SSRIs类抗抑郁药对慢性应激抑郁模型小鼠肠道的损伤作用及机制OA

OBJECTIVE To investigate the effects of five selective serotonin reuptake inhibitors(SSRIs)antidepressants on the intestine of mice with chronic stress-induced depression and explore the underlying mechanisms.METHODS ICR mice were randomly divided into control,model,model+fluoxetine 3 and 9 mg·kg-1,model+sertraline 7.5 and 22.5 mg·kg-1,model+fluvoxamine 15 and 45 mg·kg-1,model+paroxetine 3 and 7.5 mg·kg-1,and model+escitalopram 1.5 and 3 mg·kg-1 groups.The control group was raised normally without any treatment while the other groups were subjected to chronic unpredictable mild stress(CUMS)for 49 days.The sucrose preference test was used to determine the sucrose preference rate,with model establishment considered successful when the rate was significantly lower than that of the control group.After modeling,mice were intragastrically administered(once daily)with normal saline(control and model groups)or corresponding drugs for 28 consecutive days,during which time CUMS was continued.Three days before the end of administration,depressive-like behav-iors were observed using the sucrose preference test,tail suspension test,and forced swim test.Body weight was measured weekly before and after modeling and during administration.After administration,mice were dissected.The serum content of D-xylose was measured to evaluate intestinal absorption function.Gastrointestinal motility was evaluated.ELISA was applied to determine expression levels of brain-gut peptides vasoactive intestinal peptide,motilin,substance P,ghrelin and inflammatory factors interleukin-1β(IL-1β),IL-18.Hematoxylin-eosin(HE)staining was adopted to evaluate the intestinal tissue structure.Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling(TUNEL)was used to detect small intestinal epithelial cell apoptosis while immunofluorescence and Western blotting were used to detect the expressions of NOD-like receptor thermal protein domain associated protein 3(NLRP3)inflammasome,apoptosis signaling pathway protein[cysteine aspartic acid specific protease(Caspase-3),cleaved cysteine aspartic acid specific protease(cleaved Caspase-3)],pyroptosis signal-ing pathway proteins[NLRP3,gasdermin D(GSDMD),cleaved Caspase-1,Caspase-1,and apoptosis-associated speck like protein containing a CARD(ASC)],and barrier proteins[occludin,claudin-5,zonula occludens-1(ZO-1)].RESULTS Antidepressants significantly ameliorated the depressive-like behaviors in CUMS model mice.Compared with control group,the model group exhibited pronounced depressive-like behaviors,decreased body weight,reduced serum D-xylose levels,and lower gastric emptying rate and small intestinal propulsion rate.The expression of the brain-gut peptide vasoactive intestinal peptide was increased while the levels of motilin,substance P,and ghrelin were decreased.The levels of inflammatory factors IL-1β and IL-18 were elevated.HE staining revealed structural damage to the small intestinal tissue in the model group.The expression of the NLRP3 inflammasome was enhanced,the TUNEL fluorescence intensity was increased,the expression levels of proteins associated with apoptosis and pyroptosis signaling pathways were upregulated,and those of intestinal barrier proteins were decreased.Compared with the model group,body weight and serum D-xylose levels were significantly decreased,the gastric emptying rate and small intestinal propulsion rate were lowered,expressions of vasoactive intestinal peptide were increased,and those of motilin,substance P,and ghrelin were decreased while levels of inflammatory factors IL-1β and IL-18 in the intestinal tissue were elevated in the model+fluoxetine 9 mg·kg-1,sertraline 22.5 mg·kg-1,and paroxetine 7.5 mg·kg-1 groups after 28 days of administration.HE staining results showed structural damage such as intestinal villus atrophy.The expression of the NLRP3 inflammasome was significantly enhanced,the TUNEL fluores-cence intensity was increased,the expressions of proteins related to apoptosis and pyroptosis signaling pathways were upregulated,and those of intestinal barrier proteins were decreased.CONCLUSION Among SSRIs antidepressants,fluoxetine 9 mg·kg-1,sertraline 22.5 mg·kg-1,and paroxetine 7.5 mg·kg-1 can significantly impair gastrointestinal motility,absorptive function,and the intestinal barrier in a chronic stress-induced depression mouse model.The activation of inflammatory responses and the induction of apoptosis and pyroptosis in small intestinal tissue cells may be one of the underlying mechanisms.