Blocking HMGB1/RAGE Signaling by Berberine Alleviates A1 Astrocyte and Attenuates Sepsis-Associated Encephalopathy.

Jian Shi,Xingmei Li,Jia Fang,María José Cavagnaro,Huan Xu

doi:10.3389/fphar.2021.760186

Abstract

As a life-threatening multiple organ dysfunction attributable to maladjusted host immune responses to infection, sepsis is usually the common pathway to serious prognosis and death for numerous infectious diseases all over the world. Sepsis-associated encephalopathy (SAE) is frequently complicated by septic conditions, and is one of the most important reasons for increased mortality and poor outcomes in septic patients which is still an urgent clinical problem need to be solved. In this research, a conspicuously discovery of treatment-related translational use for berberine was elaborated. The results revealed that berberine treatment significantly restored cognitive impairment in sepsis mice. Reduced expression levels of TNF-α, IL-1α, and C1qA were exhibited in the hippocampus of the berberine treatment group, and attenuated effect of declining neo-neuron, activation of microglia and astrocytes in the hippocampus of mice with sepsis were also found. Moreover, berberine inhibits microglia-stressed A1 astrocytes by inhibiting HMGB1 signaling was revealed, then the molecular mechanism of HMGB1/RAGE signaling inhibition leads to the better outcome of SAE was elucidated. To summarize, this research indicated that berberine targets HMGB1/RAGE signaling to inhibit microglia-stressed A1 astrocyte and neo-neuron decline, which consequently alleviates sepsis-induced cognitive impairment. Collectively, berberine may serve as potential therapeutic drug and HMGB1/RAGE signaling would be a novel target for medicine development for treating SAE.

Highlights

Sepsis is one of the most important leading causes of mortality and morbidity worldwide
To determine the effects of berberine on Sepsis-associated encephalopathy (SAE), mice were subjected to OFT to assessing the mobility prior to the tests of Novel object recognition (NOR) and Morris water maze (MWM)
When the novel object was set in the testing phase of NOR, as predicted, sham mice administrated with either saline or berberine had a memory of the object with a discrimination ratio (DR) over 0.5, whilst mice with caecal ligation and puncture (CLP) alone lost the memory of the old object and had a DR around 0.5

Summary

Introduction

Sepsis is one of the most important leading causes of mortality and morbidity worldwide. Half of sepsis patients suffer from encephalopathy, which induced most of cognition damage and changed mentality in intensive care units (ICU) (Liddelow et al, 2017). Sepsis-associated encephalopathy (SAE) is a diffuse brain disturbance that usually occurs following infection in the body with hardly any central nervous system infection. SAE brought greater risks for long periods of cognitive impairments, which contains alteration in visual-spatial abilities, deficits in visual and functional memory with depressive and/or anxiety disorders (Iacobone et al, 2009; Feng et al, 2019). A lot of limitations and difficulties in clinical practical operation strongly impeded the accurate assessment of cognition and sensory functions in sepsis patients. SAE has enhanced harmful effects on patients and brought society a heavy and painful burden

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