Inhibition of EphA4 reduces vasogenic edema after experimental stroke in mice by protecting the blood-brain barrier integrity.
J Cereb Blood Flow Metab
; 44(3): 419-433, 2024 03.
Article
in En
| MEDLINE
| ID: mdl-37871622
ABSTRACT
Cerebral vasogenic edema, a severe complication of ischemic stroke, aggravates neurological deficits. However, therapeutics to reduce cerebral edema still represent a significant unmet medical need. Brain microvascular endothelial cells (BMECs), vital for maintaining the blood-brain barrier (BBB), represent the first defense barrier for vasogenic edema. Here, we analyzed the proteomic profiles of the cultured mouse BMECs during oxygen-glucose deprivation and reperfusion (OGD/R). Besides the extensively altered cytoskeletal proteins, ephrin type-A receptor 4 (EphA4) expressions and its activated phosphorylated form p-EphA4 were significantly increased. Blocking EphA4 using EphA4-Fc, a specific and well-tolerated inhibitor shown in our ongoing human phase I trial, effectively reduced OGD/R-induced BMECs contraction and tight junction damage. EphA4-Fc did not protect OGD/R-induced neuronal and astrocytic death. However, administration of EphA4-Fc, before or after the onset of transient middle cerebral artery occlusion (tMCAO), reduced brain edema by about 50%, leading to improved neurological function recovery. The BBB permeability test also confirmed that cerebral BBB integrity was well maintained in tMCAO brains treated with EphA4-Fc. Therefore, EphA4 was critical in signaling BMECs-mediated BBB breakdown and vasogenic edema during cerebral ischemia. EphA4-Fc is promising for the treatment of clinical post-stroke edema.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Edema
/
Brain Ischemia
/
Stroke
Limits:
Animals
/
Humans
Language:
En
Journal:
J Cereb Blood Flow Metab
Year:
2024
Document type:
Article