Recombinant human MFG-E8 attenuates cerebral ischemic injury: its role in anti-inflammation and anti-apoptosis

Neuropharmacology. 2012 Feb;62(2):890-900. doi: 10.1016/j.neuropharm.2011.09.018. Epub 2011 Sep 24.

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'.

MeSH terms

  • Animals
  • Antigens, Surface / metabolism
  • Antigens, Surface / pharmacology
  • Antigens, Surface / therapeutic use*
  • Apoptosis / drug effects*
  • Blood Pressure / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / pathology
  • Milk Proteins / metabolism
  • Milk Proteins / pharmacology
  • Milk Proteins / therapeutic use*
  • Necrosis
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function / drug effects

Substances

  • Antigens, Surface
  • Interleukin-6
  • MFGE8 protein, human
  • Milk Proteins
  • Neuroprotective Agents
  • Intercellular Adhesion Molecule-1