1235: ABBCC8 (SULFONYLUREA RECEPTOR 1) KO CONFERS NEUROPROTECTION IN SEPSIS-ASSOCIATED BRAIN INJURY

Abstract

Introduction: Sepsis-Associated Brain Injury (SABI) Is Characterized by an Acute Deterioration of Mental Status Resulting in Cognitive Impairment and Acquisition of New and Persistent Functional Limitations in Sepsis Survivors. Previously, We Reported That Septic Mice Had Evidence of Axonal Injury, Robust Microglial Activation, and Cytotoxic Edema in the Cerebral Cortex, Thalamus, and Hippocampus in the Absence of Blood-Brain Barrier Disruption. In Central Nervous System Injury, Sulfonylurea Receptor 1 (SUR1), a Member of the Adenosine Triphosphate (ATP)-Binding Cassette Protein Superfamily, Associates With the Transient Receptor Potential Melastatin 4 (TRPM4) Cation Channel to Play a Crucial Role in Cerebral Edema Development. Therefore, We Hypothesized That Knockout (KO) of Abcc8 (Sur1 Gene) Is Associated With a Decrease in Microglial Activation, Cerebral Edema, and Improved Neurobehavioral Outcomes in a Murine Cecal Ligation and Puncture (CLP) Model of Sepsis. Methods: Sepsis Was Induced in 4-6-Week-Old Abcc8 KO and Wild-Type (WT) Littermate Control Male Mice by CLP. We Used Immunohistochemistry to Define Microglial Activation Along With Parallel Studies Using Magnetic Resonance Imaging, Focusing on Cerebral Edema on Days 1 and 4 Days After CLP. Results: Abcc8 KO Mice Exhibited a Decrease in Axonal Injury and Cytotoxic Edema vs. WT on Day 1. Abcc8 KO Mice Also Had Decreased Microglial Activation in the Cerebral Cortex vs WT. These Findings Were Associated With Cognitive Improvement on Days 7–8 After CLP. Conclusions: Our Study Challenges a Key Concept in Sepsis and Suggests That Brain Injury Does Not Merely Happen as an Extension of Systemic Inflammation, but Upregulation of the SUR1-TRPM4 Channel in the Brain Directly Contributes to the CNS Pathobiology Previously Demonstrated. Benefits Conferred by Abcc8 KO in the Murine CLP Model Warrant Studies of Pharmacological Abcc8 Inhibition as a New Potential Therapeutic Strategy for SABI.