Abstract
Cyclooxygenase-2 (COX-2) is activated in response to ischemia and significantly contributes to the neuroinflammatory process. Accumulation of COX-2-derived prostaglandin E2 (PGE2) parallels the substantial increase in stroke-mediated blood-brain barrier (BBB) breakdown. Disruption of the BBB is a serious consequence of ischemic stroke, and is mainly mediated by matrix metalloproteinases (MMPs). This study aimed to investigate the role of PGE2 EP1 receptor in neurovascular injury in stroke. We hypothesized that pharmacological blockade or genetic deletion of EP1 protects against BBB damage and hemorrhagic transformation by decreasing the levels and activity of MMP-3 and MMP-9. We found that post-ischemic treatment with the EP1 antagonist, SC-51089, or EP1 genetic deletion results in a significant reduction in BBB disruption and reduced hemorrhagic transformation in an experimental model of transient focal cerebral ischemia. These neurovascular protective effects of EP1 inactivation are associated with a significant reduction in MMP-9/-3, less peripheral neutrophil infiltration, and a preservation of tight junction proteins (ZO-1 and occludin) composing the BBB. Our study identifies the EP1 signaling pathway as an important link between neuroinflammation and MMP-mediated BBB breakdown in ischemic stroke. Targeting the EP1 receptor could represent a novel approach to diminish the devastating consequences of stroke-induced neurovascular damage.
Highlights
Ischemic stroke is characterized by the occlusion of an artery supplying the brain, resulting in neuronal death within minutes in the infarct core
We hypothesized that pharmacological inhibition or genetic deletion of EP1 protects against blood-brain barrier (BBB) damage and hemorrhagic transformation by decreasing the levels and activity of matrix metalloproteinases (MMPs)-9/-3
We found that post-ischemic treatment with the EP1 receptor antagonist, SC-51089, or EP1 genetic deletion results in a significant reduction in BBB disruption and reduced hemorrhagic transformation following transient focal cerebral ischemia
Summary
Ischemic stroke is characterized by the occlusion of an artery supplying the brain, resulting in neuronal death within minutes in the infarct core. Utilizing the ischemic stroke model of middle cerebral artery occlusion (MCAO), we tested the impact of EP1 pharmacological blockade or EP1 genetic deletion on neurovascular injury after ischemia. We found that post-ischemic treatment with the EP1 receptor antagonist, SC-51089, or EP1 genetic deletion results in a significant reduction in BBB disruption and reduced hemorrhagic transformation following transient focal cerebral ischemia. These BBB protective effects of EP1 inactivation are associated with a significant reduction in MMP-9/-3, less peripheral neutrophil infiltration, and a preservation of tight junction proteins composing the neurovascular unit. Targeting the EP1 receptor could represent a novel approach to diminish the devastating consequences of stroke-induced neurovascular damage
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