title: Recombinant milk fat globule-EGF factor-8 reduces oxidative stress via integrin β3/nuclear factor erythroid 2-related factor 2/heme oxygenase pathway in subarachnoid hemorrhage rats.
abstract: OBJECTIVE
  Milk fat globule-EGF factor-8 (MFGE8) has been reported to be neuroprotective in ischemic stroke. However, the effects of MFGE8 in early brain injury after subarachnoid hemorrhage (SAH) have not been investigated. We investigated the role of MFGE8 in early brain injury and the potential mechanisms in antioxidation after SAH.
  
  
  METHODS
  Two dosages (1 μg and 3.3 μg) of recombinant human MFGE8 were injected intracerebroventricularly at 1.5 hours after SAH. SAH grades, neurological scores, and brain water content were measured at 24 and 72 hours. For mechanistic study, MFGE8 siRNA, integrin β3 siRNA, and heme oxygenase (HO) inhibitor SnPP IX were used for intervention. The oxidative stress and expression of MFGE8, integrin β3, HO-1, extracellular signal-regulated kinase, and nuclear factor erythroid 2-related factor 2 were measured by Western blots 24 hours after SAH.
  
  
  RESULTS
  The expression of MFGE8 and HO-1 increased and peaked 24 hours after SAH. Administration of recombinant human MFGE8 decreased brain water content and improved neurological functions both at 24 hours and at 72 hours after SAH. Recombinant human MFGE8 reduced oxidative stress and enhanced the expression of extracellular signal-regulated kinase, nuclear factor erythroid 2-related factor 2, and HO-1; and the effects were abolished by integrin β3 siRNA and HO inhibitor SnPP IX.
  
  
  CONCLUSIONS
  Recombinant MFGE8 attenuated oxidative stress that may be mediated by integrin β3/nuclear factor erythroid 2-related factor 2/HO pathway after SAH. Recombinant MFGE8 may serve as an alternative treatment to ameliorate early brain injury for SAH patients.
authors.affiliation: From the Department of Physiology and Pharmacology (F.L., Q.H., B.L., A.M., Y.C., Junjia Tang, Z.G., Jiping Tang, J.H.Z.) and Department of Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, Loma Linda, CA; and Department of Neurosurgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China (F.L.).
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: From the Department of Physiology and Pharmacology (F.L., Q.H., B.L., A.M., Y.C., Junjia Tang, Z.G., Jiping Tang, J.H.Z.) and Department of Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, Loma Linda, CA; and Department of Neurosurgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China (F.L.).
authors.forename: Qin
authors.initials: Q
authors.lastname: Hu
authors.affiliation: From the Department of Physiology and Pharmacology (F.L., Q.H., B.L., A.M., Y.C., Junjia Tang, Z.G., Jiping Tang, J.H.Z.) and Department of Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, Loma Linda, CA; and Department of Neurosurgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China (F.L.).
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: From the Department of Physiology and Pharmacology (F.L., Q.H., B.L., A.M., Y.C., Junjia Tang, Z.G., Jiping Tang, J.H.Z.) and Department of Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, Loma Linda, CA; and Department of Neurosurgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China (F.L.).
authors.forename: Anatol
authors.initials: A
authors.lastname: Manaenko
authors.affiliation: From the Department of Physiology and Pharmacology (F.L., Q.H., B.L., A.M., Y.C., Junjia Tang, Z.G., Jiping Tang, J.H.Z.) and Department of Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, Loma Linda, CA; and Department of Neurosurgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China (F.L.).
authors.forename: Yujie
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the Department of Physiology and Pharmacology (F.L., Q.H., B.L., A.M., Y.C., Junjia Tang, Z.G., Jiping Tang, J.H.Z.) and Department of Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, Loma Linda, CA; and Department of Neurosurgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China (F.L.).
authors.forename: Junjia
authors.initials: J
authors.lastname: Tang
authors.affiliation: From the Department of Physiology and Pharmacology (F.L., Q.H., B.L., A.M., Y.C., Junjia Tang, Z.G., Jiping Tang, J.H.Z.) and Department of Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, Loma Linda, CA; and Department of Neurosurgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China (F.L.).
authors.forename: Zongduo
authors.initials: Z
authors.lastname: Guo
authors.affiliation: From the Department of Physiology and Pharmacology (F.L., Q.H., B.L., A.M., Y.C., Junjia Tang, Z.G., Jiping Tang, J.H.Z.) and Department of Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, Loma Linda, CA; and Department of Neurosurgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China (F.L.).
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.affiliation: From the Department of Physiology and Pharmacology (F.L., Q.H., B.L., A.M., Y.C., Junjia Tang, Z.G., Jiping Tang, J.H.Z.) and Department of Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, Loma Linda, CA; and Department of Neurosurgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China (F.L.). johnzhang3910@yahoo.com.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D008297:Male; D008894:Milk Proteins / Q000378:metabolism / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013345:Subarachnoid Hemorrhage / Q000378:metabolism*
chemical_list: D000954:Antigens, Surface; D039661:Integrin beta3; C098942:MFGE8 protein, human; D008894:Milk Proteins; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D006419:Heme Oxygenase (Decyclizing)
keywords: MFGE8 protein, rat; heme oxygenase-1; oxidative stress; subarachnoid hemorrhage