Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia.
Faculty of Chemistry, University of Belgrade, 11000 Belgrade, Serbia.
Int J Mol Sci. 2021 Sep 8;22(18):9698. doi: 10.3390/ijms22189698.
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.
脓毒症是一种危及生命的疾病，由感染引起的失调和过度反应引起，伴有过度的促炎状态和脂质代谢紊乱，导致序贯器官衰竭。美度铵是一种抗缺血和抗炎药物，通过将能量产生从脂肪酸氧化转移到糖酵解，作为一种较少需要氧气的途径，从而负向干扰脂质代谢。因此，我们研究了美度铵预处理对 Sprague-Dawley 雄性大鼠粪便诱导的脓毒症的影响。令人惊讶的是，在脓毒症条件下，与未接受美度铵治疗的组相比，美度铵增加了动物的死亡率。然而，组织氧化状态的分析并没有为美度铵的有害影响提供支持，组织炎症状态的分析也没有显示美度铵的抗炎、抗凋亡和抗坏死作用。在进行组织脂质组学分析后，我们得出结论，美度铵的有害作用的潜在原因可能是脂质代谢总体降低。本研究强调了脓毒症中不间断能量产生的重要性，密切关注某些治疗方法引起的脂质动员受损可能产生的有害影响。这可能导致需要对脓毒症的临床治疗现有指南进行修订，同时为发现新的治疗方法铺平道路。
