The Antidepressant-like Effect And Mechanism Of Genistein

Depression is a chronic and recurrent mental disorder,which is recognized as one of the most common Psychiatric illnesses in humans.The prevalence of depression is about 2%-3%in general population,but the incidence doubles among postmenopausal women.A major factor underlying this scenario may be the reduction of estrogen levels in postmenopausal women.Estrogen replacement therapy(ERT) can be used to reverse the condition.Unfortunately,ERT is accompanied by many undesirable side effects,a significant concern of which is its proliferative effects on uterus and breasts.Genistein,an isoflavone phytoestrogen,is abundant in soybean products and occurs naturally in the diet.It has structure similar to estradiol and can bind to estrogen receptors(ERs),with a greater affinity for ERβthan ERα.It displays both estrogen agonist and antagonist properties,depending on the estrogen environment.Genistein has been widely studied due to its effects on cancer, osteoporosis and cardiovascular diseases,as well as its use to attenuate menopausal symptoms.However,to our knowledge there have been no reports on the influence of genistein on the depression.Therefore in our study,we propose to research the antidepressant-like effect and mechanism of genistein in ovariectomized mice.In our study,we used the ovariectomy(OVX)model,which mimic the reduction of estrogen levels in postmenopausal women;and two well-validated behavioral despair paradigms—the tail suspension test(TST)and the forced swim test(FST), which were widely used for the screening of antidepressant treatments,to assess the potential antidepressant-like effect of genistein.The results demonstrated that the immobility time in both behavioral models was significantly reduced by genistein at 12.5,25,50,and 100 mg/kg doses in the present study.And the maximum efficiency of genistein(50 mg/kg)was similar to what were seen in the sham-group and fluoxetine(10 mg/kg);low doses of genistein(8 mg/kg)and fluoxetine(2.5 mg/kg) have no effect on the immobility time in the FST.Moreover,the body weight gain and the reduction of locomotor activity induced by the reduction of estrogen levels were not reversed after injection of any dose of genistein.To further investigated the mechanisms,pretreatment of mice with ICI 182,780(2μg/mouse,i.c.v.,a nonselective estrogen receptor antagonist)significantly reversed the antidepressant-like effect of genistein(50 mg/kg)in the TST.Similarly,pretreatment with WAY-100635(1 mg/kg,s.c.,a 5-HT_1Areceptor antagonist)also reverse the effect.However,methyl-piperidino -pyrazole(MPP,10μg/mouse,i.c.v.,a specific ERαantagonist)has no effect.The combination of a sub-optional dose of genistein with fluoxetine resulted in a clear antidepressant-like effect;pretreatment of mice with WAY-100635 significantly reversed the effect.Take together;our findings suggest that genistein elicits a significant antidepressant effect via the ERβand 5-HT_1Areceptor system.