res 656:344–352, 1994 Matsuo Y, Onodera H, Shiga Y, et al: Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat. Brain Res 656:344–352, 1994
Nagasawa H, & Kogure K: Correlation between cerebral blood flow and histologic changes in a new rat model of middle cerebral artery occlusion. Stroke 20:1037–1043, 1989 Nagasawa H, Kogure K: Correlation between cerebral blood flow and histologic changes in a new rat model of middle cerebral artery occlusion. Stroke 20:1037–1043, 1989
Nielsen VG, & Webster RO: Inhibition of human polymorphonuclear leukocyte functions by ibuprofen. Immunopharmacology 13:61–71, 1987 Nielsen VG, Webster RO: Inhibition of human polymorphonuclear leukocyte functions by ibuprofen. Immunopharmacology 13:61–71, 1987
Orzalesi G, , Selleri R, & Caldini O, et al: Ibuproxam and Ibuprofen. A pharmacological comparison. Arzneimforschung 27:1006–1012, 1977 Orzalesi G, Selleri R, Caldini O, et al: Ibuproxam and Ibuprofen. A pharmacological comparison. Arzneimforschung 27:1006–1012, 1977
Patel PM, , Drummond JC, & Sano T, et al: Effect of ibuprofen on regional eicosanoid production and neuronal injury after forebrain ischemia in rats. Brain Res 614:315–324, 1993 Patel PM, Drummond JC, Sano T, et al: Effect of ibuprofen on regional eicosanoid production and neuronal injury after forebrain ischemia in rats. Brain Res 614:315–324, 1993
Penta JS, , Rozencweig M, & Guarino AM, et al: Mouse and largeanimal toxicology studies of twelve antitumor agents: relevance to starting dose for phase I clinical trials. Cancer Chemother Pharmacol 3:97–101, 1979 Penta JS, Rozencweig M, Guarino AM, et al: Mouse and largeanimal toxicology studies of twelve antitumor agents: relevance to starting dose for phase I clinical trials. Cancer Chemother Pharmacol 3:97–101, 1979
Samson D, , Batjer HH, & Bowman G, et al: A clinical study of the parameters and effects of temporary arterial occlusion in the management of intracranial aneurysms. Neurosurgery 34:22–29, 1994 Samson D, Batjer HH, Bowman G, et al: A clinical study of the parameters and effects of temporary arterial occlusion in the management of intracranial aneurysms. Neurosurgery 34:22–29, 1994
Schmid-Elsaesser R, , Zausinger S, & Hungerhuber E, et al: A critical reevaluation of the intraluminal thread model of focal cerebral ischemia: evidence of inadvertent premature reperfusion and subarachnoid hemorrhage in rats by laser-Doppler flowmetry. Stroke 29:2162–2170, 1998 Schmid-Elsaesser R, Zausinger S, Hungerhuber E, et al: A critical reevaluation of the intraluminal thread model of focal cerebral ischemia: evidence of inadvertent premature reperfusion and subarachnoid hemorrhage in rats by laser-Doppler flowmetry. Stroke 29:2162–2170, 1998
Shyu K, , Chang H, & Lin CC: Serum levels of intercellular adhesion molecule-1 and E-selectin in patients with acute ischaemic stroke. J Neurol 244:90–93, 1997 Shyu K, Chang H, Lin CC: Serum levels of intercellular adhesion molecule-1 and E-selectin in patients with acute ischaemic stroke. J Neurol 244:90–93, 1997
Sills AK Jr, , Clatterbuck RE, & Thompson RC, et al: Endothelial cell expression of intercellular adhesion molecule 1 in experimental posthemorrhagic vasospasm. Neurosurgery 41:453–461, 1997 Sills AK Jr, Clatterbuck RE, Thompson RC, et al: Endothelial cell expression of intercellular adhesion molecule 1 in experimental posthemorrhagic vasospasm. Neurosurgery 41:453–461, 1997
Solomon RA: Principles of aneurysm surgery: cerebral ischemic protection, hypothermia, and circulatory arrest. Clin Neurosurg 41:351–363, 1994 Solomon RA: Principles of aneurysm surgery: cerebral ischemic protection, hypothermia, and circulatory arrest. Clin Neurosurg 41:351–363, 1994
Takahashi H, , Kirsch J, & Hashimoto K, et al: PPBP [4-phenyl-1-(phenylbutyl) piperidine] decreases brain injury after transient focal ischemia in rats. Stroke 27:2120–2123, 1996 Takahashi H, Kirsch J, Hashimoto K, et al: PPBP [4-phenyl-1-(phenylbutyl) piperidine] decreases brain injury after transient focal ischemia in rats. Stroke 27:2120–2123, 1996
Thai QA, , Oshiro EM, & Tamargo RJ: Inhibition of experimental vasospasm in rats with the periadventitial administration of ibuprofen using controlled-release polymers. Stroke 30:140–147, 1999 Thai QA, Oshiro EM, Tamargo RJ: Inhibition of experimental vasospasm in rats with the periadventitial administration of ibuprofen using controlled-release polymers. Stroke 30:140–147, 1999
Zar JH: Biostatistical Analysis, ed 2. Englewood Cliffs, NJ: Prentice-Hall, 1984 Zar JH: Biostatistical Analysis, ed 2. Englewood Cliffs, NJ: Prentice-Hall, 1984
Zhang RL, , Chopp M, & Chen H, et al: Postischemic (1 hour) hypothermia significantly reduces ischemic cell damage in rats subjected to 2 hours of middle cerebral artery occlusion. Stroke 24:1235–1240, 1993 Zhang RL, Chopp M, Chen H, et al: Postischemic (1 hour) hypothermia significantly reduces ischemic cell damage in rats subjected to 2 hours of middle cerebral artery occlusion. Stroke 24:1235–1240, 1993
Zhang RL, , Chopp M, & Chen H, et al: 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 125:3–10, 1994 Zhang RL, Chopp M, Chen H, et al: 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 125:3–10, 1994
Zhang RL, , Chopp M, & Jiang N, et al: Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 26:1438–1443, 1995 Zhang RL, Chopp M, Jiang N, et al: Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 26:1438–1443, 1995
Zhang RL, , Chopp M, & Li Y, et al: Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 44:1747–1751, 1994 Zhang RL, Chopp M, Li Y, et al: Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 44:1747–1751, 1994
Zhang ZG, , Chopp M, & Tang WX, et al: Postischemic treatment (2-4h) with anti-CD11b and anti-CD18 monoclonal antibodies are neuroprotective after transient (2h) focal cerebral ischemia in the rat. Brain Res 698:79–85, 1995 Zhang ZG, Chopp M, Tang WX, et al: Postischemic treatment (2-4h) with anti-CD11b and anti-CD18 monoclonal antibodies are neuroprotective after transient (2h) focal cerebral ischemia in the rat. Brain Res 698:79–85, 1995
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