Therapeutic effects of human umbilical cord mesenchymal stem cell on sepsis-associated encephalopathy in mice by regulating PI3K/AKT pathway

Abstract

Sepsis-associated encephalopathy is a common brain diseases, presenting severe di fuse brain dysfunction. The umbilical cord mesenchymal stem cells have been reported to have protective role for treating diseases, while its role in sepsis-associated encephalopathy remained elusive. This brief report investigated the therapeutic effect of umbilical cord mesenchymal stem cells on sepsis-associated encephalopathy in mice model and uncovering the underlying mechanism. The sepsis-associated encephalopathy mice were injected with 3 mg/kg lipopolysaccharide. An enzyme-linked immunosorbent assay was carried out to determine the production of in lammatory cytokines. Morris water maze test was used to evaluate mice's neurological dysfunction. Cell apoptosis and tissue injury of the cerebral cortex were assessed using terminal deoxynucleotidyl transferasemediated dUTP nick end labeling (TUNEL) assay and HE staining. Evans Blue leakage detection was used to examine the blood-brain barrier integrity. The protein levels were determined using Western blot. Results showed that the productions of in lammatory cytokines including interleukin 6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), and high mobility group box protein 1 (HMGB1) and activated NF-κB were increased in sepsis-associated encephalopathy mice, which were decreased by umbilical cord mesenchymal stem cells treatment. Besides, umbilical cord mesenchymal stem cells inhibited lipopolysaccharide-induced cell apoptosis and neuron injury of the cerebral cortex in sepsis-associated encephalopathy mice. Moreover, cognitive dysfunction was observed in sepsis-associated encephalopathy mice, which was alleviated by umbilical cord mesenchymal stem cells. Furthermore, umbilical cord mesenchymal stem cells activated PI3K/AKT signaling pathway. In conclusion, umbilical cord mesenchymal stem cells alleviated in lammation, cell apoptosis and neuron injury of the cerebral cortex, and cognitive dysfunction in sepsis-associated encephalopathy animal model in a PI3K/AKT dependent pathway, making them to be a promising therapeutic strategy for treating sepsis-associated encephalopathy.

Altered Blood Brain Barrier Permeability and Oxidative Stress in Cntnap2 Knockout Rat Model

“…Quantitation of FITC in brain tissue homogenates confirmed these findings showing a significant amount in the brains of Cntnap2 − / − rats than the control group and thus indicating a compromised BBB. Another well-accepted technique to determine BBB integrity is penetration of Evans blue dye into the brain [ 84 , 85 , 86 , 87 , 88 , 89 ]. On par with our FITC permeability data, we observed significantly high amounts of Evans blue dye in the brain homogenates of Cntnap2 − / − rats, whereas very low levels were detectable in the brain tissues of the control group suggesting impaired BBB permeability.…”

The role of the peripheral system dysfunction in the pathogenesis of sepsis-associated encephalopathy

“…It was found that the injection of umbilical cord MSCs (UC-MSCs) via femoral vein significantly reduced the expression levels of TNF-α, IL-6 and HMGB1 as well as microglia activation (expression of Iba-1 markers) in brain tissue of LPS-treated mice. This improved cortical neuronal damage and cognitive impairment ( Zhang Z. et al, 2022 ). Some studies suggested that MSCs can migrate into the brain through paracellular or transcellular pathways ( Schmidt et al, 2006 ).…”