Abstract
Blood cells are transported into the brain and are thought to participate in neurodegenerative processes following hypoxic ischemic injury. We examined the possibility that transient forebrain ischemia (TFI) causes the blood-brain barrier (BBB) to become permeable to blood cells, possibly via dysfunction and degeneration of endothelial cells in rats. Extravasation of Evans blue and immunoglobulin G (IgG) was observed in the hippocampal CA1-2 areas within 8 h after TFI, and peaked at 48 h. This extravasation was accompanied by loss of tight junction proteins, occludin, and zonula occludens-1, and degeneration of endothelial cells in the CA1-2 areas. Iron overload and mitochondrial free radical production were evident in the microvessel endothelium of the hippocampus before endothelial cell damage occurred. Administration of deferoxamine (DFO), an iron chelator, or Neu2000, an antioxidant, blocked free radical production and endothelial cell degeneration. Our findings suggest that iron overload and iron-mediated free radical production cause loss of tight junction proteins and degeneration of endothelial cells, opening of the BBB after TFI.
Highlights
The blood-brain barrier (BBB) plays a critical role in the maintenance of ionic homeostasis within the CNS, and in communication between the CNS and peripheral tissues (Hawkins and Davis, 2005; Abbott et al, 2010)
Double-labeling with both Evans blue dye (EBD)-albumin and an antibody against endothelial barrier antigen (EBA) revealed that extravasation of EBD-albumin was evident in the microvasculature of the CA1-2 pyramidal cell layer 48 h after reperfusion, compared to data from the shamoperated control (Figure 1C), suggesting that BBB permeability increased primarily in CA1-2 areas after transient forebrain ischemia (TFI)
EBD-albumin was not detectable in other hippocampal areas, including the CA3 region and the dentate gyrus. This implies that TFI selectively disrupts the BBB in the hippocampal CA1-2 areas that are vulnerable to ischemic injury
Summary
The blood-brain barrier (BBB) plays a critical role in the maintenance of ionic homeostasis within the CNS, and in communication between the CNS and peripheral tissues (Hawkins and Davis, 2005; Abbott et al, 2010). Deregulation of BBB integrity has been well documented following hypoxic ischemic brain injury (Kuroiwa et al, 1988; Belayev et al, 1996; del Zoppo and Mabuchi, 2003), and has been reported to feature in other neurological diseases including neurodegenerative conditions (Zlokovic, 2008), autoimmune disorders (Minagar and Alexander, 2003), and post-infection with viruses, bacteria, or other microorganisms (Kim, 2008). Cytotoxic molecules including nitric oxide, proteases, and inflammatory cytokines are produced within and released from the infiltrating leukocytes, contributing to neuronal cell injury (Rezai-Zadeh et al, 2009). Hypoxic ischemia induces expression of inflammatory cytokines including TNF-α, IL-1β, and IL-6; these molecules stimulate the production and release of chemokines, which are chemoattractant proteins known to mediate recruitment and infiltration of leukocytes (Huang et al, 2006). Recruited neutrophils and mononuclear phagocytes induce upregulation of iNOS, matrix metalloproteinase-2 (MMP-2) and -9, and VEGF; these peptides cause disruption of BBB integrity via degradation of vascular extracellular matrix and tight junctions
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