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Thymoquinone dose-dependently attenuates myocardial injury induced by isoproterenol in rats via integrated modulations of oxidative stress, inflammation, apoptosis, autophagy, and fibrosis

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Abstract

As rats develop myocardial infarction (MI) like lesions when injected with large doses of isoproterenol (ISO), this investigation was designed to evaluate the dose-dependent effects of thymoquinone (TQ) on ISO-induced myocardial injury in rats. Adult male rats were divided into negative control, TQ20 (20 mg/kg/day), TQ50 (50 mg/kg/day), ISO positive control, TQ20 + ISO, and TQ50 + ISO groups. In these rats, biochemical, immunobiochemical, and histopathological studies were carried out to evaluate myocardial oxidative stress, inflammation, apoptosis, fibrosis, and autophagy, and the changes in serum cardiac biomarkers. The results showed that TQ pretreatment in ISO-administered rats produced a dose-dependent significant reduction of the myocardial infarct size, markedly reduced the ISO-induced elevation in serum cardiac markers and demonstrated several other important findings related to the cardioprotective efficacy of TQ. First, this study is the first reported research work showing that TQ treatment could increase the myocardial reduced glutathione baseline level, adding an indirect antioxidant effect to its known direct free radical scavenging effect. Second, pretreatment with TQ significantly reduced the markers of myocardial oxidative stress, inflammation, fibrosis, and apoptosis. Third, TQ acted as an autophagy enhancer ameliorating myocardial cell damage and dysfunction. Thus, the morphological and biochemical changes associated with ISO-induced myocardial injury were ameliorated with TQ pretreatment. The extent of this improvement was significantly greater in the TQ50 + ISO group than in the TQ20 + ISO group. The present study, for the first time, demonstrates these dose-dependent effects of TQ in experimentally induced myocardial injury. These findings raise the possibility that TQ may serve as a promising prophylactic cardioprotective therapy for patients who are at risk of developing myocardial injury and against the progression of existent myocardial injury as in cases of MI.

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Authors and Affiliations

  1. Department of Pharmacology, Medical Research Institute, Alexandria University, 165 El-Horria Avenue, P.O. El-Hadara 21561, Alexandria, Egypt

    Mahmoud M. Farag, Asmaa A. Khalifa & Wessam F. Elhadidy

  2. Department of Pathology, Medical Research Institute, Alexandria University, Alexandria, Egypt

    Radwa M. Rashad

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  1. Mahmoud M. Farag
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  2. Asmaa A. Khalifa
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Contributions

M.M.F. conceived the idea of this work and made its design. A.A.K. and W.F.E. conducted the experimental work. R.M.R. carried out the histopathological work. M.M.F. analyzed and interpreted the data and wrote the article. All authors read and approved the article before submission. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Mahmoud M. Farag.

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The protocol of this study was approved by the Animal Care and Use Committee of the Medical Research Institute, Alexandria University (Alexandria, Egypt). All experimental procedures related to the rats were carried out according to the instructions of the European Directive 2010/63/EU for animal experimentation and the guidelines of the Animal Care and Use Committee, Medical Research Institute, Alexandria University.

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Supplementary file1 Excel files showing original data (XLSX 28 KB)

210_2021_2087_MOESM2_ESM.docx

Supplementary file2 Myocardial infarction area measurement and determination of microtubule-associated protein light chain 3 (LC3) level (DOCX 370 KB)

Supplementary file3 Checking the normality of data using Shapiro-Wilk test (DOCX 22 KB)

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Farag, M.M., Khalifa, A.A., Elhadidy, W.F. et al. Thymoquinone dose-dependently attenuates myocardial injury induced by isoproterenol in rats via integrated modulations of oxidative stress, inflammation, apoptosis, autophagy, and fibrosis. Naunyn-Schmiedeberg's Arch Pharmacol 394, 1787–1801 (2021). https://doi.org/10.1007/s00210-021-02087-1

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