Cardio-protective impact of gabapentin against doxorubicin-induced myocardial toxicity in rats; emphasis on modulation of inflammatory-apoptotic signaling

• Published in: International immunopharmacology 2021-01, Vol.90, p.107125, Article 107125
• Main Authors: Samra, Yara A., Amin, Mohamed N., Said, Eman
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Aspartate aminotransferase; Biomarkers; c-Jun protein; Cardiomyocytes; Cardiotoxicity; Caspase-8; CD95L; Creatine; Creatine kinase; Disease Models, Animal; Doxorubicin; EKG; Electrocardiography; FasL protein; Gabapentin; Gabapentin - pharmacology; Heart Diseases - chemically induced; Heart Diseases - metabolism; Heart Diseases - physiopathology; Heart Diseases - prevention & control; Heart rate; Heart Rate - drug effects; Inflammation; Inflammation Mediators - metabolism; Injuries; JNK; JNK protein; Kinases; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Male; Myocardium; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Oral administration; Oxidative Stress - drug effects; Physical characteristics; Rats; Rats, Wistar; Signal Transduction; Signaling; Toxicity; TRAIL; Transcription factors; γ-Aminobutyric acid
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2020.107125

•Gabapentin revealed a cardio-protective impact against doxorubicin-induced myocardial injury.•Gabapentin improved the heart rate, ST segment elevation, QRS and T wave's amplitudes, QT and PR intervals.•Myocardial injury and myocardial oxidative status significantly improved with gabapentin.•Gabapentin reduced myocardial contents of cJNK; caspase-8, TRAIL, JNK 1/2 and CD95L.•Gabapentin preserved morphological characteristics of isolated cardiomyocytes and spontaneous beating characteristics. Cardiotoxicity is one of the most commonly encountered adverse effects observed alongside the therapeutic use of doxorubicin (DOX), thus curbing its therapeutic utility. The current study was conducted to evaluate the cardioprotective effect of gabapentin (Gaba), a Ca + 2 channel blocker with emerging pharmacological merits, against DOX-induced cardiotoxicity. Gaba was orally administered at two dose levels (10 and 30 mg/kg) for 21 days parallel to DOX injection. DOX induced significant functional, biochemical, and histopathological injury to the myocardium. Gaba treatment revealed a cardioprotective effect as manifested in the significant restoration of electrocardiogram parameters, including the heart rate, ST segment elevation, QRS and T wave amplitudes, and QT and PR intervals. The biomarkers of myocardial injury, namely serum creatine kinase, aspartate aminotransferase, and lactate dehydrogenase activities, significantly declined as well as the concomitant improvement of the myocardial oxidative status. Mechanistically, Gaba treatment significantly reduced the myocardial contents of c-Jun N-terminal kinase (JNK), the major modulator of inflammatory/apoptotic signaling. However, the myocardial contents of the apoptotic biomarkers caspase-8 and TRAIL also significantly declined. In isolated cardiomyocytes, Gaba treatment maintained the morphological characteristics of the cardiomyocytes and preserved their spontaneous beating characteristics. Nevertheless, the protein expression of caspase-8, JNK 1/2, and CD95L significantly declined with Gaba treatment. Gaba confers cardioprotective effects against DOX-induced myocardial injury and cardiotoxicity by modulating the inflammatory/apoptotic signaling pathway.