Zingerone Attenuates Carfilzomib-Induced Cardiotoxicity in Rats through Oxidative Stress and Inflammatory Cytokine Network

Abstract

Carfilzomib (CFZ) is an anticancer medication acting as a selective proteasome inhibitor. However, it can cause cardiovascular problems, increasing mortality and morbidity. This study aimed to investigate whether zingerone (ZRN) could help reduce carfilzomib-induced cardiotoxicity in Wistar albino rats. Rats were divided into five groups of six animals each. The first group received normal saline as a control (NC); the second group received multiple doses (six) of CFZ (4 mg/kg) intraperitoneally (IP); the third and fourth groups received zingerone (50 mg/kg and 100 mg/kg oral) along with six doses of CFZ for 16 days; and the fifth group received only 100 mg/kg zingerone orally. Hematological, biochemical, oxidative stress, and histopathological studies confirmed the findings of CFZ-induced cardiotoxicity. We found that ZRN significantly attenuated the effects of CFZ on oxidative stress by enhancing the antioxidant properties of glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Additionally, ZRN reduces inflammatory cytokines and apoptotic markers, such as IL-1β, IL-6, TNFα, and caspase-3. Overall, zingerone prevents carfilzomib-induced cardiotoxicity in rats, as evidenced by histopathological studies.

Keywords: apoptosis; cardiotoxicity histopathology; carfilzomib; cytokines; oxidative stress; zingerone.

Figure 1

(A,B) The effects of zingerone on lactate dehydrogenase (LDH) and creatinine kinase (CKI) after carfilzomib administration in rats. Data are represented as means ± sd (n = 8). The level of LDH and CKI increased significantly (**** p < 0.0001) in CFZ, as compared to NC. While the treatment with zingerone reduced these markers significantly (**** p < 0.0001), as compared to CFZ administrations. No changes were found in zingerone alone treatment, except in CKI. In CKI, zingerone alone treatment was significantly high, as compared to normal controls. Abbreviations: NC: Normal control, CFZ: Carfilzomib, ZRN: Zingerone.

Figure 2

(A–D) The effect of zingerone on oxidative stress after carfilzomib administration in rats. Data are represented as the mean ± sd (n = 8). The contents of MDA increase significantly (**** p < 0.0001) in CFZ as compared to NC after carfilzomib administration. Reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) were significantly reduced (**** p < 0.0001) after CFZ administrations. The pretreatment of zingerone significantly decreased in MDA level and significantly enhanced in antioxidants such as reduced glutathione, catalase, and superoxide dismutase. There were no significant changes seen with high-dose treatments of zingerone alone in LPO, GSH, CAT, and SOD. Abbreviations: NC: Normal control, CFZ: Carfilzomib, ZRN: Zingerone.

Figure 3

(A–D) The effects of zingerone on inflammatory and apoptotic markers such as IL-1β, IL-6, TNFα, and caspase-3 after CFZ administration in rats. Data are represented as the mean ± sd (n = 8). The concentrations of IL-1β, IL-6, TNFα, and caspase-3 were increased significantly (**** p < 0.0001) in CFZ as compared to NC. Pretreatment of zingerone also showed significantly (**** p < 0.0001) decreased IL-1β, IL-6, TNFα, and caspase-3 content in ZRN50 + CFZ and ZRN100 + CFZ, as compared to CFZ. There were no significant changes seen in zingerone alone treatment (ns p > 0.05) as compared to NC, except TNFα. Abbreviations: NC: Normal control, CFZ: Carfilzomib, ZRN: Zingerone, IL-1β: Interleukin beta, IL-6: Interleukin six, TNFα: Tumor necrosis factor alpha.

Figure 4

(A–F) Effects of zingerone on carfilzomib-induced myocardial histopathology of different experimental groups represented in hematoxylin and eosin (HE) staining. (A) NC with normal myocardium morphology, score—0; (B) CFZ changes heart histology with loss of myofibrils and cytoplasmic vacuolization score—3; (C,D) heart myocardial lesion was improved with zingerone treatment (50 and 100 mg/kg) score—2 and score—1; and (E) zingerone did not alter the morphology of myocardium score—0. (F) The myocardial injury score in all groups with significant injury ** p < 0.0021 vs. CFZ, **** p < 0.0001 vs. NC, ^ns p > 0.0921. Abbreviations: NC: Normal control, CFZ: Carfilzomib, ZRN: Zingerone.