Hydroxytyrosol Improves Depression-like Behavior In Mice And Its Mechanism

Depression is a common psychiatric disorder disease characterized by high recurrence rate and low remission rate,which is the main cause of global mental health related disease burden.About 30-50% of depression patients have no relief of symptoms after taking a variety of antidepressants,and are accompanied by serious side effects.Therefore,it is urgent to find new molecular targets and more effective therapeutic drugs to treat depression.A growing number of population trials and clinical data show that the Mediterranean diet can reduce the risk of depression.At present,mechanism underlying the effect of Mediterranean diet on depression is not clear.Olive oil is the main edible fat in Mediterranean diet,and the polyphenols in olive oil have a wide range of biological activities.Hydroxytyrosol(HT),the main phenolic compound in olives and olive products,has antioxidative,anti-inflammatory,neuroprotective and other physiological functions.To date,the effect of HT on depression is unclear.The study explored whether HT can improve depression-like behaviors.Firstly,the cell depression model was established by corticosterone-induced injury in hippocampal neuronal cell HT22.The survival rate of HT22 cells was detected by tetramethylazolium salt(MTT)assay.The results showed that 5 ?M HT treatment significantly improve the damage of HT22 cells induced by CORT.Then,acute and chronic depression models in mice were built by intraperitoneal injection of lipopolysaccharide(LPS)and chronic unpredictable mild stress(CUMS),respectively,and the effects of HT on depression-like behavior in mice were explored.The results showed that compared with the control group,the intraperitoneal injection of LPS decreased the sugar preference(P<0.05)of mice,prolonged the immobility time of forced swimming(P<0.05)and tail suspension(P<0.01).50,100 mg/kg HT treatment significantly reversed changes.Furthermore,results indicated that compared to control,sucrose preference(P<0.05)was significantly decreased,while immobility times in forced swimming and tail suspension were obviously increased in CUMS mice(P<0.01).These changes were reversed by HT treatment significantly.With these results we concluded that HT has antidepressant effects at both cellular and animal level.Based on the behavioral test results of acute and chronic depression mouse models,we choose the optimal dose of HT,and use the rodent depression model induced by CUMS,which is the most commonly used,effective and closest to the symptoms of depression patients,to further explore the antidepressant mechanism of HT.The results showed that:It is known that overactive HPA axis can promote the excessive secretion of corticosterone,and directly affect the function and structure of various regions of the central nervous system,which lead to depression and manic symptoms.The results showed that compared with the control group,the serum corticosterone level of mice in the CUMS group was significantly increased(P<0.05).The content of serum corticosterone in CUMS group was significantly higher than that in control group.100mg/kg HT treatment improved the hyperactivity of hypothalamus-pituitary-adrenal(HPA)axis in depressed mice by reducing the level of serum corticosterone in CUMS mice(P<0.05).Oxidative stress induced damage to the brain will have a negative impact on the normal function of the central nervous system,thus orchestrating in the occurrence and development of depression.The results showed that CUMS increased the levels of reactive oxygen species(ROS,P<0.05)and malondialdehyde(MDA,P<0.05)in the hippocampus of mice,and the activities of superoxide dismutase(SOD,P<0.01),manganese-superoxide dismutase(Mn-SOD,P<0.01)and catalase(CAT,P<0.05)were significantly decreased.100 mg/kg HT treatment alleviated oxidative stress in the hippocampus of depressed mice by reducing ROS(P<0.05)and MDA(P<0.01)levels,and increasing the activities of SOD(P<0.01),Mn-SOD(P<0.05)and CAT(P<0.05).Neuroinflammation is a complex and precise cooperative process composed of various glial cells in the central nervous system and peripheral immune cells,which is related to the occurrence and development of depression.The results indicated that CUMS could induced the activation of microglia(P<0.01)and decreased the density of astrocytes(P<0.05)in the hippocampus of mice,thereby increasing the levels of pro-inflammatory cytokines(P<0.05)and inducible nitric oxide synthase(P<0.05),and decreasing anti-inflammatory factors contents(P<0.05).After 100 mg/kg HT treatment,the above changes were significantly reversed and neuroinflammation in the hippocampus of mice was inhibited.Decreased levels of neurotrophic factors can lead to depression.Such as brainderived neurotrophic factor(BDNF),nerve growth factor(NGF),Glial cell line-derived neurotrophic factor(GDNF).The results indicated that,compared with the control group,CUMS could reduce the levels of BDNF(P<0.01)and GDNF(P<0.01)in the hippocampus of mice.100 mg/kg HT treatment could restore the level of neurotrophic factor by increasing the expression of BDNF(P<0.01)and GNDF(P<0.01).Changes in the structure and function of mitochondria will impair the energy metabolism and lead to depression.The results showed that compared with the control group,the expression of AMPK/Sir T-1/PGC-1? protein in the mitochondrial biogenesis related pathway in the hippocampus of the CUMS group decreased(P<0.05),thereby reducing the activity of mitochondrial complex ?,?,? and ?(P<0.05),which resulting in a decrease in ATP production.Treatment with 100 mg/kg HT,the above phenomena were significantly improved and the mitochondrial function was restored.In conclusion,HT has antidepressant effect in both cellular and animal depression model.In the CUMS mice depression model,HT alleviated the CUMS-induced depression-like symptoms in mice by improving the HPA axis hyperactivity,reducing oxidative stress,inhibiting neuroinflammation,increasing the content of neurotrophic factors and restoring mitochondrial function,respectively.