Abstract
Methotrexate (MTX) is a commonly used chemotherapeutic agent. Oxidative stress and inflammation have been proved in the development of MTX toxicity. Paeonol is a natural phenolic compound with various pharmacological activities including antioxidant and anti-inflammatory properties. The aim of the present study was to evaluate the protective effect of paeonol against MTX-induced cardiac toxicity in rats and to evaluate the various mechanisms that underlie this effect. Paeonol (100 mg/kg) was administered orally for 10 days. MTX cardiac toxicity was induced at the end of the fifth day of the experiment, with or without paeonol pretreatment. MTX-induced cardiac damage is evidenced by a distortion in the normal cardiac histological structure, with significant oxidative and nitrosative stress shown as a significant increase in NADPH oxidase-2, malondialdehyde, and nitric oxide levels along with a decrease in reduced glutathione concentration and superoxide dismutase activity compared to the control group. MTX-induced inflammatory effects are evidenced by the increased cardiac toll-like receptor 4 (TLR4) mRNA expression and protein level as well as increased cardiac tumor necrosis factor- (TNF-) α and interleukin- (IL-) 6 levels along with increased nuclear factor- (NF-) κB/p65 immunostaining. MTX increased apoptosis as shown by the upregulation of cardiac caspase 3 immunostaining. Paeonol was able to correct the oxidative and nitrosative stress as well as the inflammatory and apoptotic parameters and restore the normal histological structure compared to MTX alone. In conclusion, paeonol has a protective effect against MTX-induced cardiac toxicity through inhibiting oxidative and nitrosative stress and suppressing the TLR4/NF-κB/TNF-α/IL-6 inflammatory pathway, as well as causing an associated reduction in the proapoptotic marker, caspase 3.
Highlights
Methotrexate (MTX), a cytotoxic chemotherapeutic drug with folate antagonistic activity, is commonly used in the treatment of various types of malignancies such as lymphoma [1]
A phenolic compound isolated from Paeonia suffruticosa, has been shown to have a wide range of pharmacological activities including antioxidant and anti-inflammatory properties [9] that may be beneficial in various diseases such as diabetes [10], cancer [11], gastric ulcer [12], liver fibrosis [13], and myocardial infarction [14]
Paeonol has been proven to have a protection against antineoplastic-induced toxicities such as cisplatin-induced nephrotoxicity [15] and epirubicininduced cardiac toxicity [16]; to date, this role has not been investigated in MTX-induced cardiac toxicity
Summary
Methotrexate (MTX), a cytotoxic chemotherapeutic drug with folate antagonistic activity, is commonly used in the treatment of various types of malignancies such as lymphoma [1]. It is used at a low dose in the treatment of several autoimmune diseases such as rheumatoid arthritis [2]. A phenolic compound isolated from Paeonia suffruticosa, has been shown to have a wide range of pharmacological activities including antioxidant and anti-inflammatory properties [9] that may be beneficial in various diseases such as diabetes [10], cancer [11], gastric ulcer [12], liver fibrosis [13], and myocardial infarction [14]. Paeonol has been proven to have a protection against antineoplastic-induced toxicities such as cisplatin-induced nephrotoxicity [15] and epirubicininduced cardiac toxicity [16]; to date, this role has not been investigated in MTX-induced cardiac toxicity
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