Suppressing the Inflammatory Prostaglandin Signaling after Thrombotic Stroke Ameliorates Ischemic Brain Injury and Facilitates Poststroke Recovery.

Acute cerebral ischemia is a leading cause of death and disability, particularly among old adults. The narrow therapeutic window and risk of hemorrhagic transformation largely limit patient eligibility for the current treatment. The neuroinflammatory signaling pathway involving the prostaglandin E2 (PGE(2)) receptor subtype EP2 has now been clarified to contribute to the secondary neurotoxicity following ischemic stroke. We previously demonstrated the feasibility of pharmacologically targeting EP2 for ischemic stroke using an EP2 antagonist in a mouse model of transient middle cerebral artery occlusion. Herein, we evaluated the effects of a second-generation EP2 antagonist with improved potency and selectivity in a mouse model of thrombotic stroke, the most common type of stroke. We found that the EP2 antagonist, when administered hours after an ischemic stroke induced within motor and somatosensory cortices by photoactivation of a light-sensitive dye Rose Bengal, reduced cortical infarction in a dose-dependent manner. EP2 inhibition also improved the poststroke body weight recovery and reduced neurological impairments in locomotor and cognitive functions, revealed by a panel of behavioral tests. These broad benefits support the feasibility of targeting the PGE(2)/EP2 axis-mediated neuroinflammatory pathway as a novel strategy to alleviate the ischemic brain injury caused by thrombotic occlusion and accelerate poststroke recovery.