Plasma miR-370-3p As a Biomarker of Sepsis-Associated Encephalopathy, The Transcriptomic Profiling Analysis of Microrna-Arrays From Mouse Brains

: The diagnosis of sepsis-associated encephalopathy (SAE), an alteration of conscious from sepsis, is difficult due to the similarity to altered states of conscious that occur from other causes. Transcriptomic analyses between mouse-brains at 24 h after cecal ligation and puncture (CLP) (SAE brain as evaluated by SHIRPA score) and at 120 h post-CLP (survivor) were performed to discover the SAE biomarker. Then, candidate microRNAs (miRs) were validated in mouse and patient samples.As such, increased miR-370-3p in SAE mouse-brains (compared with recovery phase) was demonstrated by transcriptomic miR-profiling and was highly expressed in brain (but not other organs) of 24h-post-CLP mice. Plasma miR-370-3p also increased in CLP but was non-detectable in bilateral-nephrectomy (BiNx, a representative model of acute uremic encephalopathy) despite blood brain barrier permeability defect (determined by plasma s100β and Evan blue dye assay) in both conditions. In parallel, high plasma miR-370-3p was demonstrated in patients with SAE (but not sepsis alone or uremia) suggesting the specificity toward SAE. The association among TNF-α, miR-370-3p and brain apoptosis was demonstrated by i) high serum TNF-α and increased brain apoptosis in SAE mice, ii) TNF-α (but not other cytokines) activated miR-370-3p expression in PC-12 neuron cell and iii) increased cell apoptosis in miR-370-3p transfected PC-12 after incubation with TNF-α.In conclusion, miR-370-3p increased in brain and plasma of SAE mice but not uremic encephalopathy. Perhaps, TNF-α enhances cell susceptibility toward brain apoptosis in SAE, in part, through miR-370-3p induction in neuron. Our pilot-results in patients with SAE supported the possibility that plasma miR-370-3p is an interesting SAE biomarker candidate. Further studies are warranted.