Modulation of Nrf2 by quercetin in doxorubicin-treated rats

Abstract

Doxorubicin (DOXO), a potent and widely used chemotherapeutic agent, causes irreversible heart failure by increasing oxidative stress, which limits its clinical utility. Nuclear factor erythroid-derived 2 -like 2 (Nrf2) is a prominent central regulator of cellular impenetrable to oxidants. The purpose of the study is to assess the ameliorative outcome of quercetin in cardiomyopathic rats induced by doxorubicin. Cardiomyopathy was produced in rats by single intraperitoneal weekly with DOXO (2 mg/kg) for 4 weeks. The rats were divided into five groups: (I) control group; (II) DOXO (2 mg/kg, i.p.) group; (III-V) DOXO þ quercetin (10 mg/kg, 25 mg/kg and 50 mg/kg, orally), and were treated for 7 weeks. At the end of the treatment duration, cardiac function and biochemical parameters were assessed. Quercetin (10 mg/kg, 25 mg/kg and 50 mg/kg, orally) treatment reduced the raised blood pressure (BP) and left ventricular dysfunction. Withal, it prevented the rise in CKMB and LDH, suggesting the effect of quercetin in the maintaining the integrity of the cell membrane Besides, it also prevented the alteration in electrolyte levels, the activity of ATPase, and antioxidant status. Quercetin increased Nrf2 mRNA expression and reduced histological abnormalities compared 1 to the DOXO control group. In conclusion, quercetin protected against DOXO-induced cardiomyopathy, by increasing expression of NRF2, and thereby increasing antioxidant defense and restoring biochemical and histological abnormalities.

Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View From the Perspective of the Pathophysiologist and the Clinician

“…It is known that some of the drugs entering clinical development do not confirm their effectiveness previously demonstrated in laboratory conditions ( Pound and Ritskes-Hoitinga, 2018 ; Ferreira et al, 2020 ). This situation also applies to drugs intended for a preventive or pathogenetic effect on the course of DOX cardiomyopathy ( Weidemann and Strotmann, 2006 ; Vincent et al, 2013 ; Lipshultz et al, 2014 ; Abushouk et al, 2017 ; Kim et al, 2019 ; Wang et al, 2019 ; Sharma et al, 2020 ). Possible reasons for such low transferability can be considered the presence of species differences between humans and laboratory animals, as well as the difficulty in developing an adequate experimental model of the disease.…”

“…Other short-term models use 2–3.4 mg/kg of DOX every other day, six times intraperitoneally (the total dose is 12–20 mg/kg) ( Zbinden et al, 1978 ; Lanza et al, 1989 ; Carvalho et al, 2010 ; Razmaraii et al, 2016 ; Cappetta et al, 2018 ; Aygun and Gul, 2019 ; Barış et al, 2019 ). Long-term rat models typically use 1–5 mg/kg every week for 2–12 weeks with a cumulative dose of 3–25 mg/kg ( Villani et al, 1991 ; Sacco et al, 2001 ; Sayed-Ahmed et al, 2001 ; Rahimi Balaei et al, 2010 ; Hydock et al, 2012 ; Hole et al, 2013 ; Toblli et al, 2014 ; Kang et al, 2017 ; Medeiros-Lima et al, 2019 ; Wang et al, 2019 ; Chakouri et al, 2020 ; Sharma et al, 2020 ). Thus, a short-term high-dose injection model would be suitable for assessing acute cardiotoxicity, while a long-term low-dose model would be suitable for assessing chronic cardiotoxicity.…”

Natural compounds against doxorubicin‐induced cardiotoxicity: A review on the involvement of Nrf2/ARE signaling pathway

“…Moreover, quercetin showed protective effects against cardiac injuries, hepatotoxicity, and metabolic syndrome (Liu, Guo, Chu, & Lu, 2014; Rivera, Morón, Sánchez, Zarzuelo, & Galisteo, 2008; Vicente‐Sánchez et al, 2008). Sharma et al reported that quercetin boosted the antioxidant defense by increasing the expression of Nrf2 in rats treated with DOX (Figure 1) (Sharma et al, 2020).…”

“…Quercetin is an antioxidant bioflavonoid that is obtained from broccoli, berries, onions, citrus fruits, grapes, and cherries (Sharma et al, 2020). It possesses anti‐inflammatory, antihypertensive, anti‐cancer and anti‐hypercholesterolemia activities (Hashemzaei et al, 2017; Kleemann et al, 2011; Perez‐Vizcaino, Duarte, Jimenez, Santos‐Buelga, & Osuna, 2009).…”

The Mechanism of Honey in Reversing Metabolic Syndrome

“…For example, quercetin, caffeic acid (CA), and chlorogenic acid are polyphenols that possess iron-chelating and iron-stabilizing properties, which prevents free radical formation, making them great antioxidants [ 70 , 71 , 72 ]. Furthermore, polyphenols, such as apigenin, quercetin, and kaempferol, may also exert their anti-inflammatory properties by modulation of enzymes involved in proinflammatory activities, such as nuclear factor-kappa B (NF-κB), activator protein-1 (AP-1), or nuclear factor erythroid 2-related factor 2 (Nrf2) [ 73 , 74 , 75 ]. These bioactive compounds may contribute synergistically to the antimetabolic effects of honey.…”