Abstract
Sepsis is a life-threatening condition caused by the dysregulated and overwhelming response to infection, accompanied by an exaggerated pro-inflammatory state and lipid metabolism disturbance leading to sequential organ failure. Meldonium is an anti-ischemic and anti-inflammatory agent which negatively interferes with lipid metabolism by shifting energy production from fatty acid oxidation to glycolysis, as a less oxygen-demanding pathway. Thus, we investigated the effects of a four-week meldonium pre-treatment on faecal-induced sepsis in Sprague-Dawley male rats. Surprisingly, under septic conditions, meldonium increased animal mortality rate compared with the meldonium non-treated group. However, analysis of the tissue oxidative status did not provide support for the detrimental effects of meldonium, nor did the analysis of the tissue inflammatory status showing anti-inflammatory, anti-apoptotic, and anti-necrotic effects of meldonium. After performing tissue lipidomic analysis, we concluded that the potential cause of the meldonium harmful effect is to be found in the overall decreased lipid metabolism. The present study underlines the importance of uninterrupted energy production in sepsis, closely drawing attention to the possible harmful effects of lipid-mobilization impairment caused by certain therapeutics. This could lead to the much-needed revision of the existing guidelines in the clinical treatment of sepsis while paving the way for discovering new therapeutic approaches.
Highlights
IntroductionSepsis is a life-threatening condition caused by the dysregulated and overwhelming response to infection, accompanied by the increased sequential organ failure assessment score in clinical settings [1,2]
As we summarize the histological findings, it can be observed that meldonium exerted a protective effect in the liver, while worsening the histological score in the kidney and heart
We report that the S group exhibited a significantly increased level of high-mobility group box 1 protein (HMGB1) in the serum and in the liver, kidney, and heart whole homogenates (1.3, 1.2, 1.4, and 1.7-fold, respectively)
Summary
Sepsis is a life-threatening condition caused by the dysregulated and overwhelming response to infection, accompanied by the increased sequential organ failure assessment score in clinical settings [1,2]. The exaggerated pro-inflammatory state may cause multiple organ injuries in response to damage-associated molecular patterns (DAMPs) molecules derived from damaged host cells [3]. A cardiovascular collapse unresponsive to fluid resuscitation may be developed in the most severe cases of septic shock, urging vasopressors therapy [4]. In 2017, an estimated 48.9 million incident cases of sepsis and 11 million sepsis-related deaths were recorded worldwide, accounting for 19.7% of total global deaths [6]
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