The Effects And Underlying Mechanism Of Endogenous Hydrogen Sulfide In Depression-like Behavior Induced By Estrogen Deficiency

Perimenopausal depressive disorder?PPD?is a disease that occurs during perimenopause and the symptoms include anxiety and depression.Studies have shown that menopausal women have a 3-fold increase in depressive symptoms compared with premenopausal women,and women with no history of depression have a 2.5-fold incidence rate of PDD in premenopausal women.The pathogenesis of most PDD is related to fluctuations in ovarian hormone levels.In clinical studies,the combination of antidepressants and estrogens is more effective in improving the symptoms of PDD patients than using antidepressants alone.It suggests that the decline of ovarian function in perimenopausal women leads to low estrogen levels,which is an important cause of PDD.However,the mechanisms of estrogen in the pathogenesis of PDD have not been fully elucidated.Studies have shown that estrogen not only has the function of maintaining secondary sexual characteristics,regulating reproduction and material metabolism,but also plays the role of participating in the regulation and protection of nerves.The study found that it produced neuroprotective effects by affecting the synthesis of brain monoamine neurotransmitters,brain-derived neurotrophic factors and other related molecules.It is believed that the neuroprotective effects of estrogen are consistent with the classic hypothesis of depression?eg,monoamine neurotransmitter theory,neurotrophic factor theory,etc.?.The latest research suggests that depression is a neurological immune disorder.The body activates the immune system by releasing inflammatory factors,leading to neuroendocrine and immune system disorders.Endogenous H₂S is the third type of gasotransmitter discovered in recent years,which plays an important role in various physiological and pathological processes such as diastolic blood vessels,protecting the heart,resisting oxidative stress and inhibiting inflammatory reactions.The results of previous experimental studies in this group indicated that estrogen deficiency leads to depression-like behavior by activating the inflammatory response in the hippocampus of mice,but the mechanism is still unclear.Therefore,this article mainly studied and clarified the mechanism of endogenous H₂S in depression-like behavior caused by estrogen deficiency.In this study,we first constructed an ovariectomized?OVX?mouse model,and the mice were divided into the control group and the treatment group.The treatment group was given 17?-estradiol and estrogen receptor agonists PPT and DPN for 4weeks.Afterwards,the sucrose preference test,forced swimming test,tail suspension test and open field test were used to detect the depression-like behavior.The blood and hippocampus of mice were obtained,and serum estrogen levels and CBS,H2S,NLRP3 inflammasome,inflammatory factors,oxidative stress and mitochondrial function-related factors level in hippocampus were detected by ELISA,western blotting and other methods.On this basis,mouse hippocampus cells primarily cultured,and treated with estrogen and estrogen receptor agonists PPT and DPN for48 hours,and then changes in CBS,H₂S,NLRP3 inflammasome and inflammatory factors were observed.Finally,the OVX mouse model was constructed again,grouped and administered NaHS for 4 weeks.The blood and hippocampus of the mice were collected and the levels of CBS,H2S,NLRP3 inflammatory corpuscles,inflammatory factors,oxidative stress and mitochondrial functional factors in the hippocampus were detected.Results:?1?In the state of estrogen deficiency,mice showed depression-like behavior.In the hippocampus of mice,NLRP3 inflammasome,inflammatory factors increased,and CBS and H₂S levels decreased.Estrogen and ER?agonist DPN improved the depression-like behavior of OVX mice and reduced the levels of NLRP3inflammasome and inflammatory factors in hippocampus of mice.?2?Estrogen and ER?agonist DPN reversed the activation of NLRP3inflammasome in the microglia of hippocampal and reduced the level of inflammatory factors.?3?In the state of estrogen deficiency,the levels of reactive oxygen species?ROS?in the hippocampus of mice increased,and the total antioxidant capacity?T-AOC?level decreased.Mitochondrial ATP content and mitochondrial membrane potential JC-1 level decreased.Estrogen and ER?agonist DPN reversed oxidative stress and improve cellular mitochondrial function.?4?In the state of estrogen deficiency,H₂S inhibited oxidative stress and improved cell mitochondrial function,inhibited the activation of NLRP3inflammasome,reduced the level of inflammatory factors,and improved the depression-like behavior of mice.Conclusions:?1?Estrogen deficiency leads to oxidation/antioxidation imbalance and mitochondrial dysfunction,which stimulates microglia of hippocampal of mouse,activates NLRP3 inflammasome,and then inflammatory factors IL-1?and IL-18produces an inflammatory response,leading to depression-like behavior.?2?Estrogen produces an antidepressant effect through ER?.Estrogen improves oxidative/antioxidative imbalance and mitochondrial dysfunction,inhibits NLRP3inflammasome activation and hippocampal inflammatory response,thereby improving depression-like behavior.?3?Endogenous H₂S inhibits oxidative/antioxidative imbalance and mitochondrial dysfunction in the state of estrogen deficiency,and inhibits NLRP3inflammasome formation and hippocampal inflammatory response,thereby improving depression-like behavior.