Ameliorative effect of flavocoxid on cyclophosphamide-induced cardio and neurotoxicity via targeting the GM-CSF/NF-κB signaling pathway

Abstract

Cyclophosphamide (Cyclo) is a chemotherapeutic agent used as an immunosuppressant and as a treatment for many cancerous diseases. Many previous pieces of literature proved the marked cardio and neurotoxicity of the drug. Thus, this research provides evidence on the alleviative effect of flavocoxid on the cardiac and brain toxicity of cyclophosphamide in mice and determines its underlying mechanisms. Flavocoxid (Flavo) is a potent antioxidant and anti-inflammatory agent that inhibits the peroxidase activity of cyclooxygenase (COX-1 and COX-2) enzymes and 5-lipooxygenase (5-LOX). Flavo was administered orally (20 mg/kg) for 2 weeks, followed by Cyclo (100 mg/kg, i.p.) on day 14. Higher heart and brain weight indices, serum lactate dehydrogenase (LDH), creatine kinase (CK-MB), and nitric oxide (NO) were mitigated following Flavo administration. Flavo modulated oxidative stress biomarkers (malonaldehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD)), tumor necrosis factor-α (TNF-α), and interleukin (IL)-1β. Additionally, cardiac troponin I (cTn-I), nuclear factor kappa B (NF-κB), brain amyloid precursor protein (APP), and granulocyte macrophage colony-stimulating factor (GM-CSF) were decreased by Flavo administration. Moreover, Flavo ameliorated heart and brain histopathological changes and caspase-3 levels. Collectively, Flavo (20 mg/kg) for 14 days showed significant cardio and neuroprotective effects due to its antioxidant, anti-inflammatory, and antiapoptotic activities via modulation of oxidative stress, inflammation, and the GM-CSF/NF-κB signaling pathway.

New insights into the potential cardioprotective effects of telmisartan and nanoformulated extract of Spirulina platensis via regulation of oxidative stress, apoptosis, and autophagy in an experimental model

“…Parallel to this phenomenon, this study shows that Cyclo induces an increase in the p-Akt content and eNOS protein expression, which are in line with the findings of previous reports ( Sancho et al, 2014 ; Barberino et al, 2022 ; Elsayed et al, 2022 ). The reductions of p-Akt and eNOS by TEL, free Sp, and nano Sp pretreatments are observed in this study.…”

Molecular mechanisms underlying cyclophosphamide-induced cognitive impairment and strategies for neuroprotection in preclinical models

“…In addition, various studies demonstrated that oxidative stress elicited by cyclophosphamide in the brain is mediated through overproduction of reactive oxygen species (ROS), GSH depletion and inhibition of antioxidant enzymes activities [13,14]. In addition, it was found that the activation of angiotensin converting enzyme and the resultant excessive production of angiotensin II by cyclophosphamide has been implicated in ROS generation and hence the subsequent oxidative brain injury [15].The massive generation of ROS prompts oxidative damage to numerous cellular components resulting in lipid peroxidation, DNA damage and mitochondrial dysfunction [14,[16][17][18]. Mechanisms by which cyclophosphamide-induced oxidative stress is shown in Fig.…”

“…Ample evidence has verified the crucial role of neuroinflammation in the development and progression of chemotherapy-associated neurological abnormalities [26,27]. Likewise, several experimental studies have implied that sustained inflammatory responses alongside the immense discharge of pro-inflammatory cytokines as tumor necrosis factor alpha (TNF-α) and interleukins are the major driving force for neurodegeneration associated with cyclophosphamide [17,23,24,[28][29][30][31]. In this regard, several inflammatory signaling cascades are considered as integral elements in the pathogenesis of neuronal inflammation induced by cyclophosphamide such as nuclear Factor kappa B (NF-κB), toll-like receptors (TLR) and the nucleotidebinding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) signaling pathways [24,29,32].…”

“…In addition, flavocoxid showed anti-inflammatory properties by decreasing levels of NO, granulocyte macrophage colony stimulator factor (GM-CSF), TNF-α, and IL-1β which could be explained by downregulating expression of NF-κB measured by western blot technique. Moreover, caspase-3 immunostaining showed reduced enzyme expression following flavocoxid treatment denoting its anti-apoptotic effects [17].…”

Antioxidant Activity of the Prunus mahaleb Seed Oil Extracts Using n-Hexane and Petroleum Ether Solvents: In Silico and In Vitro Studies

“…Free radicals are produced endogenously through several enzymes, such as NADPH oxidase (NOX) [97], nitric oxide synthase (NOS) [98], myeloperoxidase (MPO) [99], 5lipoxygenase (5-LOX) [100], monoamine oxidase B (MAOB) [101], xanthine oxidase [102], and cyclooxygenase [103]. However, free radical production by various enzymes is necessary for the physiological and biological functions; overproduction of such substances could produce harmful oxidative stress, which should be neutralized through antioxidant defense mechanisms or nutraceutical antioxidants [104].…”