Integrin α5ß1 inhibition by ATN-161 reduces neuroinflammation and is neuroprotective in ischemic stroke.
J Cereb Blood Flow Metab
; 40(8): 1695-1708, 2020 08.
Article
en En
| MEDLINE
| ID: mdl-31575337
ABSTRACT
Stroke remains a leading cause of death and disability with limited therapeutic options. Endothelial cell ß1 integrin receptors play a direct role in blood-brain barrier (BBB) dysfunction through regulation of tight junction proteins and infiltrating leukocytes, potentially mediated by ß1 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, α5ß1, IgG, and CD45 + cells, and quantitative polymerase chain reaction (qPCR) was performed for matrix metalloproteinase-9 (MMP-9), interleukin (IL)-1ß, collagen IV, and CXCL12. ATN-161 significantly reduced integrin α5ß1 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-1ß 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Oligopéptidos
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Encéfalo
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Fármacos Neuroprotectores
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Integrina alfa5beta1
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Accidente Cerebrovascular Isquémico
Límite:
Animals
Idioma:
En
Revista:
J Cereb Blood Flow Metab
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos