Saxitoxin induces progressive myocardial injury via disrupting calcium-dependent excitation-contraction coupling pathway: A biochemical, radiological, and histological evaluation

Saxitoxin (SAX) is a naturally occurring toxin that has been reported to provoke severe organ toxicity. The current investigation was conducted to explore the dose-dependent cardiotoxic effects of SAX in Sprague Dawley rats. Thirty-two rats were randomly grouped into control, SAX (325 µg/kg/day), SAX (250 µg/kg/day), and SAX (175 µg/kg/day) treated group. SAX exposure progressively upregulated the expression of SLC8A1, and CAMK2D while markedly inhibited the expression of RYR2, ATP2A2, CASQ2, CACNA1C, and PLN in dose-response manner. Moreover, SAX administration provoked redox alterations via inhibiting the activities of HO-1, SOD, GPx, GSR, GST, and CAT while augmenting the levels of ROS and MDA. Additionally, SAX exposure disrupted echocardiographic parameters such as reduced heart rate coupled with elevated thickness of posterior and septal wall and enlargement of ventricular dimensions. The serum concentrations of ProBNP, C-reactive protein, Troponin (I and T), LDH, CPK, and CK-MB were elevated following the high, moderate, and low dose of SAX. Besides, SAX exposure showed escalation in the concentrations of IL-6, TNF-α, NF-κB, IL-1β, and COX-2 in cardiac tissues in dose-dependent manners. Histopathological alterations were recorded at all the tested doses (325 µg/kg/day > 250 µg/kg/day > 175 µg/kg/day). Our computational analysis validates biochemical as well as histopathological findings. These results highlight that SAX is a potent cardiotoxic agent at low, moderate, and high dose administration thereby recommending strict regulatory policies and mitigation approaches.