Simvastatin cardioprotection in cyclophosphamide-induced toxicity via the modulation of inflammasome/caspase1/interleukin1β pathway

Abstract

Drug-induced cardiotoxicity is a serious adverse effect that occurs during the administration of chemotherapeutic agents such as cyclophosphamide (CYC). Therefore, there is a critical need to find cardioprotective agents to keep the heart healthy. The current study aimed to investigate the protective effect of simvastatin (SIM) against CYC-induced heart damage and evaluate different mechanisms involved in mediating this effect, including the inflammasome/caspase1/interleukin1β (IL1β) pathway and endothelial nitric oxide synthase (eNOS). 36 rats were randomly assigned to one of four groups: a control group that received only vehicles, a CYC group that received CYC (150 mg/kg/day) i.p. on the fourth and fifth days, a CYC+SIM group that received SIM (10 mg/kg/day) orally for 5 days and CYC (150 mg/kg/day) i.p. on the fourth and fifth days, and a CYC+SIM+ Nitro- ω-L-arginine (L-NNA) group that received L-NNA (25 mg/kg/day, SIM (10 mg/kg/day) orally for 5 days and CYC (150 mg/kg/day) i.p. on the 4th and 5th days. The CYC group revealed an obvious elevation in cardiac enzymes and heart weights with toxic histopathological changes. Moreover, there was an increase in malondialdehyde (MDA), tumor necrosis factor-alpha (TNFα) levels, and up-regulation of the NLRP3inflammasome/caspase1/IL1β pathway. In addition, total antioxidant capacity (TAC), eNOS, reduced glutathione (GSH), and superoxide dismutase (SOD) significantly decreased. CYC-induced cardiotoxicity was most properly reversed by SIM through its anti-oxidant, anti-inflammatory, and anti-apoptotic actions with the stimulation of eNOS. The co-administration of L-NNA diminished the protective effect of SIM, indicating the essential role of eNOS in mediating this effect. Therefore, SIM ameliorated CYC-induced cardiotoxicity.

Adipose Tissue-Mesenchymal Stem Cells Improve Cisplatin-Induced Cardiotoxicity in Rats Via Modulating Apoptosis, Oxidative Stress, Inflammation, and Angiogenesis

“…Similar results were obtained by other cytotoxic drugs on the myocardium as cyclophosphamide (Refaie, El-Hussieny et al 2022) or doxorubicin (Pınarlı, Turan et al 2013, Huang, Lei et al, 2022 due to the toxic effects of these drugs in addition to the associated myocardial ischemia that leads to chromosomal aberrations, cardiac cell death, and apoptosis.…”

Simvastatin Significantly Reduced Alcohol-Induced Cardiac Damage in Adolescent Mice

“…In addition, Simvastatin is also effective against several toxins such as cyclophosphamide-induced toxicity via the modulation of inflammasome/caspase1/interleukin 1β [ 50 ], lipopolysaccharide-induced myocardial injury by up-regulating survivin that inhibits caspase-3 activation [ 51 ] and Ischemia–reperfusion-induced myocardial damage by reducing oxidative stress [ 52 ]. Considering the ability of Simvastatin to protect cardiac tissues from being damaged by toxins, it became necessary to explore its effectiveness against alcohol-induced cardiomyocyte damage and it is not surprising that the present study found that both Simvastatin concentrations (5 mg or 15 mg) significantly reduced alcohol-induced cardiomyocyte hypertrophy, cardiac fibrosis, and inflammation, whilst the administration of Simvastatin alone did not seem to be toxic to the cardiac tissues.…”

Cyclophosphamide: Potential Hepatorenal Toxicity and the Possible Therapeutic Role of Mesenchymal Stem Cell-Derived Exosomes in Wistar Rats

“…Its checkpoint function makes it one of the primary organs targeted by drug toxicity (Salama et al, 2022). Hepatotoxicity of CTX is also reported by Refaie et al (2022) because it is a prodrug and so undergoes hepatic metabolism. CYP34A acts on CTX in the liver, converting it to phosphoramide mustard and acrolein (Barnett et al, 2021).…”