Soluble epoxide hydrolase in perinatal brain injury

Project Summary/Abstract Many survivors of premature birth and perinatal brain injury suffer from long-term neurological sequelae including seizures, motor and cognitive deficits, elevated rates of hyperactivity, and autism. These newborns urgently need early effective and safe interventions for neuroprotection, a medical goal that is currently unmet. Oxygenated lipid mediators (oxylipins) derived from polyunsaturated fatty acids (PUFAs) are potent signaling molecules that regulate a multitude of cellular and systemic responses, including inflammation. Epoxy fatty acids (EpFAs) are cytochrome P450 (CYP)-dependent derivatives of PUFAs. They are a group of lipid mediators with potent anti-inflammatory and pro-resolving properties. However, their activities are extremely short-lived as soluble epoxide hydrolase (sEH) quickly converts EpFAs to pro-inflammatory diols. Our therapeutic hypothesis is that inhibition of sEH will increase and prolong the anti-inflammatory and pro- resolving actions of chemically stable EpFAs to exert neuroprotection. This proposal, built upon our preliminary data, will examine this therapeutic hypothesis in perinatal brain injury (PNBI). We employed a well-established mouse model of neonatal lipopolysaccharides-sensitized hypoxia-ischemic injury (LPS-HI) to replicate a major form of PNBI in which perinatal infection/inflammation sensitizes the brain to subsequent HI insult and augments brain injury. In Aim 1, we will use both genetic knockout of sEH and pharmacological inhibition of sEH by an inhibitor called TPPU to determine if sEH inhibition protects neonatal mice from LPS-HI injury. Because our preliminary data suggests that liver (hepatocyte)-targeted knockout of sEH may also protect mice from lPS-HI, we propose a sEH-regulated liver-brain mechanism in PNBI via which the liver protects the brain in a long-range fashion via regulating the lipidomic structure of the blood transporting EpFAs. To examine this hypothesis, we will conduct lipidomic profiling of liver, plasma, and brain samples to construct a basic framework for the liver → blood → brain sEH-regulated mechanism. Together, the two aims will provide proof- of-concept that sEH is a novel therapeutic target for PNBI and transformative insights into how liver may play a critical role in regulating or maintaining brain integrity during perinatal period. Completion of this project will provide a potential new avenue for managing perinatal brain injury.