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

BMC Neuroscience

Research Article

Nilendra Singh¹  Luke Soshnik-Schierling¹  Alex Dang¹  Ellis Greene¹  Abdullah S Ahmad¹  Jenna L Leclerc²  Sylvain Doré³ 

[1] Department of Anesthesiology, University of Florida, Gainesville, FL, USA;Department of Anesthesiology, University of Florida, Gainesville, FL, USA;Department of Neuroscience, University of Florida, Gainesville, FL, USA;Department of Anesthesiology, University of Florida, Gainesville, FL, USA;Department of Neuroscience, University of Florida, Gainesville, FL, USA;Departments of Neurology, Psychiatry, Psychology and Pharmaceutics, University of Florida, Gainesville, FL, USA;University of Florida College of Medicine, 1275 Center Drive, 32610-0159, Gainesville, FL, USA;

关键词: 17-pt-PGE;    EP3;    Gliosis;    Iron;    Neuroinflammation;    Neuroprotection;    PECAM;    SC-51089;    Stroke;   

DOI  :  10.1186/s12868-015-0182-2

 received in 2015-01-13, accepted in 2015-07-13,  发布年份 2015

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Leclerc et al. 2015