The Effects of a Meldonium Pre-Treatment on the Course of the LPS-Induced Sepsis in Rats.

Siniša Đurašević,Jelena Đorđević,Snežana Pejić,Zoran Todorović,Aleksandra Ružičić,Ana Todorović,Nebojša Jasnić,Sofija Glumac,Sanja Stanković,Tomislav Tosti,Saša Đurović,Iva Lakić,Dunja Drakulić

doi:10.3390/ijms23042395

Abstract

A dysregulated and overwhelming response to an infection accompanied by the exaggerated pro-inflammatory state and metabolism disturbance leads to the fatal outcome in sepsis. Previously we showed that meldonium, an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia, strongly increases mortality in faecal-induced peritonitis (FIP) in rats. We postulated that the same mechanism that is responsible for the otherwise strong anti-inflammatory effects of meldonium could be the culprit of the increased mortality. In the present study, we applied the LPS-induced model of sepsis to explore the presence of any differences from and/or similarities to the FIP model. When it comes to energy production, despite some shared similarities, it is evident that LPS and FIP models of sepsis differ greatly. A different profile of sympathoadrenal activation may account for this observation, as it was lacking in the FIP model, whereas in the LPS model it was strong enough to overcome the effects of meldonium. Therefore, choosing the appropriate model of sepsis induction is of great importance, especially if energy homeostasis is the main focus of the study. Even when differences in the experimental design of the two models are acknowledged, the role of different patterns of energy production cannot be excluded. On that account, our results draw attention to the importance of uninterrupted energy production in sepsis but also call for much-needed revisions of the current recommendations for its treatment.

Highlights

In comparison to the data from our previous model of sepsis induction [5], it can be concluded that mortality in both S and M + S groups was far higher in the faecal-induced peritonitis (FIP) model
nuclear factor erythroid 2-related factor 2 (Nrf2) analysis in the FIP model, we previously showed that meldonium increases liver and the kidney Nrf2 expression level is otherwise decreased by the ischemia/reperfusion [6,7]
Despite some shared similarities, when it comes to energy production, it is evident that LPS and FIP models of sepsis induction differ greatly

Summary

Introduction

We showed that meldonium, an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia [4], strongly increases (50/100%) mortality in faecalinduced sepsis in rats [5] It appears that the same mechanism responsible for the otherwise strong anti-inflammatory effects of meldonium [6,7] could be responsible for the increased mortality in sepsis. By inhibiting both the biosynthesis and transport of L-carnitine, meldonium prevents long-chain FFAs from entering mitochondria [8] and redirects them to peroxisomes instead, where they are metabolised into medium- and short-chain metabolites, some of which are further oxidised in mitochondria [9]. The decreased ability of tissues to use oxygen despite its availability suggests that a sort of metabolic ischemia is present in sepsis due to impaired energy homeostasis [14]

Methods

Results

Conclusion