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

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.

Cordycepin Confers long-term neuroprotection via inhibiting neutrophil infiltration and neuroinflammation after traumatic brain injury

“…Endogenous IgG in the blood can leak into brain parenchyma through dysfunctional BBB, which makes IgG an important endogenous biomarker to assess the BBB leakage [34]. We stained 3d-post-TBI frozen section with anti-mouse IgG antibody to detect the leakage of endogenous substance.…”

Blood-Brain Barrier: More Contributor to Disruption of Central Nervous System Homeostasis Than Victim in Neurological Disorders

“…Transplantation of mesenchymal stem cells (MSCs) is a prominent research focus as they can promote neurogenesis and angiogenesis in the BBB (Dabrowska et al, 2019). Integrin α5β1 mediates leukocyte infiltration and subsequent BBB dysfunction; the integrin α5β1 inhibitor, ATN-161, can preserve claudin-5 and collagen-IV expression and reduce MMP-9 transcription, thus protecting BBB integrity (Edwards et al, 2019). Perlecan, a major heparan sulfate proteoglycan component of the BM, can maintain and repair the injured BBB by reinforcing the BM (Nakamura et al, 2019).…”

The Inflammatory Response After Ischemic Stroke: Targeting β2 and β1 Integrins

“…The change in expression localization and morphology is attributed to non-movement as the leukocyte cannot detach α 5 β 1 from the vascular wall (Pierini et al, 2000). Recently, Edwards et al (2019) found that inhibition of α 5 β 1 integrin by the small peptide ATN-161 prevented CD45+ leukocytes from infiltrating the brain parenchyma following the tandem/transient common carotid artery/middle cerebral artery occlusion model. Additionally, mice were observed to have reduced BBB permeability, functional deficits, edema, and infarct volume following middle cerebral artery occlusion (Roberts et al, 2015; Edwards et al, 2019).…”

“…Recently, Edwards et al (2019) found that inhibition of α 5 β 1 integrin by the small peptide ATN-161 prevented CD45+ leukocytes from infiltrating the brain parenchyma following the tandem/transient common carotid artery/middle cerebral artery occlusion model. Additionally, mice were observed to have reduced BBB permeability, functional deficits, edema, and infarct volume following middle cerebral artery occlusion (Roberts et al, 2015; Edwards et al, 2019). Thus, targeting α 5 β 1 after ischemic stroke could be a new avenue for reduction of inflammation following ischemic stroke.…”