title: Neuroprotective effects of intravenous immunoglobulin are mediated through inhibition of complement activation and apoptosis in a rat model of sepsis.
abstract: BACKGROUND
  Intravenous (IV) immunoglobulin (Ig) treatment is known to alleviate behavioral deficits and increase survival in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated.
  
  
  METHODS
  Sepsis was induced by cecal ligation perforation (CLP) in rats. The animals were divided into five groups: sham, control, CLP + saline, CLP + immunoglobulin G (IgG) (250 mg/kg, iv), and CLP + immunoglobulins enriched with immunoglobulin M (IgGAM) (250 mg/kg, iv). Blood and brain samples were taken in two sets of experiments to see the early (24 h) and late (10 days) effects of treatment. Total complement activity, complement 3 (C3), and soluble complement C5b-9 levels were measured in the sera of rats using ELISA-based methods. Cerebral complement, complement receptor, NF-κB, Bax, and Bcl-2 expressions were analyzed by western blot and/or RT-PCR methods. Immune cell infiltration and gliosis were examined by immunohistochemistry using CD3, CD4, CD8, CD11b, CD19, and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining.
  
  
  RESULTS
  IVIgG and IgGAM administration significantly reduced systemic complement activity and cerebral C5a and C5a receptor expression. Likewise, both treatment methods reduced proapoptotic NF-κB and Bax expressions in the brain. IVIgG and IgGAM treatment induced considerable amelioration in glial cell proliferation and neuronal apoptosis which were increased in non-treated septic rats.
  
  
  CONCLUSIONS
  We suggest that IVIgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. In both treatment methods, these beneficial effects might be mediated through reduction of anaphylatoxic C5a activity and subsequent inhibition of inflammation and apoptosis pathways.
authors.affiliation: Department of Anesthesiology, Istanbul Faculty of Medicine, Istanbul University, Capa-Fatih, 34039, Istanbul, Turkey.
authors.forename: Figen
authors.initials: F
authors.lastname: Esen
authors.affiliation: Department of Anesthesiology, Istanbul Faculty of Medicine, Istanbul University, Capa-Fatih, 34039, Istanbul, Turkey.
authors.forename: Gunseli
authors.initials: G
authors.lastname: Orhun
authors.affiliation: Department of Anesthesiology, Istanbul Faculty of Medicine, Istanbul University, Capa-Fatih, 34039, Istanbul, Turkey. pergin@istanbul.edu.tr.
authors.forename: Perihan Ergin
authors.initials: PE
authors.lastname: Ozcan
authors.affiliation: Department of Anesthesiology, Istanbul Faculty of Medicine, Istanbul University, Capa-Fatih, 34039, Istanbul, Turkey.
authors.forename: Evren
authors.initials: E
authors.lastname: Senturk
authors.affiliation: Neuroscience, Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Melike
authors.initials: M
authors.lastname: Kucukerden
authors.affiliation: Neuroscience, Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Murat
authors.initials: M
authors.lastname: Giris
authors.affiliation: Neuroscience, Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Ugur
authors.initials: U
authors.lastname: Akcan
authors.affiliation: Department of Physiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Canan Ugur
authors.initials: CU
authors.lastname: Yilmaz
authors.affiliation: Neuroscience, Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Nurcan
authors.initials: N
authors.lastname: Orhan
authors.affiliation: Department of Forensic Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Nadir
authors.initials: N
authors.lastname: Arican
authors.affiliation: Department of Physiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kaya
authors.affiliation: Immunology, Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Sema Bilgic
authors.initials: SB
authors.lastname: Gazioglu
authors.affiliation: Neuroscience, Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Erdem
authors.initials: E
authors.lastname: Tuzun
keywords: Apoptosis; Cecal ligation and puncture; Complement activation; Immunoglobulins; Sepsis