title: High-dose ibuprofen for reduction of striatal infarcts during middle cerebral artery occlusion in rats.
abstract: OBJECTIVE
  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 degrees 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.
authors.affiliation: Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, Maryland 21287, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Antezana
authors.forename: Richard E
authors.initials: RE
authors.lastname: Clatterbuck
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Murphy
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Anderson
authors.forename: James
authors.initials: J
authors.lastname: Frazier
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Hurn
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Traystman
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Tamargo
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D001921:Brain / Q000098:blood supply; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D003342:Corpus Striatum / Q000098:blood supply* / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D007052:Ibuprofen / Q000008:administration & dosage / Q000627:therapeutic use*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018799:Intercellular Adhesion Molecule-1; D007052:Ibuprofen