Integrin α5β1 inhibition by ATN-161 reduces neuroinflammation and is neuroprotective in ischemic stroke

J Cereb Blood Flow Metab. 2020 Aug;40(8):1695-1708. doi: 10.1177/0271678X19880161. Epub 2019 Oct 1.

Abstract

Stroke remains a leading cause of death and disability with limited therapeutic options. Endothelial cell β1 integrin receptors play a direct role in blood-brain barrier (BBB) dysfunction through regulation of tight junction proteins and infiltrating leukocytes, potentially mediated by β1 integrins. Following tandem transient common carotid artery/middle cerebral artery occlusion on wild-type mice, we administered the integrin a5b1 inhibitor, ATN-161, intraperitoneal (IP) injection at 1 mg/kg acutely after reperfusion, on post-stroke day (PSD)1 and PSD2. Systemic changes (heart rate, pulse distension, and body temperature) were determined. Additionally, infarct volume and edema were determined by 2,3-triphenyltetrazolium chloride and magnetic resonance imaging, while neurological changes were evaluated using an 11-point Neuroscore. Brain immunohistochemistry was performed for claudin-5, α5β1, IgG, and CD45 + cells, and quantitative polymerase chain reaction (qPCR) was performed for matrix metalloproteinase-9 (MMP-9), interleukin (IL)-1β, collagen IV, and CXCL12. ATN-161 significantly reduced integrin α5β1 expression in the surrounding peri-infarct region with no systemic changes. Infarct volume, edema, and functional deficit were significantly reduced in ATN-161-treated mice. Furthermore, ATN-161 treatment reduced IgG extravasation into the parenchyma through conserved claudin-5, collagen IV, CXCL12 while reducing MMP-9 transcription. Additionally, IL-1β and CD45 + cells were reduced in the ipsilateral cortex following ATN-161 administration. Collectively, ATN-161 may be a promising novel stroke therapy by reducing post-stroke inflammation and BBB permeability.

Keywords: Blood-brain barrier permeability; inflammation; integrin α5β1; stroke; tight junctions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / blood supply
  • Brain / drug effects*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Inflammation
  • Integrin alpha5beta1 / antagonists & inhibitors*
  • Ischemic Stroke / drug therapy*
  • Ischemic Stroke / immunology
  • Ischemic Stroke / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / therapeutic use*
  • Neutrophil Infiltration / drug effects
  • Neutrophil Infiltration / immunology
  • Oligopeptides / administration & dosage
  • Oligopeptides / therapeutic use*

Substances

  • Cytokines
  • Integrin alpha5beta1
  • Neuroprotective Agents
  • Oligopeptides
  • acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide