Abdelrahim Alqudah , Esam Qnais , Yousra Bseiso , Sireen Abdul Rahim Shilbayeh , Alaa A.A. Aljabali , Omar Gammoh
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引用次数: 0
Abstract
Background
Doxorubicin (DOX) clinical utility is limited by its dose-dependent cardiotoxicity. This study aimed to evaluate the cardioprotective potential of 2′,3,3,5′-Tetramethyl-4′-nitro-2′H-1,3′-bipyrazole (TMNB) in a rat model of DOX-induced cardiac injury.
Methods
Rats were divided into control, DOX, TMNB, and TMNB + DOX groups. TMNB was administered for 14 days. A single dose of DOX was given on day 7. Serum, oxidative stress, cytokines, apoptosis markers, and Nrf2 pathway gene expression were assessed. One-way ANOVA followed by Tukey's post-hoc test were used.
Results
TMNB pretreatment reduced CK-MB and LDH levels by 42.9 % and 50 %, respectively (Cohen's d > 6.4, p < 0.001). Histologically, TMNB significantly reduced myocardial damage (d = 6.63). MDA levels declined by 45.1 % in TMNB-treated rats (d = 7.18), while antioxidant enzymes SOD and CAT increased by 99.4 % and 74.1 %, respectively (p < 0.001). TMNB restored GSH and GPx-1 levels, reversing DOX-induced oxidative depletion (all d > 4.7). Pro-inflammatory cytokines TNF-α and IL-1β were reduced with TMNB pretreatment by over 40 % (d > 9.3, p < 0.001). Similarly, TMNB significantly downregulated NF-κB gene expression (d = 9.46). Caspase-3 and Bax were reduced by 44.9 % and 65.5 %, respectively (p < 0.001), while Bcl-2 expression was restored. TUNEL staining confirmed reduced apoptosis (d = 11.20). TMNB increased Nrf2, HO-1, and NQO1 expression (Nrf2 d = 8.21) while decreasing Keap1 (p < 0.0001).
Conclusion
TMNB significantly mitigates DOX-induced cardiotoxicity likely via Nrf2 pathway activation. These findings support TMNB's potential as a cardioprotective adjunct during chemotherapy, warranting further investigation in chronic and clinical models.
期刊介绍:
The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems.
The scope includes:
Behavioural pharmacology
Neuropharmacology and analgesia
Cardiovascular pharmacology
Pulmonary, gastrointestinal and urogenital pharmacology
Endocrine pharmacology
Immunopharmacology and inflammation
Molecular and cellular pharmacology
Regenerative pharmacology
Biologicals and biotherapeutics
Translational pharmacology
Nutriceutical pharmacology.