The Anti-Inflammation Effects Of Ultra-Low Dose Dextromethorphan(DM) In Rodent LPS-Mediated Sepsis Model And Brain Complement C3 Plays Critical Roles In Sustaining Chronic Neuroinflammation And Causing Neurodegeneration

Sepsis is the systemic inflammatory response syndrome(SIRS)induced by infection.In the clinic,especially in the intensive care unit(ICU),sepsis is an important factor leading to death of patients,although anti-infective treatment and organ function support technology has been made much progress,but the mortality rate of sepsis patients is still as high as 30% to 70%.Dextromethorphan(DM),a wildly used antitussive drug found in many over-the-counter cold and cough medicines,is reported to have anti-inflammatory effects.Previously,we and others have demonstrated that DM at micromolar concentrations displays potent hepatoprotective effects and enhances mice survival in a sepsis model.Moreover,we also observed potent anti-neuroinflammatory and neuroprotective effects of subpicomolar concentrations of DM in rodent primary neuronglial cultures.The purpose of this study was to improve the medication safty of DM and exploring a novel treatment of sepsis.We provide a proof of principle that ultralow dose DM displays anti-inflammatory and cytoprotective effects in animal studies.Here,we report that subpico-and micromolar concentrations of DM showed comparable efficacy in protecting mice from lipopolysaccharide/D-galactosamine(LPS/Gal N)-induced hepatotoxicity and mortality.Our results showed that DM at subpicomolar concentrations promoted survival rate in LPS/Gal N-injected mice.Ultralow dose DM also significantly reduced serum alanine aminotransferase activity,TNF-α level and liver cell damage of endotoxemia mice.Mechanistic studies using primary liver Kupffer cell cultures revealed that subpicomolar of DM reduced the NADPH oxidase-generated superoxide free radicals from Kupffer cells,which in turn reduced the elevation of its downstream reactive oxygen species(i ROS)to relief the oxidative stress and decreased TNF-α production in Kupffer cells.Taken together,these findings suggest a novel therapeutic concept of using ultralow concentrations of DM for the intervention of sepsis or septic shock.According to the clinical observation of sepsis cases,patients with sepsis have a significantly higher chance of developing neurodegenerative diseases,including Alzheimer’s disease or Parkinson’s disease.In addition,the findings in the rodent inflammation models support the same conclusion.Therefore,in my dissertation,except studying the therapeutic application of ultra-low concentration of DM in the acute phase of sepsis,we also studied why sepsis-related peripheral inflammation can induce following neurodegenerative diseases after recovery and its pathogenesis.Previous studies have shown that peripheral inflammation induced by sepsis can cause inflammation of the central nervous system and nueronal damage or death.Endogenous molecules,like dangerous molecular patterns(DAMPs),released by damaged or dead neurons,can bind to the Mac-1 receptor on microglia to activate NADPH oxidase,NOX2.The superoxide radicals produced by NOX2 will trigger oxidative stress in central nervous system,leading to a slow and continuous neurodegenerative process.In this paper,we found that cytokines and superoxide free radicals released by microglia in the phase of acute neuroinflammation can trigger astrocytes to produce complement 3(C3).C3 binds to Mac-1 receptor on microglia to promote the continuous production of superoxides and oxidative stress.In addition,C3 will also mark damaged neurons to attract microglia to recognize and clear these damaged neurons: 1)C3 can activate microglia by binding to C3 receptors(also known as Mac-1 receptors on microglia);2)activated C3 can also bind to damaged neurons destined to be phagocytosed by microglia.Together,the study has shown that this process between microglia,astrocytes and neurons can form a vicious cycle of the chronic inflammation,and reducing or removing C3 expression can prevent chronic neurodegeneration induced by sepsis.This study proves that C3 plays a very important role in chronic inflammation and may become an potential therapeutic target for the treatment of neurodegenerative diseases.