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.
Highlights
Traumatic brain injury (TBI) is the deadliest and most disabling form of acute brain trauma and has no current effective treatment
Various biological actions of the specific prostaglandins are mediated via activation of several different isotypes of their cognate membrane G-protein-coupled receptors (GPCRs), and far the data suggest that the prostaglandin receptors, which exert most of their action through activation of intracellular calcium (Ca2+)signaling, such as closely related prostaglandin E2 (PGE2) receptor EP1 and PGF2a receptor FP [11, 17,18,19], exacerbate neuronal dysfunction after ischemic and excitotoxic brain injuries [11, 17, 19,20,21,22,23]
Based on the previous data indicating that blockade or ablation of Ca2+ -modulating EP1 receptor [18, 19] provides neuroprotection in ischemic stroke and excitotoxicity models [19, 22, 23], and that the same interventions against the closely related FP receptor with similar mechanisms of action [17] limit anatomical brain damage and neurological deficits following both experimental ischemic stroke [17, 20] and TBI [21], we hypothesized that pharmacological inhibition or genetic deletion of the EP1 receptor may have a protective effect in a model of TBI
Summary
Traumatic brain injury (TBI) is the deadliest and most disabling form of acute brain trauma and has no current effective treatment. Selective and non-selective COX-2 inhibitors have been widely used in the clinic for the treatment of different disorders and preclinical data suggest that their use might be beneficial in some neurological disorders, including certain types of stroke and TBI [5, 6, 8, 14, 15]. Based on our recent data obtained using a model of intracerebral hemorrhage (ICH) [24], the roles of prostaglandin receptors are complex and the outcomes of inhibition or genetic deletion of some of these receptors, such as EP1, may have opposing effects in different neurological conditions, such as ischemic and hemorrhagic strokes [19, 22,23,24]. In the later study, improvements in doi:10.1371/journal.pone.0113689.g001
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