title: Recombinant human MFG-E8 attenuates cerebral ischemic injury: its role in anti-inflammation and anti-apoptosis.
abstract: Excessive inflammation and apoptosis contribute to the pathogenesis of ischemic stroke. MFG-E8 is a 66-kDa glycoprotein that has shown tissue protection in various models of organ injury. However, the potential role of MFG-E8 in cerebral ischemia has not been investigated. We found that levels of MFG-E8 protein in the brain were reduced at 24 h after cerebral ischemia. To assess the potential role of MFG-E8 in cerebral ischemia, adult male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO). At 1 h post-stroke onset, an intravenous administration of 1 ml saline as vehicle or 160 μg/kg BW recombinant human MFG-E8 (rhMFG-E8) as treatment was given. The optimal dose of rhMFG-E8 was obtained from previous dose-response organ protection in rat sepsis studies. Neurological scores were determined at 24 h and 48 h post-MCAO. Rats were sacrificed thereafter and brains rapidly removed and analyzed for infarct size, histopathology, and markers of inflammation and apoptosis. Compared with saline vehicle, rhMFG-E8 treatment led to significant decreases in sensorimotor and vestibulomotor deficits, and infarct size at 24 h and 48 h post-MCAO. Measures associated with improved outcome included reduced microglial inflammatory cytokine secretion, adhesion molecules and neutrophil influx, cleaved caspase-3, and upregulation of peroxisome proliferator activated receptor-γ (PPAR-γ), and Bcl-2/Bax ratio leading to decreased apoptosis. Thus, rhMFG-E8 treatment is neuroprotective against cerebral ischemia through suppression of inflammation and apoptosis. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
authors.affiliation: The Feinstein Institute for Medical Research, Elmezzi Graduate School of Molecular Medicine, United States.
authors.forename: Cletus
authors.initials: C
authors.lastname: Cheyuo
authors.forename: Asha
authors.initials: A
authors.lastname: Jacob
authors.forename: Rongqian
authors.initials: R
authors.lastname: Wu
authors.forename: Mian
authors.initials: M
authors.lastname: Zhou
authors.forename: Lei
authors.initials: L
authors.lastname: Qi
authors.forename: Weifeng
authors.initials: W
authors.lastname: Dong
authors.forename: Youxin
authors.initials: Y
authors.lastname: Ji
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Chaung
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nicastro
authors.forename: Gene F
authors.initials: GF
authors.lastname: Coppa
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008894:Milk Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D009336:Necrosis; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects
chemical_list: D000954:Antigens, Surface; D015850:Interleukin-6; C098942:MFGE8 protein, human; D008894:Milk Proteins; D018696:Neuroprotective Agents; D018799:Intercellular Adhesion Molecule-1