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Cardioprotective Effects of Oroxylum indicum Extract Against Doxorubicin and Cyclophosphamide-Induced Cardiotoxicity

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Abstract

Administration of Chemotherapeutics, especially doxorubicin (DOX) and cyclophosphamide (CPS), is commonly associated with adverse effects such as myelosuppression and cardiotoxicity. At this time, few approved therapeutic options are currently available for the management of chemotherapy-associated cardiotoxicity. Thus, identification of novel therapeutics with potent cardioprotective properties and minimal adverse effects are pertinent in treating Doxorubicin and Cyclophosphamide-induced cardiotoxicity. Oroxylum indicum extract (OIE, Sabroxy®) is a natural product known to possess several beneficial biological functions including antioxidant, anti-inflammatory and cytoprotective effects. We therefore set to investigate the cardioprotective effects of OIE against Doxorubicin and Cyclophosphamide-induced cardiotoxicity and explore the potential cardioprotective mechanisms involved. Adult male mice were treated with DOX and CPS in combination, OIE alone, or a combination of OIE and DOX & CPS. Swimming test was performed to assess cardiac function. Markers of oxidative stress were assessed by levels of reactive oxygen species (ROS), nitrite, hydrogen peroxide, catalase, and glutathione content. The activity of interleukin converting enzyme and cyclooxygenase was determined as markers of inflammation. Mitochondrial function was assessed by measuring Complex-I activity. Apoptosis was assessed by Caspase-3 and protease activity. Mice treated with DOX and CPS exhibited reduced swim rate, increased oxidative stress, increased inflammation, and apoptosis in the heart tissue. These cardiotoxic effects were significantly reduced by co-administration of OIE. Furthermore, computational molecular docking studies revealed potential binding of DOX and CPS to tyrosine hydroxylase which validated our in vivo findings regarding the inhibition of tyrosine hydroxylase activity. Our current findings indicated that OIE counteracts Doxorubicin and Cyclophosphamide-induced cardiotoxicity—through inhibition of ROS-mediated apoptosis and by blocking the effect on tyrosine hydroxylase. Taken together, our findings suggested that OIE possesses cardioprotective effects to counteract potentially fatal cardiac complications associated with chemotherapy treatment.

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Authors and Affiliations

  1. Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, 36849, USA

    Satyanarayana R. Pondugula, Kodye L. Abbott & Julia M. Salamat

  2. Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA

    Aisha Harshan, Sindhu Ramesh, Manoj Govindarajulu, Mohammed Almaghrabi, Rishi Nadar, Mansour Alturki, Forrest Smith, Timothy Moore & Muralikrishnan Dhanasekaran

  3. Sabinsa Corporation, 20 Lake Drive, East Windsor, NJ, 08520, USA

    Muhammed Majeed & Kalyanam Nagabhushanam

  4. Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 200032, China

    Jun Ren

  5. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98195, USA

    Jun Ren

  6. Department of Pharmacology, Faculty of Medicine, University of Jeddah, Jeddah, 23881, Saudi Arabia

    Mohammed Majrashi

  7. Department of Medicinal Chemistry, College of Pharmacy, Taibah University, Medina, Saudi Arabia

    Mohammed Almaghrabi

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  1. Satyanarayana R. Pondugula
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Correspondence to Satyanarayana R. Pondugula or Muralikrishnan Dhanasekaran.

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Pondugula, S.R., Harshan, A., Ramesh, S. et al. Cardioprotective Effects of Oroxylum indicum Extract Against Doxorubicin and Cyclophosphamide-Induced Cardiotoxicity. Cardiovasc Toxicol 22, 67–77 (2022). https://doi.org/10.1007/s12012-021-09701-x

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