Genetic deletion of the PGE2 EP3 receptor improves anatomical and functional outcomes after intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a stroke subtype associated with high mortality and morbidity. Following ICH, excitotoxicity and inflammation significantly contribute to secondary brain injury and poor outcomes. Prostaglandin E 2 (PGE 2 ) levels rise locally with insult to the nervous system, and PGE 2 is known to modulate these processes mainly through its E prostanoid (EP) receptors, EP1–4. EP3 is the most abundant EP receptor in the brain and we have previously shown that signaling through the PGE 2 -EP3 axis exacerbates excitotoxicity and ischemic stroke outcomes. This study aimed to investigate the contribution of this pathway in modulating anatomical outcomes and functional recovery following ICH. Genetic deletion of the EP3 receptor resulted in 48.2 ± 7.3% less ICH-induced brain injury (p < 0.005) and improved functional recovery (p < 0.05), as identified by neurological deficit scoring. To start investigating the mechanisms involved in neuroprotection with impaired PGE 2 -EP3 signaling, histological staining was performed to evaluate blood and ferric iron accumulation, neuroinflammation, blood brain barrier dysfunction, and peripheral neutrophil infiltration. After ICH, EP3 −/− mice demonstrated 49.5 ± 8.8% and 42.8 ± 13.1% less blood (p < 0.01) and ferric iron content (p < 0.05), respectively. Furthermore, EP3 −/− mice had significantly reduced astrogliosis, microglial activation, blood brain barrier breakdown, and neutrophil infiltration. Collectively, these results suggest an injurious role for the PGE 2 -EP3 signaling axis in modulating brain injury, inflammation, and neurologic functional recovery after ICH. Modulation of the PGE 2 -EP3 signaling axis may represent a putative therapeutic avenue for the treatment of ICH.