Targeting Sur1-Trpm4 in sepsis-induced brain injury

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Abstract Sepsis-induced brain injury is associated with an acute deterioration of mental status resulting in long-term cognitive deficits, increased functional morbidity, and diminution in the quality of life. There are limited diagnostic adjuncts, and as no targeted therapy is available, clinical management of septic patients with central nervous system (CNS) symptomatology is limited to the treatment of the underlying infection and optimal critical care management of shock. Therefore, a better understanding of the pathobiology is needed to define acute brain derangements in sepsis. We have previously demonstrated that magnetic resonance imaging of the brain in mice subjected to cecal ligation and puncture (CLP) was notable for an early and marked decrease in fractional anisotropy consistent with axonal swelling and/or axonal injury that was associated with microglial activation, and the subsequent development of cytotoxic edema as evidenced by a significant decrease in apparent diffusion coefficient values four days after CLP. Sulfonylurea receptor -1(Sur1) is a transmembrane receptor in the ATP binding cassette transporter family ABCC8 that upregulates after CNS injury to form an obligate association with Ca2+ sensitive transient receptor potential melastatin-4 (Trpm4) resulting in edema. Our preliminary data demonstrate the upregulation of Sur1 in murine septic brains. In this proposal, in aim 1, we will determine the temporal correlation between Sur1-Trpm4 expression and edema in the murine septic brain. In aim 2, we will determine if inhibition of Sur1-Trpm4 is associated with a decrease in microglial activation and edema, thereby leading to a subsequent improvement in outcomes in a murine CLP model of sepsis. The availability of an FDA approved Sur1-Trpm4 inhibitor further raises interest in this approach.