Prostaglandin E₂ EP2 Receptor Deletion Attenuates Intracerebral Hemorrhage-Induced Brain Injury and Improves Functional Recovery

Abstract

Intracerebral hemorrhage (ICH) is a devastating type of stroke characterized by bleeding into the brain parenchyma and secondary brain injury resulting from strong neuroinflammatory responses to blood components. Production of prostaglandin E2 (PGE2) is significantly upregulated following ICH and contributes to this inflammatory response in part through its E prostanoid receptor subtype 2 (EP2). Signaling through the EP2 receptor has been shown to affect outcomes of many acute and chronic neurological disorders; although, not yet explored in the context of ICH. Wildtype (WT) and EP2 receptor knockout (EP2−/−) mice were subjected to ICH, and various anatomical and functional outcomes were assessed by histology and neurobehavioral testing, respectively. When compared with age-matched WT controls, EP2−/− mice had 41.9 ± 4.7% smaller ICH-induced brain lesions and displayed significantly less ipsilateral hemispheric enlargement and incidence of intraventricular hemorrhage. Anatomical outcomes correlated with improved functional recovery as identified by neurological deficit scoring. Histological staining was performed to begin investigating the mechanisms involved in EP2-mediated neurotoxicity after ICH. EP2−/− mice exhibited 45.5 ± 5.8% and 41.4 ± 8.1% less blood and ferric iron accumulation, respectively. Furthermore, significantly less striatal and cortical microgliosis, striatal and cortical astrogliosis, blood–brain barrier breakdown, and peripheral neutrophil infiltration were seen in EP2−/− mice. This study is the first to suggest a deleterious role for the PGE2-EP2 signaling axis in modulating brain injury, inflammation, and functional recovery following ICH. Targeting the EP2 G protein-coupled receptor may represent a new therapeutic avenue for the treatment of hemorrhagic stroke.

Blood–brain barrier and brain fatty acid uptake: Role of arachidonic acid and PGE2

“…Ablation of the EP2 receptor reduces hemorrhage‐induced brain injury‐associated BBB breakdown (Leclerc et al . ). In these mice, there is also a significant reduction in microglial and astrocyte activation associated with the hemorrhage‐induced brain injury, suggesting an important interplay between the EP2‐PGE 2 axis.…”

“…; Leclerc et al . ). This increases PGE 2 movement from the vascular space into the brain, where it can stimulate an anti‐inflammatory response in microglia (Zhang and Rivest ; Blais et al .…”

Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice

“…Interestingly, contrary to their in vitro data and our in vivo data, the same group later reported that EP2 deletion decreases ICH-induced brain damage and improves functional recovery in young adult mice. 42 Such contradictory in vivo data may be attributable to the differences in the age of the animals studied (middle-aged mice versus young adult mice) and the lesion size of the wild-type control mice (4.3 versus 17.8 mm 3 ). This discrepancy supports a previous hypothesis that the effect of ICH on activation of certain pathways depends on hematoma size.…”

Therapeutic implications of the choroid plexus–cerebrospinal fluid interface in neuropsychiatric disorders

“…Consequently, inflammation-related inhibition of the PGTand OAT3-mediated PGD 2 transport regulates the PGD 2 levels in the CSF, hence, this should be considered when developing new therapeutic targets for insomnia . Nevertheless, care should be taken as PGE 2 is implicated in neuroinflammation (Leclerc et al, 2015) and PGE 2 clearance occurs via the same transporters as PGD 2 (e.g. OAT3) .…”