Paeoniflorin Ameliorates Depressive-like Behavior In Prenatally Stressed Offspring Through The HPA Axis And GR

Background: Depression is an affective disorder.The World Health Organization predicts that depression may be the top ten mental illness in the world by 2030.Depression will cause serious harm to human physical and mental health.It has been reported that stress can significantly increase the sensitivity of individuals to depression.Stress experiences in the early stages of life are more likely to damage health.For example,prenatal stress(PS)can cause offspring to be born with low birth weight,delayed brain development,and lead to mental illness such as depression and decreased learning and memory in offspring.Paeoniflorin(PA)is an amorphous glycoside isolated from the root water extracts of peony and white peony plants.Studies have found that it has a variety of pharmacological effects in the nervous system.It can not only increase the proliferation of neural stem cells and the formation of neurospheres,but also maintain the normal morphology of the nerve cell skeleton and inhibit cell apoptosis.Objective: To investigate the effect and mechanism of PA on the depression-like behavior of PS offspring rats and provide experimental evidence for the treatment of depression and the development of new drugs.Methods: Pregnant rats were used for restraint stress to construct a depression-like model of male PS offspring rats to study the antidepressant effect and mechanism of PA.Male PS offspring rats were weaned 21 days later and were divided into control group,model(PS)group,PA low-dose group(PA-L,15 mg/kg /day),PA medium-dose group(PA-M,30 mg/kg /day),PA high-dose group(PA-H,60 mg/kg /day),fluoxetine group(FLX,20 mg/kg /day),intragastric administration for 4 weeks.Subsequently,we measured,sucrose preference test,open field test,forced swimming experiments,Nissil staining,immunohistochemical assay for neurogranin(Ng)and enzyme-linked immunosorbent assay(ELISA)for hypothalamic-pituitary-adrenal(HPA)axis and Glutamate(Glu).In addition,we evaluated the regulation of hippocampal glucocorticoid receptor(GR)nuclear translocation and SNARE complex expression by Western Blot.At the same time,we also constructed a SH-SY5 Y excitatory neurotoxicity model induced by Glu,and examined the protective effect of PA on nerve cells by measuring cell viability,mitochondrial membrane potential,reactive oxygen species(ROS),and cell apoptosis.Results: The results showed that administration of PA(15,30,and 60 mg/kg/day,i.g.)for 28 days markedly increased sucrose intake and decreased the immobility time and the total number of crossings,center crossings,rearing,and grooming in male PS offspring.In addition,PA significantly reduced the serum levels of corticosterone(CORT),adrenocorticoid hormone(ACTH),corticotropin releasing hormone(CRH)and hippocampal Glu in male PS offspring rats,which were stimulated by an increase of GR nuclear translocation.In addition,PA significantly increased the number of neurons in the hippocampal CA3 area of male PS rats and the expression of Ng protein.PA also inhibits the expression of SNAP25,VAMP2,Syntaxin1 a and related proteins,the formation of SNARE complex,and the expression of NR1,NR2 A and FKBP5 proteins,thereby significantly reducing the concentration of Glu in the hippocampus.The results of in vitro cell experiments show that PA can significantly increase the cell viability of SH-SY5 Y induced by Glu,reduce the decrease of mitochondrial membrane potential and the production of intracellular ROS,inhibiting apoptosis and exerting neuroprotective effects.Conclusion: In summary,the results of this study show that PA can play an antidepressant-like effect by improving HPA axis activity,GR dysfunction and Glu transport system in male PS offspring rats.