Elnoury Heba A, Elgendy Salwa A, Baloza Samar H, Ghamry Heba I, Soliman Mohamed, Abdel-Aziz Eman Abdel-Mohsen
Department of Pharmacology, Faculty of Medicine, Benha University, Benha 13511, Egypt.
Genetic and Genetic Engineering, Animal Wealth Development Department, Faculty of Veterinary Medicine, Benha University, Benha 13736, Egypt.
Toxicol Res (Camb). 2022 Jun 20;11(4):592-604. doi: 10.1093/toxres/tfac023. eCollection 2022 Aug.
Doxorubicin (DOX) is a powerful antitumor agent with a well-known cardiaotoxic side effects. In the current study, the ameliorative combined impacts of montelukast (Mont) and Klotho against doxorubicin-induced cardiac toxicity were examined. Fifty-six adult male rats (2 months age and weighting 150-200 g) were grouped into 7 groups (8 rats per group). Animals received doxorubicin alone or in combination with either Mont or Klotho. After 2 weeks of treatments, serum samples were examined to assess the changes in cardiac activity biomarkers such as LDH, CK-MB, cardiac troponin-I (cTn-I), and heart fatty acid binding protein (H-FABP). Serum changes of IL-6, inducible nitric oxide synthase (iNOS), and caspase-3 levels were assayed. The oxidative stress biomarkers such as total antioxidant capacity (TAC) and inflammatory (rat IL-1β and rat TNF-α,) and anti-inflammatory (rat IL-10) cytokines were examined. Heart histology and transforming growth factor-β1 (TGF-β1) immunoreactivity were measured. DOX induced cardiomyopathy, which was reflected by the increases in all examined cardiac parameters. Real-time PCR confirmed that DOX upregulated the expression of TNF-α and IL-1β and decreased the expression of IL-10. Moreover, DOX showed marked elevation in the ST segment T wave complex, causing profound tachycardia. Heart histology assessments showed cardiac cell necrosis, inflammatory cell infiltration, interstitial congestion, and increased TGF-β1 immunoreactivity. Montelukast and Klotho administration ameliorated all the altered parameters when administered alone or in combination to DOX-intoxicated rats. Klotho was more effective compared with montelukast in terms of reductions in heart rate, ST segment T wave complex elevation, cardiac enzymes (lactate dehydrogenase; LDH, creatine kinase-MB; CK-MB, cardiac troponin I; cTn-I, heart fatty acid binding protein; H-FABP) cardiac histology, and caspase-3 levels and increases in TAC activity. Montelukast was more effective in reducing serum levels of IL6 and iNOS, expression of TNF-α and IL-1β, and the upregulation of IL-10 expression. The co-administration of both drugs led to significantly more synergistic results in terms of reducing cardiac toxicity. In conclusion, montelukast and Klotho either alone or in combination were confirmed to be effective in suppressing DOX-induced cardiac toxicity in rats.
多柔比星（DOX）是一种强效抗肿瘤药物，具有众所周知的心脏毒性副作用。在本研究中，研究了孟鲁司特（Mont）和α-klotho蛋白对多柔比星诱导的心脏毒性的改善联合作用。将56只成年雄性大鼠（2月龄，体重150 - 200 g）分为7组（每组8只）。动物单独接受多柔比星或与孟鲁司特或α-klotho蛋白联合使用。治疗2周后，检测血清样本以评估心脏活性生物标志物的变化，如乳酸脱氢酶（LDH）、肌酸激酶同工酶（CK-MB）、心肌肌钙蛋白I（cTn-I）和心脏脂肪酸结合蛋白（H-FABP）。检测白细胞介素-6（IL-6）、诱导型一氧化氮合酶（iNOS）和半胱天冬酶-3水平的血清变化。检测氧化应激生物标志物，如总抗氧化能力（TAC）以及炎症（大鼠IL-1β和大鼠肿瘤坏死因子-α，TNF-α）和抗炎（大鼠IL-10）细胞因子。测量心脏组织学和转化生长因子-β1（TGF-β1）免疫反应性。多柔比星诱导了心肌病，这通过所有检测的心脏参数增加得以体现。实时聚合酶链反应（PCR）证实多柔比星上调了TNF-α和IL-1β的表达并降低了IL-10的表达。此外，多柔比星使ST段T波复合波明显升高，导致严重心动过速。心脏组织学评估显示心肌细胞坏死、炎症细胞浸润、间质充血以及TGF-β1免疫反应性增加。单独或联合给予多柔比星中毒大鼠孟鲁司特和α-klotho蛋白可改善所有改变的参数。在降低心率、ST段T波复合波升高、心脏酶（乳酸脱氢酶；LDH、肌酸激酶同工酶；CK-MB、心肌肌钙蛋白I；cTn-I、心脏脂肪酸结合蛋白；H-FABP）、心脏组织学和半胱天冬酶-3水平以及增加TAC活性方面，α-klotho蛋白比孟鲁司特更有效。孟鲁司特在降低血清IL-6和iNOS水平、TNF-α和IL-1β的表达以及上调IL-10表达方面更有效。两种药物联合使用在降低心脏毒性方面产生了显著更多的协同效果。总之，孟鲁司特和α-klotho蛋白单独或联合使用均被证实可有效抑制大鼠多柔比星诱导的心脏毒性。
