有氧运动联合百合知母汤改善慢性不可预测性轻度应激小鼠抑郁样行为的作用机制OA

Objective Based on the perspective of inflammation-metabolism crosstalk,to investigate the mechanism of aerobic exercise combined with Baihe Zhimu Decoction in ameliorating depressive-like behaviors in chronic unpredictable mild stress(CUMS)mice.Methods Forty male C57BL/6 mice were randomly divided into a control group(n=8)and a disease model group(n=32).After 6 weeks of CUMS stimulation to establish a depression model,successfully modeled mice were randomly assigned to four groups including model group,aerobic exercise group,Baihe Zhimu Decoction group,and aerobic exercise combined with Baihe Zhimu Decoction group,with 8 mice in each group.The Baihe Zhimu Decoction group and aerobic exercise combined with Baihe Zhimu Decoction group received intragastric administration of Baihe Zhimu Decoction at 5.2 g/kg,while other groups received equivalent volumes of normal saline,once daily for 4 consecutive weeks.The aerobic exercise group and aerobic exercise combined with Baihe Zhimu Decoction group underwent treadmill exercise intervention(speed 10～15 m/min,treadmill grade 0°,exercise duration 60 min/d,frequency 6 d/week)for 4 consecutive weeks.The body weight of the mice was measured every two weeks;and behavioral tests were conducted at weeks 0,6,and 10 to evaluate the depressive-like behaviors of the mice;the level of interleukin-6(IL-6)was measured by ELISA;hypothalamic tissue pathological changes were observed by HE staining;IL-6 mean fluorescence intensity in the hypothalamic region was detected by immunofluorescence;hypothalamic tissue expression of IL-6,janus kinase 2(JAK2),phosphorylated janus kinase 2(p-JAK2),signal transducer and activator of transcription 3(STAT3),phosphorylated signal transducer and activator of transcription 3(p-STAT3),insulin receptor substrate 1(IRS-1),phosphorylated insulin receptor substrate 1(p-IRS-1),and glucose transporter type 4(GLUT4)proteins were detected by Western blotting.Results Compared with the control group,model group mice exhibited significant depressive-like behaviors,with decreased body weight,sucrose preference rate,total locomotor activity distance,and center area dwelling time,and prolonged immobility time in the tail suspension test(P<0.05);the level of IL-6 in the serum increased(P<0.05);the average fluorescence intensity of IL-6 in the hypothalamic region also increased(P<0.05),and the pathological damage of hypothalamic neurons was significant;increased the protein levels of IL-6,JAK2,and STAT3,and elevated the p-JAK2/JAK2 and p-STAT3/STAT3 ratios(P<0.05),decreased the protein levels of IRS-1 and GLUT4,and reduced the p-IRS-1/IRS-1 ratio(P<0.05).Compared with the model group,mice in aerobic exercise group,Baihe Zhimu Decoction group,and aerobic exercise combined with Baihe Zhimu Decoction group showed increased body weight,sucrose preference rate,total activity distance,and center area dwelling time(P<0.05),decreased immobility time(P<0.05);the level of IL-6 in the serum decreased(P<0.05);the average fluorescence intensity of IL-6 in the hypothalamic region decreased(P<0.05),and the pathological damage of hypothalamic neurons was alleviated;the levels of IL-6,JAK2,and STAT3 decreased(P<0.05),the p-JAK2/JAK2 and p-STAT3/STAT3 ratios reduced(P<0.05),the protein levels of IRS-1 and GLUT4(P<0.05)and the p-IRS-1/IRS-1 ratio increased(P<0.05).Conclusion Aerobic exercise combined with Baihe Zhimu Decoction may ameliorate depressive-like behaviors in CUMS mice,potentially through inhibiting the hypothalamic IL-6/JAK2/STAT3 inflammatory signaling pathway and thereby attenuating its suppression of the downstream IRS-1/GLUT4 pathway,leading to restoration of hypothalamic glucose transport and energy metabolism.