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Research Article
Effects of meldonium on the behavior of rats in a model of lipopolysaccharide-induced systemic inflammation
expand article infoKlementina Moneva-Marinova‡, Silvia Gancheva‡, Nadezhda Hvarchanova‡, Marieta Georgieva‡, Stanila Stoeva-Grigorova‡, Maya Radeva-Ilieva‡, Kaloyan D. Georgiev‡
‡ Medical University - Varna, Varna, Bulgaria

Corresponding author: Maya Radeva-Ilieva ( mayapr89@gmail.com )

Academic editor: Plamen Peikov
© 2025 Klementina Moneva-Marinova, Silvia Gancheva, Nadezhda Hvarchanova, Marieta Georgieva, Stanila Stoeva-Grigorova, Maya Radeva-Ilieva, Kaloyan D. Georgiev.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation: Moneva-Marinova K, Gancheva S, Hvarchanova N, Georgieva M, Stoeva-Grigorova S, Radeva-Ilieva M, Georgiev KD (2025) Effects of meldonium on the behavior of rats in a model of lipopolysaccharide-induced systemic inflammation. Pharmacia 72: 1-7. https://doi.org/10.3897/pharmacia.72.e152698
Open Access

Abstract

Meldonium is a metabolic modulator used for its cardioprotective properties and presumed ergogenic effects. The current study aimed to determine its psychopharmacological effects in rats subjected to a model of neuroinflammation. Male Wistar rats were allocated into 4 groups (n = 6 per group): Control, LPS, LPS + CS and LPS + meldonium. Control group received saline and the other groups received lipopolisacharides intraperitoneally every other day for induction of subchronic systemic inflammation. LPS + CS and LPS + meldonium rats were orally daily treated with dexamethasone and meldonium, respectively. The duration of the study was 10 days. At the end of the experiment behavioral tests for assessment of locomotor activity, recognition memory and anxiety- and depression-like behavior were performed. Meldonium increased rat locomotor activity and prevented the suppression of exploratory behavior induced by lipopolysaccharide administration. Meldonium did not affect the recognition memory of the rats, as well as the parameters of anxiety- and depression-like behavior.

Keywords

meldonium, neuroinflammation, locomotor activity, exploratory behavior

Introduction

Meldonium is a synthetic drug considered to be a metabolic modulator due to its ability to inhibit the final step of L-carnitine synthesis, therefore causing a decrease in fatty acid beta-oxidation, and to activate glucose metabolism, causing a shift from lipids to carbohydrates as the main source of ATP for the myocardium. This approach aims to reduce the accumulation of cytotoxic intermediate products of fatty acid beta-oxidation, especially under the condition of insufficient oxygen supply. Moreover, a direct stimulation of glycolysis by meldonium has been described, since it stimulates the expression of the enzyme hexokinase type 1 (Görgens et al. 2015). These effects together with the antioxidant activity of meldonium are at least partly responsible for the anti-anginal properties exerted by the drug. Although meldonium first gained recognition because of its cardioprotective properties, increasing evidence suggests that it might have efficacy as a neuroprotective substance as well (Isajevs et al. 2011; Klusa et al. 2013a; Demir et al. 2019). Anti-degenerative and anti-inflammatory properties, at least partly mediated by targeting mitochondria, have been shown to contribute to the neuroprotective efficacy (Pupure et al. 2010). Meldonium has been observed to modulate the expression of proteins implicated in synaptic plasticity, neuroinflammation and apoptosis (Klusa et al. 2013b). Anticonvulsant and antihypnotic effects have been described (Zvejniece et al. 2010). Its use has been explored in the context of Alzheimer`s disease (Beitnere et al. 2013) as well as Parkinson`s disease (Klusa et al. 2010). Meldonium exerted beneficial effects in models of stress- and haloperidol-induced memory impairment (Beitnere et al. 2014). Vasodilative properties, involving nitric oxide-dependent mechanisms, have also been reported (Eser et al. 2020). The drug was first synthesized in the Latvian Institute of Organic Synthesis and is currently registered in several European and Asian countries as a cardioprotective and neuroprotective substance. Meldonium has been present on the World Anti-Doping Agency (WADA) list since 2016 in the “Metabolic and hormonal modulators” category because of presumed ergogenic effects (Berlato et al. 2020). Suspected performance-enhancing abilities could be attributed to meldonium’s influence on myocardial oxygen requirements, its impact on mitochondrial function and glucose metabolism (Bellman 2024). Despite these speculative suggestions, though, evidence confirming the capacity of meldonium to improve physical performance is limited and inconclusive, which calls into question the justification behind WADA’s decision. The potential cognitive effects of the drug have also spiked the interest of scientists lately (Bellman 2024). Cognitive effects could hardly be attributed to L-carnitine inhibition, though, since fatty acids are not a major source of energy for the brain cells. Therefore, non-carnitine mechanisms of action seem to be involved (Sjakste et al. 2005). Data suggest that brain hemodynamics, electrolyte balance and oxygenation processes are improved and glucose absorption in the central nervous system is promoted following meldonium use in the context of cerebrovascular disorders (Berlato et al. 2020).

The aim of the current study was to determine the effects of meldonium on the behavior of rats in a model of lipopolysaccharide (LPS)-induced systemic inflammation and extend the knowledge of the neuropsychopharmacological activities of the drug.

Materials and methods

Experimental animals

For the purpose of the experiment, 24 albino male Wistar rats, bred in the Vivarium of Medical University of Varna, were used. They were housed under standard laboratory conditions – room temperature 22 ± 2 °C, controlled light/dark cycle 12/12 h and free access to food and drinking water. All experimental procedures were performed in accordance with Directive 2010/63/EU and were approved by Bulgarian Food Safety Agency (Document № 175)

The animals were allocated into 4 groups of 6 animals each: Control, LPS, LPS + CS and LPS + meldonium. The rats from the Control group were orally treated with saline daily. The animals from groups LPS, LPS + CS and LPS + meldonium received 0.5 mg/kg (0.5 ml/kg) of LPS (purchased from Sigma-Aldrich, GmbH) intraperitoneally every other day. The rats from group LPS+CS received also a corticosteroid (CS), dexamethasone (purchased from a local pharmacy), at a dose of 1 mg/kg, and the animals from group LPS+meldonium received meldonium (provided by Grindex Latvia) at a dose of 100 mg/kg (1 ml/kg). Dexamethasone and meldonium were administered orally daily. The duration of the treatment was 10 days. On days 7, 8, 9 and 10 of the experiment, behavioral tests were conducted.

Open field test

Open field test evaluates the locomotor activity of experimental animals. The test was performed on a white wooden arena (100 × 100 cm) with walls with a height of 40 cm. The floor of the arena was divided by blue lines into 25 equally sized squares. Each animal was individually placed in the center of the arena. Its behavior was observed for 5 minutes. The number of horizontal movements (number of lines that were crossed with all 4 paws of the animal) and the number of vertical movements (standing up on the hind paws) were registered as indices of rat locomotor activity.

Elevated plus maze test

Elevated plus maze test is a classic tool for assessing anxiety-like behavior. The apparatus consists of two open and two closed arms, connected by a central platform. The maze is elevated at a 50 cm height from the floor. During the test each of the animals was individually put on the central platform facing one of the open arms of the apparatus. For 5 minutes, the number of entries and the time spent in the open arms were registered as inverse indices of anxiety-like behavior. The number of entries and the time spent in the closed arms were registered for calculation of the ratios of the number of entries in open arms to total number of entries in any arm and the time spent in open arms to total time spent in any arm. These ratios are also used as inverse indices of anxiety-like behavior. The locomotor activity of the animals is evaluated in this test by the total number of entries in any of the arms of the maze.

Object recognition test

Object recognition test evaluates the recognition memory of the animals. The test was conducted in an arena with dimensions 60 × 40 cm with a wall height of 40 cm. The test was performed in two sessions with a 30-minute interval between them. In the first session, two identical objects were symmetrically placed in the arena. They were firmly attached to the floor so that it was not possible for the animals to move them. Each rat was allowed to freely explore the arena and the objects for a period of 3 minutes and the time spent in exploration of the objects was registered. During the second session (also lasting 3 minutes) one of the objects was replaced with a new one of a different shape, but the same size and color. The time exploring the familiar object (A) as well as the time exploring the novel object (B) were registered. The discrimination index B/(А+B) was calculated as a parameter of recognition memory.

Forced swim test

Forced swim test is a method for detection of depression-like behavior. The test was conducted in a glass cylinder with a diameter of 17 cm and a height of 50 cm. The cylinder was filled with water (25 °C) up to a level that did not allow the animal to reach the bottom with its hind paws or tail. The test was conducted in two sessions on two consecutive days with a 24-hour interval between them. In each of the sessions, each rat was individually placed in the cylinder and its behavior was monitored for 3 minutes. The immobility time was registered as an index of depression-like behavior.

Statistical methods

Statistical analysis was conducted with GraphPad Prism Software 5.00. Data are presented as mean ± SEM. One-way analysis of variance (ANOVA) with Tukey’s multiple comparison posttest and Student’s t-test were used. Values of p < 0.05 were considered statistically significant.

Results

Open field test

The locomotor activity of the animals during the Open field test is presented on Fig. 1. The horizontal activity (Fig. 1A) was significantly affected by the treatment (F(3,19) = 3.855, p = 0.026 according to one-way ANOVA). Tukey’s posttest revealed an increase in the number of lines crossed in group LPS+meldonium compared to both group LPS (p < 0.05) and group LPS+CS (p < 0.05). The number of vertical movements (Fig. 1B) did not significantly differ among the experimental groups, although the same tendency as in the number of horizontal movements was observed.

Figure 1. 

Rat behavior in the Open field test – horizontal (A) and vertical (B) activity; Control – control rats; LPS – rats subjected to a model of lipopolysaccharide-induced inflammation; LPS + CS – rats with a model of inflammation receiving dexamethasone; LPS+meldonium – rats with a model of inflammation receiving meldonium; # p < 0.05 versus group LPS, & p < 0.05 versus group LPS + CS.

Elevated plus maze test

The results from the Elevated plus maze test are presented on Fig. 2 and Table 1. One-way ANOVA revealed a significant difference in the number of total entries in any of the arms of the maze between the groups (F(3,20) = 3.170; p = 0.047). The posttests showed that, compared to the Control group, the locomotor activity was reduced in LPS group (borderline significance; p = 0.056) and in LPS + CS group (p < 0.05). The experimental animals that received meldonium did not differ in the number of total entries when compared to the Control group (Fig. 2). One-way ANOVA and the posttests did not reveal differences among the experimental groups in the measures for assessment of anxiety-like behavior (Table 1).

Figure 2. 

Number of total entries in any of the arms of the apparatus in the Elevated plus maze test; Control – control rats; LPS – rats subjected to a model of lipopolysaccharide-induced inflammation; LPS + CS – rats with a model of inflammation receiving dexamethasone; LPS+meldonium – rats with a model of inflammation receiving meldonium; * p < 0.05, (*) p = 0.056 versus group Control.

Table 1.
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Indicators of anxiety-like behavior in the Elevated plus maze test – time spent in open arms, number of entries in open arms, ratio of the time spent in open arms to total time spent in any arm and ratio of the number of entries in open arms to total number of entries in any arm; Control – control rats; LPS – rats subjected to a model of lipopolysaccharide-induced inflammation; LPS+CS – rats with a model of inflammation receiving dexamethasone; LPS+meldonium – rats with a model of inflammation receiving meldonium.

Group Time in open arms Number of entries in open arms Time spent in open arms/ total time spent in any arm Number of entries in open arms/ total number of entries in any arm
Control 29.84 ± 4.44 3.5 ± 0.76 0.11 ± 0.02 0.25 ± 0.03
LPS 21.28 ± 6.51 2 ± 0.68 0.08 ± 0.02 0.21 ± 0.05
LPS+CS 20.63 ± 7.1 2.67 ± 0.76 0.08 ± 0.03 0.41 ± 0.11
LPS+meldonium 22.73 ± 1.60 2.67 ± 0.61 0.09 ± 0.01 0.26 ± 0.07

Object recognition test

Fig. 3 presents the results from the training session (Fig. 3A) and the test session (Fig. 3B) of the Object recognition test. One-way ANOVA revealed a significant difference between the groups in the time spent for exploration of the objects during the training session (F(3,19) = 4.374, p = 0.0168). The posttest showed that the exploration time was decreased in group LPS compared to group Control (p < 0.05). Groups LPS + CS and LPS + meldonium did not differ significantly from the Control one (Fig. 3A). According to one-way ANOVA, there was no difference in the discrimination index B/(A+B). A t-test comparison analysis revealed a significant decrease in group LPS + CS compared to the Control one (p < 0.01). The decrease in groups LPS and LPS + meldonium was insignificant (Fig. 3B).

Figure 3. 

Rat performance in the Object recognition test during the training session (A) and the test session (B); Control – control rats; LPS – rats subjected to a model of lipopolysaccharide-induced inflammation; LPS + CS – rats with a model of inflammation receiving dexamethasone; LPS + meldonium – rats with a model of inflammation receiving meldonium;* p < 0.05, **p < 0.01 compared to group Control.

Forced swim test

Results from the Forced swim test are presented in Table 2. One-way ANOVA and posttests did not reveal any significant difference in the immobility time between the experimental groups, though in all animal groups with LPS-induced inflammation a slight increase was observed.

Table 2.
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Immobility time (sec) in the Forced swim test; Control – control rats; LPS – rats subjected to a model of lipopolysaccharide-induced inflammation; LPS+CS – rats with a model of inflammation receiving dexamethasone; LPS+meldonium – rats with a model of inflammation receiving meldonium.

Group Control LPS LPS + CS LPS + meldonium
Immobility time [sec] 84.00 ± 15.45 111.2 ± 13.07 101.8 ± 14.07 111.3 ± 14.98

Discussion

LPSs are components of the outer membrane surrounding the cell wall of Gram (-) bacteria. When applied to experimental animals, LPSs induce an immune response and stimulate the host immune cells to release inflammatory cytokines. Therefore, LPS administration by different routes is often used for modeling various inflammatory diseases, such as sepsis, myocarditis/cardiac dysfunction, acute lung injury, acute pancreatitis, mastitis, etc (Zhang et al. 2024). A major pathogenetic event following the administration of LPSs is the activation of the toll-like receptor 4 (TLR4) signaling pathway (Skrzypczak-Wiercioch and Sałat 2022). While this pattern-recognition receptor plays a central role in the innate immune response, its overactivation impairs immune homeostasis, giving rise to inflammatory cytokine and chemokine production (Kim et al. 2023). Microglia activation, release of inflammatory cytokines such as TNF-ɑ and IL-1β, neuronal loss, and various other mechanisms have been implicated in the pathogenesis of neurodegenerative disorders and all of them have been consistently described in response to LPS injection, both intraperitoneal and intracerebroventricular (Zhao et al. 2019). Therefore, LPS administration has been used as a valid model for inducing memory and cognitive disturbances (Skrzypczak-Wiercioch and Sałat 2022). Neuroinflammation is crucial for the pathogenesis of not only neurodegenerative but also depressive disorders and LPS administration has been utilized to induce depressive-like behavior in rodents (Yin et al. 2023).

In the context of the presumed ergogenic effect of meldonium and increasing evidence for its neuroprotective effect, in the current study we aimed to investigate its neuropsychopharmacologial activity in a model of LPS-induced inflammation.

The locomotor activity of experimental animals was tested through Open filed test and Elevated plus maze test. In our study, meldonium produced a stimulatory effect on spontaneous motor activity of the rats. In the Open field test, the number of lines crossed by the rats receiving the drug was increased in comparison to that of the other LPS-treated animals. The Elevated plus maze test demonstrated that meldonium administration prevented the suppression of motor activity induced by the LPSs, as the number of total entries in any of the arms of the maze was lower in all LPS treated groups compared to the control one, except for the LPS + meldonium group. There are several studies reporting that meldonium could improve the physical working capacity and performance of athletes, as well as muscle recovery after exercise, because of its action as a metabolic modulator in skeletal muscle cells (Schobersberger et al. 2017). However, the activation of glucose metabolism can hardly explain the stimulation of spontaneous motor activity that we observed in our study, since such augmentation is generally regarded as a sign of a psychostimulant effect produced through a central mechanism of action. In the available scientific literature, we could find only few experimental studies evaluating the effect of meldonium on rodent behavior with which to compare our results. The spontaneous motor activity and exploratory behavior of the animals is underexamined, as the scientific interest of researchers is directed mainly towards indicators of anxiety-like behavior and cognition. In a study of Beitnere at al. (2014), meldonium did not affect motor activity in a murine model of Alzheimer’s disease and a further study of Gureev et al. (2020) reported a decrease of research behavior of healthy mice subjected to long-term meldonium administration. In the current study, we evaluated the research activity of the animals during the training session of the Object recognition test by registering the time spent for exploration of the objects. We observed changes in rat exploratory behavior, that were opposite to those reported by Gureev et al. (2020) – the LPS-induced inflammation significantly reduced exploration time of the animals, while both the treatment with dexamethasone and with meldonium prevented this decrease. We may easily explain the seemingly contradictory experimental results since the animals of Gureev et al. (2020) were healthy and ours were subjected to a model of inflammation. In addition, the changes in the exploratory behavior observed by Gureev et al. (2020) developed at the 10th week of the treatment and were related to an unfavorable action of the drug on the gut microbiome. Our study was shorter and our experimental animals were treated with meldonium only for 10 days – a period of time that is insufficient for development of dysbiosis. The preventive effect of meldonium against the impairment of motor activity and exploration behavior induced by LPS administration, that we observed in our study, synchronize with the results of Zvejniece et al. (2010) who reported an antihypnotic action of meldonium in an ethanol-induced loss of righting reflex test. The authors explained the antihypnotic effect of the drug with its influence on alpha-2 adrenergic receptors and nitric oxide synthesis. We can assume that these mechanisms, along with the drug’s anti-inflammatory properties, likely contribute to the psychostimulant effects of meldonium observed in the present study.

We evaluated the recognition memory of our experimental animals by calculating the discrimination index B/(A+B) from the data registered during the test session of the Object recognition test. The index showed a tendency towards decrease in all groups with LPS-induced inflammation, but only reached statistical significance in the group receiving dexamethasone. This observation suggests that CSs contribute to memory impairment. Although glucocorticosteroids are a powerful and well-established anti-inflammatory weapon, it has been repeatedly shown that when it comes down to neuroinflammation they may even exacerbate the pathology (Skrzypczak-Wiercioch and Sałat 2022). Prolonged CS exposure has been shown to potentiate the pro-inflammatory response related to MAP kinase-NFkB pathway – the one involved in mediation of the LPS-induced inflammation – under certain conditions (Duque and Munhoz 2016). The hippocampus, long known to be a key region involved in memory processing and retrieval, is particularly susceptible to the neuroinflammatory effects of CSs due to the dense distribution of CS receptors in this region of the brain (Bolshakov et al. 2021). Meldonium has been previously shown to stimulate learning and memory in healthy and scopolamine-treated male Wistar rats, possibly involving an effect on the glutamatergic and/or cholinergic system (Klusa et al. 2013b). The neuroprotective properties of meldonium have been additionally confirmed in a transgenic murine model of Alzheimer’s disease (Beitnere at al. 2014) and in aged mice (Shaforostova et al. 2022). In the current study, LPS-administration was not sufficient to induce impairment of recognition memory. This can explain the lack of memory-enhancement effect of meldonium in our study.

The current study did not observe anxiety- and depressive-like behavior following the LPS administration as shown by the Elevated plus maze test and Forced swim test. In both tests, LPS-treated animals demonstrated slight changes in the behavior indicators, pointing to tendency to anxiety- and depressive-like behavior, compared to the control rats. However, the parameters did not differ significantly. Treatment with either dexamethasone or meldonium also did not exert a significant effect on the indicators of anxiety-like behavior and immobility time of the rats. Although neuroinflammation is implicated in the pathophysiology of depression in numerous ways, such as modulation of neurogenesis and neuroplasticity, activation of the hypothalamic-pituitary-adrenal axis and affecting the synthesis and metabolism of monoamines (Mohamed et al. 2024), it has been suggested that the repeated constant doses of LPSs may in certain cases lead to tolerance development in rodents and therefore diminished behavioral responses (Yin et al. 2023).

Conclusion

Our experimental results suggest that meldonium might increase spontaneous motor activity and prevent the impairment of exploratory behavior in a model of subchronic LPS-induced systemic and neuroinflammation in rats. The beneficial effects are likely related to the neuroprotective, neurorestorative and anti-inflammatory activities of the drug. Further accumulation of experimental data is crucial for filling the knowledge gap regarding the neuropsychopharmacological effects of meldonium and successfully transferring preclinical findings to the field of clinical medicine.

Additional information

Conflict of interest

The authors have declared that no competing interests exist.

Ethical statements

The authors declared that no clinical trials were used in the present study.

The authors declared that no experiments on humans or human tissues were performed for the present study.

The authors declared that no informed consent was obtained from the humans, donors or donors’ representatives participating in the study.

Experiments on animals: Document № 175, Bulgarian Food Safety Agency.

The authors declared that no commercially available immortalised human and animal cell lines were used in the present study.

Funding

This research was financed by the European Union – Next Generation EU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project № BG-RRP-2.004-0009-C02.

Author contributions

Conceptualization, methodology and research: KMM, SG, SS, NH, MRI, KDG, MG. Literature search and analysis: KMM, SG, SS, NH, MRI, KDG, MG. Data acquisition and analysis: NH, KDG, MRI. Statistical analysis: KMM, SG. Writing of the manuscript – draft: KMM, SG. Review and editing of the original manuscript: SS, NH, MRI. Final review and approval of the manuscript: KDG, MG.

Author ORCIDs

Klementina Moneva-Marinova https://orcid.org/0000-0001-9565-6018

Silvia Gancheva https://orcid.org/0000-0001-5101-7716

Nadezhda Hvarchanova https://orcid.org/0000-0002-8760-8654

Stanila Stoeva-Grigorova https://orcid.org/0000-0002-0528-0289

Maya Radeva-Ilieva https://orcid.org/0000-0001-5778-4043

Kaloyan D. Georgiev https://orcid.org/0000-0003-1839-1452

Data availability

All of the data that support the findings of this study are available in the main text.

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