Charina Benavidez

Introduction. Sepsis associated encephalopathy (SAE) is an inflammatory-mediated complication that arises as a secondary effect of an infection that originated in another part of the body¹. It causes a generalized cerebral dysfunction without any actual invasion or infection of the central nervous system^1,2. SAE is the most common cause of encephalopathy found in medical-surgical ICUs with about half of septic patients presenting with encephalopathy¹. Manifestation of prolonged inflammatory response and overproduction of ROS have shown physiological involvement of SAE^2,4,7. With the mitochondria being a major source of ROS, current research has focused on the use of mitochondrial division inhibitor 1 (Mdivi-1) in mitigating oxidative stress that occurs in the brain during SAE³. Methods. Mice models were utilized. Oxidative stress was induced using lipopolysaccharide (LPS) or through cecal ligation and puncture (CLP). Non-control mice were administered varying concentrations of Mdivi-1. Western blots were used to detect protein levels; TUNEL staining provided data on in situ cell death presentation. Transmission electron microscopy (TEM) of mitochondrial samples was performed for visual analyses. Results. LPS treated mice showed upregulation of Drp1, the protein in charge of mitochondrial fissions, and downregulation of OPA1 associated with fusions³. Mice model that underwent CLP procedure without Mdivi-1 treatment exhibited significant fragmentation 12-18 hours later^5,6,8,9. Mdivi-1 demonstrated a dose-dependent protective effect towards lowering SAE effects in mice. Experimental sepsis fragmentation was observed in liver tissue. Levels of MDA accumulation, GSH, and SOD were elevated in LPS treated mice. Through Western Blot analysis, Drp1 levels showed down regulation with dose-dependent administration of Mdivi-1 compared to models only treated with LPS³. Administration of Mdivi-1 in mice prior to CLP demonstrated lowered inhibition of ETC complexes and apoptosis in hepatocyte cells^5,9. Conclusion. Mitochondrial division inhibitor-1 (Mdivi-1) is a potential small drug inhibitor that is being tested on mice for its effects in attenuating mitochondrial fission and cellular apoptosis. This would allow for fusion to occur in higher rates, which would support the cell’s ability to return to a self-sustaining state of repair. Mdivi-1’s actions as a Drp1 reversible inhibitor is observable in detail through these studies, but its beneficial effects on respiration and ROS clearance are still a highly new topic for exploration.

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