Synergistic impacts of Montelukast and Klotho against doxorubicin-induced cardiac toxicity in Rats

摘要

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-1 beta and rat TNF-alpha,) and anti-inflammatory (rat IL-10) cytokines were examined. Heart histology and transforming growth factor-beta 1 (TGF-beta 1) 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-alpha and IL-1 beta 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-beta 1 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-alpha and IL-1 beta, 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.