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A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Polyphenolic-Rich Compounds From Dillenia pentagyna (Roxb.) Attenuates the Doxorubicin-Induced Cardiotoxicity: A
Kalyani Tene1, M Kalyan Kumar2, G Basveshwar2
1Department of Biotechnology, National Institute of Pharmaceutical Education and Research- Guwahati, Assam, India.
Abstract:
Cardiovascular complications are the foremost concern in patients undergoing anticancer therapy. There is an unmet need to address the problems arising from the drug-induced toxicity for the long-term benefit of the patients undergoing chemotherapy. Alternative medicines are gaining their prosperity in addressing the various drug-induced organ toxicity. Dillenia pentagyna Roxb (DP) is an ethnomedicinal plant rich in flavonoids and phenolic contents. In India & Nepal, DP is a common ingredient of traditional medicines used to treat multiple ailments like inflammation, cancer, and diabetes. However, its protective role against doxorubicin (Dox) induced cardiotoxicity remains unexplored. Herein, we investigated the potential effects of various extracts/fractions obtained from the DP's bark against Dox-induced cardiotoxicity, both in-vitro and in-vivo. The anti-oxidant content of the extracts/fractions was evaluated by using DPPH, ABTS and FRAP chemical assays. The results indicated that the hydroalcoholic (HA) extract of DP has intense anti-oxidant potential. Further fractionation of DP revealed that the phenolic-rich fraction (F1) has a high anti-oxidant potential. The protective effect of extract/fraction was also investigated in the H9c2 cell line following the Dox-induced cardiotoxicity model. We observed that the pre-treatment of extract/fraction in cardiomyocytes had exhibited increased cell viability. Fluorescence-based chemical assays indicated a decreased ROS levels in the treated groups in comparison to the Dox control group. The effect of DP was evaluated further in balb/c mice by the Dox-induced cardiotoxicity model. Non-invasive techniques like high-frequency ultrasonography and electrocardiogram revealed that the mice pre-treated with DP had improved cardiac functionality (left ventricular ejection fraction and stroke volume) and normalized the electrocardiograms compared to the Dox control group. Further, biochemical analysis with the cardiac tissues revealed that the cytoprotective proteins like HO-1, SOD-2, and Nrf-2 were elevated in the DP treated groups compared to the Dox control group. Overall, our results suggested that the bioactive extract/fractions of DP helped alleviate the Dox-induced cardiotoxicity. LC-QTOF-ESI-MS analysis of DP and F1 indicated that polyphenolic anti-oxidant compounds like gallic acid, syringic acid, and sinapic acid could be responsible for the potent -cardioprotective effect. Future understanding of the pharmacokinetics and pharmacodynamic parameters can help translate from the bench to the bedside.
Insights
Dillenia pentagyna (DP) extract protects against doxorubicin-induced cardiotoxicity by reducing oxidative stress and improving cardiac function. This natural compound shows promise in mitigating chemotherapy side effects for cancer patients.
Area of Science:
- Pharmacology and Toxicology
- Natural Product Chemistry
- Cardiovascular Research
Background:
- Cardiovascular complications are a major concern in patients undergoing chemotherapy, necessitating strategies to mitigate drug-induced cardiotoxicity.
- Doxorubicin (Dox), a widely used anticancer agent, is known to cause significant cardiotoxicity, limiting its long-term use.
- Ethnomedicinal plants like Dillenia pentagyna (DP) are explored for their potential therapeutic benefits, including organ protection.
Purpose of the Study:
- To investigate the cardioprotective effects of Dillenia pentagyna (DP) bark extracts and fractions against doxorubicin (Dox)-induced cardiotoxicity.
- To evaluate the antioxidant potential of DP extracts and fractions using in vitro chemical assays.
- To assess the efficacy of DP in improving cardiac function and reducing oxidative stress in vivo.
Main Methods:
- DP bark extracts and fractions were prepared and their antioxidant content was assessed using DPPH, ABTS, and FRAP assays.
- In vitro studies involved evaluating cell viability and reactive oxygen species (ROS) levels in H9c2 cardiomyocytes exposed to Dox and DP pre-treatment.
- In vivo studies utilized a Dox-induced cardiotoxicity model in balb/c mice, assessing cardiac function via ultrasonography and ECG, and analyzing cardiac tissue for cytoprotective proteins.
Main Results:
- The hydroalcoholic (HA) extract and phenolic-rich fraction (F1) of DP exhibited significant antioxidant potential.
- DP pre-treatment increased cardiomyocyte viability and reduced ROS levels in vitro.
- In vivo, DP pre-treatment improved cardiac function (ejection fraction, stroke volume), normalized ECG, and elevated cardioprotective proteins (HO-1, SOD-2, Nrf-2) in Dox-treated mice.
Conclusions:
- Bioactive extracts and fractions of Dillenia pentagyna (DP) effectively alleviate doxorubicin-induced cardiotoxicity.
- The cardioprotective effects are attributed to the antioxidant properties of DP, likely mediated by polyphenolic compounds such as gallic acid, syringic acid, and sinapic acid.
- DP demonstrates potential as a complementary therapy to mitigate chemotherapy-induced cardiac damage.
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