Treating myocardial infarction combined with depression via regulating M1/TNF-α/TNFR1/NF-κB

To further explore the underlying mechanism by which the traditional Mongolian medicine Anshen Buxin Liuwei Pills (ABLP) alleviates cardiac dysfunction and depressive behaviors in a model of myocardial infarction (MI) combined with depression.

Eighteen eight-week-old C57BL/6JNifdc male mice were divided into sham group (n = 6), MI + NS group (n = 6), MI + ABLP group (n = 6). Mice in the MI + ABLP group were treated with ABLP for 4 weeks. Seventeen eight-week-old wide-type (SERT^+/+) mice and reduced SERT expression (SERT^+/-) mice were allocated into SERT^+/+ NS group (n = 5), SERT^+/+ ABLP group (n = 4), SERT^+/- NS group (n = 4), and SERT^+/- ABLP group (n = 4). Mice in the SERT^+/+ ABLP and SERT^+/- ABLP group were treated with ABLP for 1 week. Open field test (OFT) and sucrose preference test (SPT) were conducted for assessing depressive behaviors. The echocardiographic measurements were taken for the left ventricle fractional shortening (LVFS), and left ventricle ejection fraction (LVEF). Masson's trichrome staining was carried out to assess pathological alterations in the mice myocardium. Spleen samples were collected for detecting macrophages (M), M1, M2 by flow cytometry. ELISA was performed on serum, cardiac, and cortical tissues to quantify levels of TNF-α, TNFR1, TNFR2, P65, IKB-α, 5-HT, and hs-TNI. RT-qPCR was implemented to quantify TNFR1 mRNA expression in cardiac, cortical, and hippocampal tissues. SPSS version 24.0 software was applied for statistic analysis.

MI mice exhibited lower level of LVEF and LVFS than the sham mice, which were elevated by ABLP treatment. MI mice displayed depressive behaviors, as evidenced by a shorter total distance, slower speed, longer immobility time, shorter activity time, reduced center distance, shorter center time, decreased center entry times, shorter peripheral distance, decreased peripheral entry times, decreased sucrose water consumption and sucrose preference than the sham group (all P < 0.05); these behavioral deficits were rescued by ABLP administration. MI mice presented elevated levels of M1 cells, cardiac TNFR1, TNF-α, IKB-α and P65 proteins and TNFR1 mRNA expression, along with reduced TNFR2 proteins, relative to the sham group. ABLP significantly decreased the concentration of M1 cells, IKB-α, P65 (P < 0.05). Both the MI + NS and MI + ABLP groups had significantly higher level of cortex TNFR1, TNF-α, IKB-α, P65 proteins and TNFR1 mRNA expression, as well as lower level of cortex TNFR2 than the sham group (P < 0.05). There were no significant differences in serum hs-TNI, LVFS, LVEF, and SPT results among SERT^+/+ NS, SERT^+/+ ABLP, SERT^+/- NS, and SERT^+/-ABLP groups (all P > 0.05). SERT^+/- NS group had longer activity time, peripheral time, shorter immobility time, center time, higher level of serum 5-HT,and lower level of cortex 5-HT than the SERT^+/+ ABLP group (P < 0.05). The concentration of M1 cells, and cortex IKB-α in SER^+/-± NS group and SER^+/-± ABLP group was significantly higher than SERT^+/+ NS, and SERT^+/+ ABLP groups (P < 0.05).

ABLP treatment exerts beneficial effects in improving cardiac dysfunction and alleviating depressive behaviors in MI mice by inhibiting the M1/TNF-α/TNFR1/NF-κB signaling pathway. The underlying inflammatory response may be associated with cortical 5-HT levels.