Salvianolic Acid B Alleviates Depressive-like Behaviors In High-fat-fed And Stress-treated Mice Through The RAGE-DIAPH1 Pathway

With the increasing prevalence of obesity,the incidence of depression is on the rise annually and obesity has become a risk factor for depression.Due to the complexity of the comorbidity mechanisms of obesity and depression,such patients do not benefit from existing anti-depressants.The common biological mechanisms between obesity and depression are theoretical basis for the development of appropriate drugs for prevention and treatment.Neuroinflammation is the pathological link between obesity and depression,with central immune cells called “microglia” as important participants.Microglia sense and respond to stress through surface membrane receptors mainly,which cause neuroinflammation and damage to neuron,and then induce behavioral disorders.The receptor for advanced glycation end products（RAGE）is the surface membrane receptor on microglia,which can initiate inflammatory response and cause persistent cell dysfunction after activation.Notably,it is considered to be the core of chronic inflammatory response.Diaphanous1（DIAPH1）interacts with the cytoplasmic domain of RAGE to induce cascade amplification of inflammatory signals.Salvianolic acid B（Sal B）is the main bioactive ingredient of Salvia miltiorrhiza and previous studies have confirmed that Sal B inhibits the inflammatory activation of microglia and has antidepressant effects.In this thesis,we will further explore the antidepressant effect and mechanism of Sal B in high-fat-fed and stress-treated mice.In this study,the model of comorbidity was established by combining high fat diet with chronic mild stress,and the effects of Sal B on animal behaviors were evaluated by experiments such as sucrose preference test,forced swimming test and so on.Microglial phenotype,expression of proinflammatory cytokines,and neuropathological damage were detected by immunohistochemical staining and RT-PCR.Western blot and co-immunoprecipitation were used to analyze the molecular mechanism of drug in vitro and in vivo.The results showed that Sal B at 20 mg/ml improved significantly abnormal physiological states and depressive-like behaviors of high-fat-fed and stress-treated mice.The microglial activation,increased expression of pro-inflammatory cytokines and neuron loss were induced by the comorbidity.Moreover,the gene and protein expression of RAGE and DIAPH1 were increased,and the expression of gene downstream of the RAGE-DIAPH1 pathway was also increased in microglia.Similarly,the lipid accumulation was excessive in microglia.However,Sal B at 20 mg/ml and 40μM inhibited the RAGE-DIAPH1 pathway and alleviated microglial activation effectively,thereby reducing neuron loss.In conclusion,the inflammatory activation of microglia dependent on the RAGE-DIAPH1 pathway played important part in the comorbidity.Sal B showed antidepressant effect in the comorbidity of obesity and depression by inhibiting the RAGE-DIAPH1 pathway of microglia,which might expand the use of SalB.