ATN-161 Ameliorates Ischemia/Reperfusion-induced Oxidative Stress, Fibro-inflammation, Mitochondrial damage, and Apoptosis-mediated Tight Junction Disruption in bEnd.3 Cells.

Inflammation

Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, Room 1349, 131 S. Robertson, Ste 1300, New Orleans, LA, 70112, USA.

Published: December 2021

AI Article Synopsis

  • - The study highlights the role of the α5β1 integrin in endothelial cells, showing that its knockout in mice leads to increased resistance to ischemic stroke by preserving the blood-brain barrier (BBB) through the tight junction protein claudin-5.
  • - The peptide ATN-161 inhibits α5β1 integrin and demonstrates benefits in a mouse ischemic stroke model by reducing brain injury markers such as infarct volume and inflammation while stabilizing the BBB.
  • - Mechanistic analysis reveals that ATN-161 counteracts damage from oxygen and glucose deprivation by reducing oxidative stress, inflammation, and apoptosis, further supporting its potential use as a therapy for ischemic stroke.

Article Abstract

We have previously demonstrated the significance of endothelial cell-expressed α5β1 integrin in ischemic stroke, having shown that α5β1 integrin endothelial cell-selective knockout mice are significantly resistance to ischemic stroke injury via preservation of the tight junction protein claudin-5 and subsequent stabilization of the blood-brain barrier (BBB). In addition, inhibition of α5β1 by the small peptide noncompetitive integrin α5 inhibitor, ATN-161, is beneficial in a mouse model of ischemic stroke through reduction of infarct volume, edema, stabilization of the BBB, and reduced inflammation and immune cell infiltration into the brain. In continuation with our previous findings, we have further evaluated the mechanistic role of ATN-161 in vitro and found that oxygen and glucose deprivation and reperfusion (OGD/R)-induced inflammation, oxidative stress, apoptosis, mitochondrial depolarization, and fibrosis attenuate tight junction integrity via induction of α5, NLRP3, p-FAK, and p-AKT signaling in mouse brain endothelial cells. ATN-161 treatment (10 µM) effectively inhibited OGD/R-induced extracellular matrix (ECM) deposition by reducing integrin α5, MMP-9, and fibronectin expression, as well as reducing oxidative stress by reducing mitochondrial superoxide radicals, intracellular ROS, inflammation by reducing NLRP3 inflammasome, tight junction loss by reducing claudin-5 and ZO-1 expression levels, mitochondrial damage by inhibiting mitochondrial depolarization, and apoptosis via regulation of p-FAK and p-AKT levels. Taken together, our results further support therapeutically targeting α5 integrin with ATN-161, a safe, well-tolerated, and clinically validated peptide, in ischemic stroke.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380192PMC
http://dx.doi.org/10.1007/s10753-021-01509-9DOI Listing

Publication Analysis

Top Keywords

tight junction
16
ischemic stroke
16
oxidative stress
12
mitochondrial damage
8
α5β1 integrin
8
integrin α5
8
mitochondrial depolarization
8
p-fak p-akt
8
atn-161
5
mitochondrial
5

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!