Intracerebral hemorrhage (ICH) is the deadliest and most disabling form of stroke. Clinical studies show that the elderly are especially vulnerable to ICH, and given the aging of the population, the incidence of ICH is expected to grow over the next decades. Neuroinflammation significantly contributes to the propagation of ICH-induced brain injury, and upregulation of proinflammatory cyclooxygenase (COX)-2 and PGE2 has been implicated in ICH etiopathology. PGE2 may control the propagation of inflammation and notably is known to accumulate in the perihematomal area. PGE2 acts mainly on four G-protein-coupled receptors (GPCR;EP1-4) that have distinct signal transduction profiles, and often, opposing cellular actions. Based on the current knowledge and preliminary observations, our current working hypothesis is that PGE2 EP1 and EP3 receptors would promote ICH acute injury, whereas EP2 and EP4 receptors would promote neuroprotection after ICH. Consequently, four aims have been designed taking advantage of two translational ICH mouse models: the collagenase and autologous blood models.
Our aims are 1) To determine the PGE2 levels and relative expression and distribution of COX, PGES, and the EP1-4 receptors at different times after ICH;2) To determine whether the EP1 or EP3 receptor aggravates anatomical brain injury and neurobehavioral deficits after ICH;3) To determine whether the EP2 and EP4 receptors attenuate anatomical brain injury and neurobehavioral deficits after ICH;4) To determine the effects of PGE2 EP1-4 receptor activation and inhibition on neuronal survival in in vitro models of heme-related toxicity and other toxicity models. We will use our available EP receptor knockout (-/-) C57BL/6 mice, namely the EP1-/-, EP2-/-, and EP3-/- mice. Because the EP4-/- mice are not viable, we will use selective pharmacologic agents. The most appropriate and selective antagonists/agonists will be tested post-ICH to determine the optimal dose and extended therapeutic window. Considering potential gender differences and that the aged population is more vulnerable to ICH, all significant results obtained in 2-month-old males will be further extended in females and in the 24-month-old age group. Finally, to obtain additional information about potential neuronal actions, we will culture primary postnatal neurons from male or female pups of the various knockouts. These neuronal cultures will be treated with selective drugs following heme-induced toxicity. By investigating the post-ICH roles of PGE2 receptors, we will gain a better understanding of the physiology underlying ICH and be able to address potential novel therapeutic avenues with the use of PGE2 receptor drugs.
Because there are no effective pharmacologic interventions for the treatment of intracerebral hemorrhage (ICH), and neuroinflammation significantly contributes to the propagation of ICH- induced brain injury, our main objective is to understand the role of each of the four prostaglandin E2 receptors that mediate the pro-inflammatory cascade downstream of the COX-2 enzyme. By using genetic and pharmacologic approaches, we plan to characterize these receptor functions and at the same time test selective drugs that can reduce brain damage and its associated neurological deficits. Such information is required to develop and test receptor agonist/antagonist interventions for potential use in clinical trials for hemorrhagic stroke.
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