Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 200120, China.
Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
Chin J Integr Med. 2022 Jul;28(7):586-593. doi: 10.1007/s11655-022-3570-3. Epub 2022 Mar 23.
To investigate the therapeutic effect of Yixin Ningshen Tablet (YXNS) on comorbidity of myocardial infarction (MI) and depression in rats and explore the underlying mechanism.
The Sprague-Dawley rats were randomly divided into 5 groups with 7 rats in each group according to their weights, including control, model, fluoxetine (FLXT, 10 mg/kg), low-dose YXNS (LYXNS, 100 mg/kg), and high-dose YXNS (HYXNS, 300 mg/kg) groups. All rats were pretreated with corresponding drugs for 12 weeks. The rat model of MI and depression was constructed by ligation of left anterior descending coronary artery and chronic mild stress stimulation. The echocardiography, sucrose preference test, open field test, and forced swim test were performed. Myocardial infarction (MI) area and myocardial apoptosis was also detected. Serum levels of interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), 5-hydroxytryptamine (5-HT), adrenocorticotrophic hormone (ACTH), corticosterone (CORT), and norepinephrine (NE) were determined by enzyme linked immunosorbent assay. The proteins of adenosine 5'-monophosphate -activated protein kinase (AMPK), p-AMPK, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and nuclear respiratory factor 1 (NRF1) in heart were detected by Western blot analysis. The expression levels of TNF-α, IL-6, indoleamine 2,3-dioxygenase (IDO1), kynurenine 3-monooxygenase (KMO), and kynureninase (KYNU) in hippocampus were detected by real-time quantitative polymerase chain reaction.
Compared with the model group, the cardiac function of rats treated with YXNS improved significantly (P<0.01). Meanwhile, YXNS effectively reduced MI size and cardiomyocytes apoptosis of rats (P<0.01 or P<0.05), promoted AMPK phosphorylation, and increased PGC-1α protein expression (P<0.01 or P<0.05). HYXNS significantly increased locomotor activity of rats, decreased the levels of TNF-α, IL-6 and IL-1β, and increased the serum levels of 5-HT, NE, ACTH, and CORT (all P<0.05). Moreover, HYXNS decreased the mRNA expressions of IDO1, KMO and KYNU (P<0.05).
YXNS can relieve MI by enhancing myocardial energy metabolism. Meanwhile, YXNS can alleviate depression by resisting inflammation and increasing availability of monoamine neurotransmitters. It may be used as a potential drug to treat comorbidity of MI and depression.
探讨益心宁神片（YXNS）治疗心肌梗死（MI）合并抑郁共病大鼠的疗效及其作用机制。
将 SD 大鼠按体重随机分为 5 组，每组 7 只，分别为对照组、模型组、氟西汀（FLXT，10mg/kg）组、低剂量 YXNS（LYXNS，100mg/kg）组和高剂量 YXNS（HYXNS，300mg/kg）组。所有大鼠均用相应药物预处理 12 周。通过结扎左前降支和慢性轻度应激刺激构建 MI 和抑郁大鼠模型。进行超声心动图、蔗糖偏好试验、旷场试验和强迫游泳试验。还检测了心肌梗死（MI）面积和心肌细胞凋亡。采用酶联免疫吸附试验检测血清白细胞介素（IL）-6、IL-1β、肿瘤坏死因子-α（TNF-α）、5-羟色胺（5-HT）、促肾上腺皮质激素（ACTH）、皮质酮（CORT）和去甲肾上腺素（NE）水平。采用 Western blot 分析检测心脏中腺苷 5'-单磷酸激活蛋白激酶（AMPK）、磷酸化 AMPK（p-AMPK）、过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC-1α）和核呼吸因子 1（NRF1）的蛋白表达。采用实时定量聚合酶链反应检测海马中 TNF-α、IL-6、吲哚胺 2,3-双加氧酶（IDO1）、犬尿氨酸 3-单加氧酶（KMO）和犬尿氨酸酶（KYNU）的表达水平。
与模型组相比，YXNS 治疗大鼠的心脏功能明显改善（P<0.01）。同时，YXNS 有效减少了大鼠的 MI 面积和心肌细胞凋亡（P<0.01 或 P<0.05），促进了 AMPK 磷酸化，增加了 PGC-1α 蛋白表达（P<0.01 或 P<0.05）。高剂量 YXNS 还显著增加了大鼠的运动活动，降低了 TNF-α、IL-6 和 IL-1β 的水平，增加了血清 5-HT、NE、ACTH 和 CORT 的水平（均 P<0.05）。此外，高剂量 YXNS 降低了 IDO1、KMO 和 KYNU 的 mRNA 表达（P<0.05）。
YXNS 通过增强心肌能量代谢缓解 MI，通过抑制炎症和增加单胺神经递质的可用性缓解抑郁。它可能被用作治疗 MI 和抑郁共病的潜在药物。
