PGE2 EP1 and EP3 receptors as therapeutic targets in intracerebral hemorrhage

描述（由申请人提供）：PGE2 EP1和EP3受体作为脑出血的治疗靶点脑出血（intracerebral hemorrhage， ICH）是死亡率和发病率最高的脑卒中亚型；不幸的是，这种情况得到的研究关注远远少于缺血性中风。炎症机制，包括某些前列腺素（pg）介导的炎症机制，已被认为有助于脑出血损伤的进展。特别是，PGE2，主要存在于大脑中，在血肿周围区域产生和积累。PGE2通过四种g蛋白偶联受体亚型EP1- EP4起作用。在脑缺血动物模型中，每种受体都有不同的信号级联反应。EP1和EP3受体的基因缺失或选择性抑制已被证明可以减少体内和体外的缺血性脑损伤。这是总体目标

DESCRIPTION (provided by applicant): PGE2 EP1 and EP3 receptors as therapeutic targets in intracerebral hemorrhage Intracerebral hemorrhage (ICH) is the stroke subtype with the highest mortality and morbidity; unfortunately, this condition has received far less research attention than has ischemic stroke. Inflammatory mechanisms, including those mediated by certain prostaglandins (PGs), have been suggested to contribute to the progression of ICH injury. In particular, PGE2, which is predominant in the brain, is produced and accumulates in the perihematomal region. PGE2 acts through four G-protein-coupled receptor subtypes known as EP1- EP4. Each of these receptors has distinct signaling cascades in animal models of cerebral ischemia. Genetic deletion or selective inhibition of the EP1 and EP3 receptors has been shown to reduce ischemic brain injury both in vivo and in vitro. The overall objective of this R01 is to investigate whether inhibition of PGE2 EP1 and EP3 receptors can be used as neuroprotective therapy in ICH, and if so, to generate preclinical efficacy data and elucidate the underlying mechanisms. We have been investigating the specific roles of PGE2 receptors in ICH injury and have preliminary data showing that deletion or inhibition of the EP1 or EP3 receptor reduces ICH injury and improves functional outcomes. Our data also indicate that Src kinase mediates EP1 toxicity and Rho kinase (ROCK) mediates EP3 toxicity after ICH. Consequently, we will test the hypothesis that PGE2 EP1 receptor blockade reduces ICH injury through the Src kinase signaling pathway, whereas EP3 receptor blockade reduces ICH injury through the ROCK signaling pathway. We have designed three specific aims that utilize the autologous blood ICH model and collagenase-induced ICH model. Considering that an increase in PGE2 production contributes to age-related dysfunction of the inflammatory responses and that aging and sex differences affect ICH outcomes, this research will be carried out in young male and female and aged male mice to enhance the clinical relevance. Aim 1 will determine whether inhibition of EP1 or EP3 receptors improves ICH outcomes; Aim 2 will determine whether inhibition of Src kinase signaling contributes to the neuroprotection afforded by EP1 receptor blockade after ICH and whether EP1 receptor inhibition decreases thrombin-induced brain damage; and Aim 3 will determine whether inhibition of ROCK signaling contributes to the neuroprotection afforded by EP3 receptor blockade after ICH and whether EP3 receptor inhibition decreases thrombin-induced brain damage. Through pharmacologic, genetic, imaging, histologic, molecular, and cellular biologic approaches, this work will provide novel information about the efficacy of selective PGE2 EP1 and EP3 receptor inhibition to protect against ICH-induced brain injury and the mechanisms by which such protection occurs. This proof-of-concept information is required to plan more detailed preclinical assessment of selective EP1 and EP3 receptor antagonists in ICH. PUBLIC HEALTH RELEVANCE: Intracerebral hemorrhage (ICH) is a devastating clinical event in which a burst blood vessel releases blood into the brain. We propose to test the efficacy of PGE2 EP1 and EP3 receptor inhibition in two mouse ICH models and to elucidate the underlying mechanisms by which such inhibition provides neuroprotection. If EP1 and EP3 receptor inhibition shows consistent neuroprotection in the two mouse ICH models, it could contribute to the design of novel therapeutic interventions for ICH.