Alamandine significantly reduces doxorubicin-induced cardiotoxicity in rats

Abstract

Doxorubicin (DOX) is an anthracycline antibiotic. Despite its unwanted side effects, it has been successfully used in tumor therapy. Given that oxidative stress and inflammatory factors are essential to cardiotoxicity caused by DOX, we assumed that alamandine, which enhances endogenous antioxidants and has anti-inflammatory effects, may prevent DOX-induced cardiotoxicity. Rats received DOX (3.75 mg/kg) i.p on days 14, 21, 28, and 35 (total cumulative dose = 15 mg/kg) and alamandine (50 μg/kg/day) via mini-osmotic pumps for 42 days. At the end of the 42-day period, we evaluated hemodynamic parameters, electrocardiogram, cardiac troponin I (cTnI), superoxidase dismutase (SOD), total antioxidant capacity (TAC), malondialdehyde (MDA), inflammatory cytokines (tumor necrosis factor-α (TNF-α), IL-1β, NF-κB), apoptosis markers (caspase 3), and histopathology of haemotoxylin- and eosin-stained cardiac muscle fibers were evaluated. DOX significantly increased QT, corrected QT (QTc), and RR intervals. Alamandine co-therapy prevented ECG changes. Alamandine administration restored DOX-induced disruptions in the cardiac muscle architecture and vascular congestion. Alamandine co-therapy also alleviated other effects of DOX, including cardiac contractility, decreased systolic and diastolic blood pressure, and increased left ventricular end-diastolic pressure. Moreover, alamandine co-therapy substantially decreased the elevation of oxidative stress markers, inflammatory cytokines, and caspase 3 in DOX-treated rats. The results suggest that alamandine reduced DOX-induced cardiotoxicity via antioxidant, anti-inflammatory, and anti-apoptotic activities.

Alamandine alleviated heart failure and fibrosis in myocardial infarction mice

“…Accordingly, it was found that the anti-oxidant, vitamin E or probucol, could markedly prevent post-MI cardiac remodeling and hemodynamics, while scavenging oxidative stress [ 72 , 83 ]. Also, Ala co-therapy could improve LPS or Doxorubicin (DOX)-induced cardiac dysfunction by its antioxidant and anti-apoptotic activities [ 28 , 84 ]. The inhibitory effects of non-secretory renin in ODG-induced oxidative stress and cardiomyoblasts apoptosis provides us further incentives to explore the role of oxidative stress in the anti-apoptotic and anti-fibrotic effects of Ala in OGD-induced cardiac fibroblast [ 85 ].…”

Prevention and treatment of anthracycline-induced cardiotoxicity: A bibliometric analysis of the years 2000–2023

“…TNF-α/TNFR1 pathway is a key factor in the inflammatory response to DOX [ 40 , 41 ]. Cardioprotective agents such as fisetin, Achillea fragrantissima and Alamandine can exert cardioprotective effects by inhibiting inflammatory factors NF-κB, TNF-α, IL-1β, IL-6 and cyclooxygenase (COX) 2 pathways [ [42] , [43] , [44] ]. Cell death: Cell death is one of the main manifestations of cardiotoxicity, and cell death mechanisms such as apoptosis, autophagy, and necroptosis have been described to explain the cardiotoxicity of DOX [ [45] , [46] , [47] ].…”

“…TNF-α/TNFR1 pathway is a key factor in the inflammatory response to DOX [ 40 , 41 ]. Cardioprotective agents such as fisetin, Achillea fragrantissima and Alamandine can exert cardioprotective effects by inhibiting inflammatory factors NF-κB, TNF-α, IL-1β, IL-6 and cyclooxygenase (COX) 2 pathways [ [42] , [43] , [44] ].…”

Counter-regulatory renin-angiotensin system in hypertension: Review and update in the era of COVID-19 pandemic

“…Like Ang (1-7), alamandine has been found to attenuate hypertension in SHRs and renal vascular hypertensive rats, which involves local vascular tone regulation as well as a central regulatory effect [152] , [162] , [163] , but the mechanism of its anti-hypertensive effect is complicated. Alamandine also appears to exert several beneficial effects, including anti-hypertrophy, anti-remodeling, anti-fibrosis, anti-oxidation, and anti-inflammation [164] , [165] , [166] , [167] , [168] , [169] , [170] . Long-term administration of alamandine to isoproterenol-treated Wistar rats is associated with reduced accumulation of collagens and fibronectin in the heart [171] .…”