Cardioprotective potential of azaleatin against sodium arsenite instigated sub-chronic cardiotoxicity via targeting TLR4/MyD88, JAK1/STAT3, and NF-κB in Sprague Dawley rats

Abstract

Background

Sodium arsenite (SA) is a potent carcinogenic compound which is evident to prompt multiple organs damage including the heart. Azaleatin (AZA) is a novel therapeutic agent with excellent biological properties.

Objectives

The current investigation was executed to evaluate the mitigative efficacy of AZA against SA induced sub-chronic cardiotoxicity in rats through the evaluation of biochemical and histological parameters.

Methodology

Thirty-two rats were apportioned into control, SA (10 mg kg⁻¹), SA (10 mg kg⁻¹) + AZA (25 mg kg⁻¹), and AZA (25 mg kg⁻¹) exposed group. Biochemical parameters were evaluated through different techniques including qRT-PCR, ELISA and already reported standard assays. Histological analysis was performed to validate the tissue damage. The curative potential of AZA was re-validated through in-silico approaches.

Findings

SA intoxication upregulated the expression of nuclear factor-kappa B (NF-κB), myeloid differentiation primary response 88 (MyD88), janus kinase 1 (JAK1), toll-like receptor 4 (TLR4), tumor necrosis factor-α (TNF-α), signal transducer and activator of transcription 3 (STAT3), interleukin-1β (IL-1β), interleukin-6 (IL-6), & cyclooxygenase-2 (COX-2) while increasing the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Moreover, the enzymatic activities glutathione peroxidase (GPx), glutathione reductase (GSR), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), heme-oxygenase-1 (HO-1) and glutathione (GSH) were lowered whereas the levels of Troponin I, ProBNP, C-reactive protein, LDH, troponin-T, BNP and CPK were exacerbated following the SA exposure. Furthermore, SA intoxication promoted the levels of Bax, Caspase-9, and Caspase-3 while lowering the levels of Bcl-2. Cardiac tissues showed impaired histology after SA administration. Nonetheless, AZA therapy excellently ameliorated cardiac toxicity owing to its anti-inflammatory, antioxidative and anti-apoptotic potential.

Conclusion

SA intoxication induced severe cardiac toxicity via disrupting biochemical and histological parameters while AZA excellently restored cardiac health profile. Collectively, AZA may serve as a cardioprotective agent in counteracting SA induced sub-chronic cardiotoxicity.