Eyüp AYDOĞAN, İshak Suat ÖVEY, Oğuz KARAHAN
Neuro-Cell Molecular Research - 2026;3(1):13-19
Bupivacaine, a widely used local anesthetic, induces cardiotoxicity through mitochondrial dysfunction, oxidative stress, and apoptosis. However, the role of TRPV1 channels in this process and the potential protective effect of melatonin remain elucidated. We hypothesised that melatonin mitigates bupivacaine-induced cardiotoxicity by attenuating TRPV1-mediated apoptosis, ROS production, and mitochondrial depolarization in human cardiomyocytes. Human cardiomyocytes were divided into the following experimental groups: control, bupivacaine (1 mM, 24 h), bupivacaine+melatonin (50 muM), bupivacaine+melatonin+capsazepine (a TRPV1 antagonist, 0.1 mM), bupivacaine+capsazepine, and capsaicin (a TRPV1 agonist) groups. Apoptosis was quantified using the APOPercentage assay, while intracellular ROS levels and mitochondrial membrane potential were assessed using Dihydrorhodamine 123 and JC-1 staining, respectively. Bupivacaine administration significantly increased apoptosis, ROS levels, and mitochondrial depolarization compared to control group (p<0.001). Co-treatment with melatonin markedly attenuated all three parameters (p<0.001 vs bupivacaine). The TRPV1 antagonist capsazepine further enhanced the protective effect, whereas the TRPV1 agonist capsaicin exacerbated bupivacaine-induced injury (p<0.001). Our findings demonstrate that bupivacaine activates TRPV1 channels, leading to calcium overload, ROS burst, mitochondrial depolarization, and apoptosis. Melatonin mitigates these effects by modulating TRPV1-dependent pathways, which is consistent with previous reports on digoxin-induced cardiotoxicity and melatonin's antioxidant properties. Melatonin effectively protects human cardiomyocytes against bupivacaine-induced cardiotoxicity by attenuating TRPV1-mediated apoptosis, ROS production, and mitochondrial depolarization. This novel mechanism suggests that melatonin may serve as a potential adjunctive therapy to prevent local anesthetic-induced cardiac toxicity. Further in vivo studies are warranted to confirm these findings.
