Sepsis-induced multiple organ dysfunction arises from the highly complex pathophysiology encompassing the interplay of inflammation, oxidative stress, endothelial dysfunction, mitochondrial damage, cellular energy failure, and dysbiosis. Over the past decades, numerous studies have been dedicated to elucidating the underlying molecular mechanisms of sepsis in order to develop effective treatments. Current research underscores liver and cardiac dysfunction, along with acute lung and kidney injuries, as predominant causes of mortality in sepsis patients. This understanding of sepsis-induced organ failure unveils potential therapeutic targets for sepsis treatment. Various novel therapeutics, including melatonin, metformin, palmitoylethanolamide (PEA), certain herbal extracts, and gut microbiota modulators, have demonstrated efficacy in different sepsis models. In recent years, the research focus has shifted from anti-inflammatory and antioxidative agents to exploring the modulation of energy metabolism and gut microbiota in sepsis. These approaches have shown a significant impact in preventing multiple organ damage and mortality in various animal sepsis models but require further clinical investigation. The accumulation of this knowledge enriches our understanding of sepsis and is anticipated to facilitate the development of effective therapeutic strategies in the future.

After being discovered over a century ago, insulin was long considered to be a hormone exclusively produced by the pancreas. Insulin presence was later discovered in the brain, which was originally accounted for by its transport across the blood-brain barrier. Considering that both insulin mRNA and insulin were detected in the central nervous system (CNS), it is now known that this hormone is also synthesized in several brain regions, including the hypothalamus, hippocampus, cerebral and cerebellar cortex, and olfactory bulb. Although many roles of insulin in the CNS have been described, it was initially unknown which of them could be attributed to brain-derived and which to pancreatic insulin or whether their actions in the brain overlap. However, more and more studies have been emerging lately, focusing solely on the roles of brain-derived insulin. The aim of this review was to present the latest findings on the roles of brain-derived insulin, including neuroprotection, control of growth hormone secretion, and regulation of appetite and neuronal glucose uptake. Lastly, the impairment of signaling initiated by brain-derived insulin was addressed in regard to memory decline in humans.

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.

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.

Sepsis-associated encephalopathy (SAE) is a common yet poorly understood complication of sepsis, which poses a burden in clinical settings, as its management relies on supportive care without targeted pharmacological interventions. Meldonium is a drug approved for ischemic heart disease but has also gained attention for its neuroprotective effects. In animal models of sepsis, meldonium pretreatment exerted antioxidative, antiapoptotic, and anti-inflammatory effects, but its neurological effects have not been studied in SAE. In the present study, rats were pretreated with meldonium for 4 weeks, before sepsis was induced via a faecal intraperitoneal injection (FIP) or a lipopolysaccharide (LPS) injection. The cerebellum, medulla oblongata, and prefrontal cortex were examined due to their involvement in functions that are often impaired in sepsis. Eight hours post-sepsis induction, markers of brain injury were assessed, including reflexes scores, dry to wet brain mass ratio, prooxidant-antioxidant balance (PAB), advanced oxidation protein products (AOPP), lipid peroxidation (LPO), phosphatidylcholine (PC) to lysophosphatidylcholine (LPC) ratio, HMGB1 and haptoglobin protein expression, and CD73 activity. Meldonium-pretreated FIP-septic rats showed an earlier decline in reflex scores compared to the sepsis-only group, accompanied by a slight brain water accumulation. However, in both models of sepsis, meldonium pretreatment prevented alterations in the PAB, AOPP, and LPO in a region-specific manner. It also preserved the PC/LPC ratio in the prefrontal cortex of FIP-septic rats and in all regions of LPS-septic rats. Haptoglobin protein content was altered only in FIP-septic rats, and preserved by meldonium pretreatment in the cerebellum and medulla oblongata of these rats. Additionally, meldonium pretreatment preserved CD73 activity in the medulla oblongata and prefrontal cortex of FIP-septic rats and in the cerebellum and prefrontal cortex of LPS-septic rats. In conclusion, our study is the first to demonstrate that pretreatment with meldonium, a drug that has shown neuroprotective effects in other invasive models can also provide benefits in SAE, with the extent of protection depending on both the model of sepsis induction and the specific brain region investigated. Our findings support the discussion on the importance of selecting the right sepsis model and studying individual brain regions when investigating SAE and potential therapeutic approaches.