Explore The Neuroimmune Mechanism Of Type 2 Diabetes Complicated With Depression In Zebrafish And The Effect Of Sea Cucumber Enzymatic Hydrolysate Treatment

Patients with diabetes have a higher risk of depression than healthy people.Diabetes mellitus(DM)is a kind of chronic metabolic disease,can damage the immune system and cause inflammation.Although depression belongs to central nervous system(CNS)dysfunction,the macrophage hypothesis proposes inflammation is one of the causes of depression.It’s hypothesized here that the disorder of glucose and lipid metabolism during the formation of DM leads to peripheral inflammation,which will change the permeability of blood-brain-barrier,promote the central inflammatory responses,and over-activate the Hypothalamic-pituitary-adrenal(HPA)axis,then affect the brain-derived-neurotrophicfactor(BDNF)function,change the role of microglia and astrocytes,promote cell apoptosis,change the function of neurons,reduce the content of monoamine neurotransmitters,eventually cause depression.Stress may accelerate the progression of the disease.Antidepressant drugs have poor efficacy and large side effects.Natural products such as sea cucumber,having good immune improvement effect but few side effects to people,have a good prospect for the treatment of DM complicated with depression.This thesis aims to explore the pathogenesis of diabetic depression and the effect of sea cucumber from the perspective of neuroimmunoinflammation.1.Establishment of type 2 diabetes(T2DM)complicated with depression model in zebrafish by high glucose and high fat.The zebrafish T2 DM model was induced by a high glucose environment(2% glucose aquaculture)and a high-fat diet(containing 10% cholesterol)for 19 days.In the DM group,the body contents of glucose,triglyceride,total cholesterol,and low-density cholesterol were significantly increased,while high-density cholesterol(LDL)was decreased.At the same time peripheral cortisol and m RNA expression of glucocorticoid(GR)in the brain were increased.Meanwhile,the expression of peripheral IFN-γ and IL-4 increased,central microglia and astrocytes were activated,the expression of TNF-α,IL-6,and its receptor IL-6R in the brain increased significantly too,while the anti-inflammatory factors remained unchanged.With regards to astrocyte function,the m RNA expression of BDNF and its receptors Trk B and p75 were up-regulated.Also,contents of monoamine neurotransmitters 5-HT and NE decreased,while their metabolism was reinforced.2.The effect of sea cucumber enzymatic hydrolysate on DM complicated with depression.Two kinds of hydrolysate(0.5 m L/L,1 m L/L)with similar effects were screened out by pre-experiment to intervene T2 DM complicated with the depression-like syndrome.The sea cucumber group was soaked in enzymatic hydrolysate for 20 minutes every day,the other groups were soaked in culture water as control at the same time.It was found that 1 m L/L sea cucumber hydrolysate better improved abnormal symptoms found in Experiment 1.However,compared with the DM group,LDL,the m RNA expression of the glucagon in zebrafish muscle,and p75 in the brain,were not effectively improved by sea cucumber enzymatic hydrolysate.3.The effect of chronic stress on DM complicated with depression.Zebrafish were treated with high glucose,high fat,or stress for 2 weeks at the same time.It was found that compared with the DM group,stress aggravated the depressive behavior of zebrafish,increased the level of blood glucose,but down-regulated BMI index.In the inflammatory aspect,stress further increased the expression of brain IL-6 and its receptor IL-6R m RNA,further activated microglia but suppressed astrocyte activity.The m RNA expression of BDNF and Trk B were inhibited,while the expression of p75 increased.Furthermore,compared with the DM group,the expression of GR m RNA in the brain was further upregulated after stress,while cortisol remained unchanged.Conclusion: high glucose and high cholesterol can induce T2 DM in zebrafish with depression-like symptoms.The occurrence of depression-like symptoms is probably due to the dysfunction of glucose and lipid metabolism,which leads to peripheral inflammation and over-activation of the HPI axis,leading to central inflammation and damage to the CNS.By exerting a strong anti-inflammatory effect,sea cucumber enzymatic hydrolysate largely reversed the abnormal glucose and lipid metabolism and depression-like behaviors caused by high glucose and lipid treatment of zebrafish.In addition,on the basis of the weak metabolism and immune system function of T2 DM,stress further destroys the function of blood glucose regulation,aggravates the occurrence of inflammation and the damage of neuroimmune function,greatly increases the risk of DM complicated with depression finally.