Novel NOX2 inhibitor Mito‐Apocynin Protects Against LPS‐induced Endotoxemia Pre‐Clinical Animal Model

Abstract

Sepsis is a serious medical condition caused by the body's response to an infectious or noninfectious insult. Various experimental data suggests that systemic inflammation resulting from the release of pro‐inflammatory cytokines and the chronic activation of the innate immune system is a key pathophysiological contributor to sepsis. The existing therapy for sepsis has largely been ineffective due to the heterogeneity in clinical severity and presentation among individuals. Commonly, Lipopolysaccharide (LPS) is used as an endotoxin to generate a pre‐clinical mouse model of sepsis model. Intraperitoneal injection of purified LPS has been shown to trigger systemic activation of the innate immune response followed by organ injury and mortality in mice. Recently, we demonstrated a newly‐synthesized and orally available derivative of apocynin that targets mitochondria, mito‐apocynin (Mito‐Apo), to be efficacious as an anti‐neuroinflammatory agent to inhibit NOX2 activity, oxidative damage and improve mitochondrial function in both cellular and pre‐clinical animal models of Parkinson's disease. Herein, we further evaluated the pre‐clinical efficacy of Mito‐Apo in the LPS‐induced endotoxemic mouse model of sepsis. C57BL6 mice were administered LPS (5 mg/kg, i.p. once) and Mito‐Apo (30 mg/kg, oral gavage, four times every 6 h at 0, 6, 12 and 18 h), and blood was collected at 1, 3 and 24 h post‐LPS treatment. Mice were sacrificed at 24 h post‐LPS injection. Initial results showed that oral interval administration of Mito‐Apo significantly attenuates LPS‐induced systemic inflammation evidenced by reduced circulating pro‐inflammatory cytokines interleukin‐β (IL‐1β) and tumor necrosis factor‐α (TNF‐α) in plasma and decreased proIL‐1β/TNF‐α mRNA expression levels in mouse liver. Importantly, Mito‐Apo was also shown to significantly reduce LPS‐induced mortality and protect against LPS‐induced motor deficits. Collectively, these findings demonstrate that Mito‐Apo could be used as a novel plausible therapeutic agent for treating sepsis.Support or Funding InformationNS088206, ES026892 and NS100090, Lloyd Endowed ChairThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.