The Antidepressant-like Effects Of Piperine In Ovariectomized Mice And Its Potential Mechanism

Depression is a common neurological disease.According to statistics,depression affects21%of the world's population.The core symptoms of depression include low mood,lack of pleasure,lack of interest,fatigue,insomnia and even suicide.With the increase of social pressure,the number of patients suffering from depression has also increased,and women are twice as likely as men to suffer depression,so the treatment of depression urgently needs to be overcome.Nowadays,many studies have been focused on the treatment and pathogenesis of depression,but the pathogenic factors of depression are complex and the symptoms of depression are diverse.Depression is related to gender,age,social pressure,environment,etc.In clinical treatment,depression can be treated with drugs therapy(such as monoamine oxidase inhibitors,tricyclic antidepressants,selective serotonin reuptake inhibitor,Selective Noradrenaline and Serotonin Reuptake Inhibitors,etc.)and non-drug therapy(such as cognitive behavioral therapy,electroconvulsive therapy,exercise therapy,etc.).These drugs are effective in the treatment of depression or anxiety,but most of them have disadvantages.The commonly used drugs for the treatment of depression in clinical practice have many problems such as poor efficacy,large side effects and drug interaction.In order to avoid harmful adverse reactions and improve the efficacy of drugs,current research is seeking alternatives to conventional antidepressants.Pepper has been widely used in human diets and is known for its pungency.In addition to cooking,it is also used as a preservative,insecticide and medicine.In traditional Chinese medicine,pepper can be used to treat convulsion,pain,bronchitis,rheumatism,diarrhea and fatigue,and its medicinal properties are mainly attributed to an alkaloid-piperine.Piperine,extracted from the fruits of piperine plants,is a cinnamamide alkaloid compound,and it is the quality standard component of pepper in traditional Chinese medicine.According to studies,piperine has analgesic,anti-inflammatory,anticonvulsant and antioxidant effects.At the same time,the studies of piperine in central nervous system diseases has also received widespread attention,such as epilepsy,depression,anxiety,Alzheimer's disease and Parkinson's disease.Studies have shown that piperine has antidepressant effects in male mice treated with chronic mild stress,chronic unpredictable mild stress,or corticosterone.However,whether piperine has an antidepressant effect in female mice has not been reported yet.In our studies,we constructed depression model mice by ovariectomy,and studied the effects of piperine on depression induced by ovariectomy in mice via behavioral experiment,western blotting and immunohistochemistry.First,we investigated the effect of repeated administration of piperine on depression-like behaviors in mice through forced swimming tests and open field tests.Our results revealed that piperine has no effect on the locomotor activity or rearing in mice,and repeated administration of piperine to ovariectomized female mice dose dependently reduced depression-like behavior,indicating that piperine has antidepressant-like effects in ovariectomized mice.In order to study the underlying mechanism of the antidepressant effect of piperine,the ratios of p CREB/CREB and levels of BDNF in prefrontal cortex and hippocampus were measured by western blotting.Our results revealed that the ratios of p CREB/CREB and BDNF levels in prefrontal cortex and hippocampus were decreased by ovariectomy,while piperine reversed the reduction,and ritanserin reversed the up-regulation of piperine.In order to further clarify the effect of piperine on depression-like behavior induced by ovariectomy and the mechanism of 5-HT₂receptor regulation,we used immunohistochemical experiments to investigate the c-fos expression in the prefrontal cortex and hippocampus of mice.Our results found that compared with female mice with only ovarian removal,repeated administration of piperine dose-dependently up-regulated the expression of c-fos in the Cg1,IL and Pr L(the subregions of the prefrontal cortex),and up-regulated the expression of c-fos in CA1 and DG(subregions of hippocampus).In addition,ritanserin can reverse the effect of piperine on the expression of c-fos in the subregions of prefrontal cortex and hippocampus.These findings suggest that piperine can alleviate the depression-like behavior induced by ovariectomy in a dose-dependent manner.The CREB-BDNF pathway in the prefrontal cortex and hippocampus of ovariectomized mice is partly involved in the antidepressant effect of piperine.This effect may be mediated by the activation of 5-HT₂receptors.On the other hand,piperine can increase the activation of neurons in the Cg1,IL,and Pr L subregions of the mice prefrontal cortex and the CA1 and DG subregions of the hippocampus,and then active the pathway of CREB-BDNF and finally playing an antidepressant effect.This effect may be mediated by the activation of 5-HT₂ receptors.In summary,the regulation of CREB-BDNF pathway and neural activity in the prefrontal cortex and hippocampus are partially involved in the antidepressant-like effects of piperine in ovariectomized mice,and these effects may be mediated by the activation of5-HT₂ receptors.We believe that piperine is a potential new type of antidepressant,which can reverse depression-like symptoms caused by ovariectomy.Our studies provided a theoretical basis for the antidepressant effect of piperine,but its potential mechanism remains to be studied in the further.