Edaravone Improves Septic Cardiac Function by Inducing an HIF‐1α/HO‐1 Pathway

Abstract

Septic myocardial dysfunction remains prevalent and raises mortality rate in patients with sepsis. During sepsis, tissues undergo tremendous oxidative stress which contributes critically to organ dysfunction. Edaravone, a potent radical scavenger, has been proved beneficial in ischemic injuries involving hypoxia-inducible factor- (HIF-) 1, a key regulator of a prominent antioxidative protein heme oxygenase- (HO-) 1. However, its effect in septic myocardial dysfunction remains unclarified. We hypothesized that edaravone may prevent septic myocardial dysfunction by inducing the HIF-1/HO-1 pathway. Rats were subjected to cecal ligation and puncture (CLP) with or without edaravone infusion at three doses (50, 100, or 200 mg/kg, resp.) before CLP and intraperitoneal injection of the HIF-1α antagonist, ME (15 mg/kg), after CLP. After CLP, rats had cardiac dysfunction, which was associated with deformed myocardium, augmented lipid peroxidation, and increased myocardial apoptosis and inflammation, along with decreased activities of catalase, HIF-1α, and HO-1 in the myocardium. Edaravone pretreatment dose-dependently reversed the changes, of which high dose most effectively improved cardiac function and survival rate of septic rats. However, inhibition of HIF-1α by ME demolished the beneficial effects of edaravone at high dose, reducing the survival rate of the septic rats without treatments. Taken together, edaravone, by inducing the HIF-1α/HO-1 pathway, suppressed oxidative stress and protected the heart against septic myocardial injury and dysfunction.

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

“…Also, pretreatment with DHMF inhibits phosphorylation of NFκB and leads to an accumulation of HIF1α by increasing the hydroxylation of Pro residues by PHDs and pVHL . This is in contrast with the previous study, where HIF1α activation is increased . Treatment with the statin Simvastatin protects mice against lethal LPS injection by decreasing the hepatocellular degeneration in early phases of sepsis by reducing HIF1α levels .…”

“…Pretreatment of mice with another PHD inhibitor, 3,4‐dihydroxybenzoate (3,4‐DHB), improves renal function after cecal ligation and puncture (CLP); however, the PHD inhibition leads to an increased mortality rate due to liver dysfunction with massive glycogen loss and apoptosis of hepatocytes . Treatment with Edaravone, a potent radical scavenger, suppresses oxidative stress and protects against septic myocardial injury and dysfunction by HIF1α activation and subsequent heme oxygenase 1 induction . 5,7‐dihydroxy‐8‐methoxyflavone (DHMF) is able to protect against LPS‐induced acute lung injury by upregulating antioxidant enzymes.…”

Baicalein Exerts Neuroprotective Effects in FeCl3-Induced Posttraumatic Epileptic Seizures via Suppressing Ferroptosis

“…Oxidative stress is intricately involved in the pathogenesis of a variety of neurological diseases, including epilepsy, AD, PD, cerebral ischemia–reperfusion injury, etc. (Butterfield and Lauderback, 2002; Wang et al, 2011; Carvalho et al, 2017; Pauletti et al, 2017; Pearson-Smith and Patel, 2017; Su et al, 2017; Cheignon et al, 2018; Deng et al, 2018; He et al, 2018; Xie et al, 2018b; Xiao et al, 2019). Previous studies indicated that the brain was particularly sensitive to lipid peroxidation-induced damage due to high consumption of oxygen and abundant PUFAs (Salim, 2017).…”

Role of Edaravone as a Treatment Option for Patients with Amyotrophic Lateral Sclerosis

“…Not only in PD and oral mucositis, but edaravone also shows positive effect in severe carotid territory stroke, Alzheimer’s disease, and septic myocardial dysfunction, or sepsis, referring to a systemic deleterious inflammation to an injury or an infection [ 45 ]. In one of the studies, an early administration of edaravone delayed the progression of infarction and edema in severe carotid territory stroke patients, also reducing the mortality rate during the acute phase.…”