Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

Abstract

Brain injuries promote upregulation of so-called proinflammatory prostaglandins, notably prostaglandin E2 (PGE2), leading to overactivation of a class of its cognate G-protein-coupled receptors, including EP1, which is considered a promising target for treatment of ischemic stroke. However, the role of the EP1 receptor is complex and depends on the type of brain injury. This study is focused on the investigation of the role of the EP1 receptor in a controlled cortical impact (CCI) model, a preclinical model of traumatic brain injury (TBI). The therapeutic effects of post-treatments with a widely studied EP1 receptor antagonist, SC-51089, were examined in wildtype and EP1 receptor knockout C57BL/6 mice. Neurological deficit scores (NDS) were assessed 24 and 48 h following CCI or sham surgery, and brain immunohistochemical pathology was assessed 48 h after surgery. In wildtype mice, CCI resulted in an obvious cortical lesion and localized hippocampal edema with an associated significant increase in NDS compared to sham-operated animals. Post-treatments with the selective EP1 receptor antagonist SC-51089 or genetic knockout of EP1 receptor had no significant effects on cortical lesions and hippocampal swelling or on the NDS 24 and 48 h after CCI. Immunohistochemistry studies revealed CCI-induced gliosis and microglial activation in selected ipsilateral brain regions that were not affected by SC-51089 or in the EP1 receptor-deleted mice. This study provides further clarification on the respective contribution of the EP1 receptor in TBI and suggests that, under this experimental paradigm, the EP1 receptor would have limited effects in modulating acute neurological and anatomical pathologies following contusive brain trauma. Findings from this protocol, in combination with previous studies demonstrating differential roles of EP1 receptor in ischemic, neurotoxic, and hemorrhagic conditions, provide scientific background and further clarification of potential therapeutic application of prospective prostaglandin G-protein-coupled receptor drugs in the clinic for treatment of TBI and other acute brain injuries.

Role of the PGE2 receptor subtypes EP1, EP2, and EP3 in repetitive traumatic brain injury

“…This finding supports in part our previous finding that demonstrated neither the deletion nor activation of the EP1 receptor has a significant effect on astrogliosis in a controlled cortical impact (CCI) model . It suggested that astrocyte markers may not be directly affected by EP1 receptor activity and are probably linked with other components of injury, such as other prostaglandin receptors . Since there was no significant difference in astrogliosis in EP2 −/− and EP3 −/− mice when compared to WT mice, our findings indicate that the deletions of EP receptors do not affect astrogliosis under this relatively mild concussion model.…”

“…We found no significant difference in astrogliosis between either genotype or age group. This finding supports in part our previous finding that demonstrated neither the deletion nor activation of the EP1 receptor has a significant effect on astrogliosis in a controlled cortical impact (CCI) model . It suggested that astrocyte markers may not be directly affected by EP1 receptor activity and are probably linked with other components of injury, such as other prostaglandin receptors .…”

“…It indicates that the activation of the EP receptors, specifically the EP1 receptor, may play a role in the delayed improvement in the cognitive deficits after TBI in the aged mice. Since the ability of the mice to learn a task did not diminish after mild TBI, our finding further confirms the behavioral outcomes of previous studies that used CHI mouse models . In general, both young and aged mice across different genotypes did not experience cognitive deficits on day 2.…”

“…In previous in vivo and in vitro studies, selective agonists/antagonists of different prostanoid receptors have been considered as a potential alternative treatment in place of COX inhibitors for neurological conditions such as ischemic stroke and TBI that involve acute excitotoxicity . Various teams, including ours, have studied the effects of the different types of PGE 2 receptors separately in different neurological conditions, but there are currently no studies to our knowledge that have compared the effects of these receptor subtypes in CHI.…”

Animal Models of Posttraumatic Seizures and Epilepsy

“…Pharmacological blockade or genetic deletion of FP receptor improves some outcomes in mouse TBI model [94]. However, the role of the EP1 receptor is complex and its blockade differentially affects outcomes in different neurological conditions such as ischemia [88–92], hemorrhagic stroke [85, 95], excitotoxicity [88, 89, 91], epilepsy [96, 97], surgical brain injury [98], and TBI [49, 99]. Interestingly, blockade of the EP1 receptor was tested as a strategy in the treatment of epilepsy [96, 97], but to reach a desired effect, it required up to a 1000-fold higher dose of one of the commonly used antagonists (i.e., SC-51089) [97] than that used in models of stroke and NMDA-induced excitotoxicity [100].…”