Intracerebral hemorrhage outcomes following selective blockade or stimulation of the PGE2 EP1 receptor

Abstract

BackgroundInflammation following intracerebral hemorrhage (ICH) significantly contributes to secondary brain damage and poor outcomes. Prostaglandin E2 (PGE2) is known to modulate neuroinflammatory responses and is upregulated in response to brain injury as a result of changes in inducible cyclooxygenase 2 (COX-2) and the membrane-bound type of PGE synthase. Inhibition of COX-2 activity has been reported to attenuate ICH-induced brain injury; however, the clinical utility of such drugs is limited due to the potential for severe side effects. Therefore, it is now important to search for downstream targets capable of preferentially modulating PGE2 signaling, and the four E prostanoid receptors, EP1-4, which are the main targets of PGE2, remain a viable therapeutic option. We have previously shown that EP1 receptor deletion aggravates ICH-induced brain injury and impairs functional recovery, thus the current study aimed to elaborate on these results by including a pharmacologic approach targeting the EP1 receptor.ResultsChronic post-treatment with the selective EP1 receptor antagonist, SC-51089, increased lesion volume by 30.1 ± 14.5% (p < 0.05) and treatment with the EP1 agonist, 17-pt-PGE2, improved neuromuscular functional recovery on grip strength (p < 0.01) and hanging wire (p < 0.05) behavioral testing. To begin identifying the mechanisms involved in EP1-mediated neuroprotection after ICH, histology was performed to assess ferric iron content, neuroinflammation, leukocyte transendothelial migratory potential, and peripheral neutrophil and immunoglobulin infiltration. Following ICH, mice treated with the antagonist displayed increased ferric iron (p < 0.05) and cortical microgliosis (p < 0.05), whereas treatment with the agonist decreased cortical (p < 0.01) and striatal (p < 0.001) astrogliosis, leukocyte transendothelial migratory potential (p < 0.01), neutrophil infiltration (p < 0.05), and blood brain barrier breakdown (p < 0.05).ConclusionsIn agreement with our previous results, selective antagonism of the EP1 receptor aggravated ICH-induced brain injury. Furthermore, EP1 receptor agonism improved anatomical outcomes and functional recovery. Thus, the present data continues to reinforce a putative role for EP1 as a new and more selective therapeutic target for the treatment of ICH that could reduce the side effects associated with COX-2 inhibition while still exploiting the beneficial effects.

Genetic Deletion of PGF2α-FP Receptor Exacerbates Brain Injury Following Experimental Intracerebral Hemorrhage

“…However, without following this work with further experiments that utilize a FP receptor selective antagonist and agonist, caution should be used when interpreting the potential for the FP receptor as a therapeutic target for the treatment of ICH. Our findings are similar to those found with EP1 −/− mice post-ICH, and recently our group has shown that following activation of the EP1 receptor, astrogliosis, neutrophil infiltration, blood-brain barrie breakdown, and functional recovery all improved (Leclerc et al, 2015a ). Based on these findings, we hypothesize that the activation of the FP receptor will result in measurable changes in the improvement of functional and anatomical outcomes following ICH.…”

“…This may explain why our findings with the FP −/− mice are consistent with our previous findings with the EP1 −/− mice using the same ICH model; the EP1 −/− mice showed greater deteriorated outcomes compared to WT control mice (Singh et al, 2013 ). Our groups also found recently that use of EP1 receptor agonists improved anatomical outcomes and functional recovery (Leclerc et al, 2015a ). In contrast to ICH, the genetic deletion and/or pharmacological blockade of either the EP1 or FP receptor types attenuated brain injury and improved neurological outcomes in excitotoxicity and mouse ischemic stroke models (Ahmad et al, 2006 , 2008 ; Saleem et al, 2007 , 2009 ).…”

PGE2-EP3 signaling exacerbates intracerebral hemorrhage outcomes in 24-mo-old mice

“…The inducible isoforms of these enzymes, COX-2 and mPGES-1, are increased after brain injury and have been reported to have damaging effects in stroke models (11,20). PGE 2 exerts a broad range of physiologic and pathologic effects that can be both neuroprotective and neurotoxic through its ability to bind mainly to four different EP receptors, EP1-4, which are a family of G protein-coupled receptors with different downstream signaling pathways (1,2,19,20,24). In this study, we focus on the role of the EP3 receptor, the most abundant EP receptor in the body, including the brain (20,36).…”

Distinctive effect of anesthetics on the effect of limb remote ischemic postconditioning following ischemic stroke

“…The NDS was assessed at 24, 48, and 72 h post-MCAO surgery in a double-blind fashion by two investigators. We followed a 24-point neurological scoring system, as we described previously [29,30]. In brief, the test includes six parameters: body symmetry, gait, climbing, circling behavior, front-limb symmetry, and compulsory circling.…”