Ewa Trojan - Academia.edu (original) (raw)

Papers by Ewa Trojan

Research paper thumbnail of Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Ureidopropanamides as Formyl Peptide Receptor 2 (FPR2) Agonists to Target the Resolution of Inflammation in Central Nervous System Disorders

Research paper thumbnail of Additional file 7 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 7: Figure S6. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 7: Figure S6. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the CA3 field of the hippocampus of PND7 offspring after MIA induced by Poly I:C treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 4 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 4: Figure S3. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 4: Figure S3. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the CA1 field of the hippocampus of PND7 offspring after MIA induced by LPS treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 3 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 3: Figure S2. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 3: Figure S2. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the DG of the hippocampus of PND7 offspring after MIA induced by Poly I:C treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 5 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 5: Figure S4. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 5: Figure S4. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the CA1 field of the hippocampus of PND7 offspring after MIA induced by Poly I:C treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 6 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 6: Figure S5. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 6: Figure S5. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the CA3 field of the hippocampus of PND7 offspring after MIA induced by LPS treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 2 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 2: Figure S1. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 2: Figure S1. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the DG of the hippocampus of PND7 offspring after MIA induced by LPS treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 1 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 1: Table S1. A list of genes (with corresponding catalogue numbers of TaqMan prob... more Additional file 1: Table S1. A list of genes (with corresponding catalogue numbers of TaqMan probes) examined in the hippocampi and the frontal cortices of male offspring at PND7 using qRT-PCR. B2m or Hprt were used as the reference genes.

Research paper thumbnail of The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Exhibits Anti-Inflammatory Activity in LPS-Stimulated Organotypic Hippocampal Cultures

Cells, 2021

Accumulating evidence indicates a pivotal role for chronic inflammatory processes in the pathogen... more Accumulating evidence indicates a pivotal role for chronic inflammatory processes in the pathogenesis of neurodegenerative and psychiatric disorders. G protein-coupled formyl peptide receptor 2 (FPR2) mediates pro-inflammatory or anti-/pro-resolving effects upon stimulation with biased agonists. We aimed to evaluate the effects of a new FPR2 ureidopropanamide agonist, compound MR-39, on neuroinflammatory processes in organotypic hippocampal cultures (OHCs) derived from control (WT) and knockout FPR2−/− mice (KO) exposed to bacterial endotoxin (lipopolysaccharide; LPS). Higher LPS-induced cytokine expression and basal release were observed in KO FPR2 cultures than in WT cultures, suggesting that a lack of FPR2 enhances the OHCs response to inflammatory stimuli. Pretreatment with MR-39 abolished some of the LPS-induced changes in the expression of genes related to the M1/M2 phenotypes (including Il-1β, Il-6, Arg1, Il-4, Cd74, Fizz and Cx3cr1) and TNF-α, IL-1β and IL-4 release in tissu...

Research paper thumbnail of The effect of chronic tianeptine administration on NLRP3 inflammasome pathway - study in an animal model of depression

Endocrine Abstracts, 2017

A growing body of evidence has focused on the impact of mitochondrial disturbances in the develop... more A growing body of evidence has focused on the impact of mitochondrial disturbances in the development of depression, but little data exist regarding the effects of chronic administration of antidepressant drugs on the brain's mitochondrial protein profile. The aim of this study was to investigate the impact of chronic treatment with an atypical antidepressant drug-tianeptine-on the mitochondria-enriched subproteome profile in the hippocampus and the frontal cortex of 3-month-old male rats following a prenatal stress procedure. Rats that were exposed to a prenatal stress procedure displayed depressive-and anxiety-like disturbances based on the elevated plus-maze and Porsolt tests. Moreover, twodimensional electrophoresis coupled with mass spectrometry showed structure-dependent mitoproteome changes in brains of prenatally stressed rats after chronic tianeptine administration. A component of 2-oxoglutarate and succinate flavoprotein subunit dehydrogenases, isocitrate subunit alpha, was upregulated in the hippocampus. In the frontal cortex, there was a striking increase in the expression of glutamate dehydrogenase and cytochrome bc1 complex subunit 2. These findings suggest that mitochondria are underappreciated targets for therapeutic interventions, and mitochondrial function may be crucial for the effective treatment of stress-related diseases.

Research paper thumbnail of Time-Dependent Protective and Pro-Resolving Effects of FPR2 Agonists on Lipopolysaccharide-Exposed Microglia Cells Involve Inhibition of NF-κB and MAPKs Pathways

Cells, 2021

Prolonged or excessive microglial activation may lead to disturbances in the resolution of inflam... more Prolonged or excessive microglial activation may lead to disturbances in the resolution of inflammation (RoI). The importance of specialized pro-resolving lipid mediators (SPMs) in RoI has been highlighted. Among them, lipoxins (LXA4) and aspirin-triggered lipoxin A4 (AT-LXA4) mediate beneficial responses through the activation of N-formyl peptide receptor-2 (FPR2). We aimed to shed more light on the time-dependent protective and anti-inflammatory impact of the endogenous SPMs, LXA4, and AT-LXA4, and of a new synthetic FPR2 agonist MR-39, in lipopolysaccharide (LPS)-exposed rat microglial cells. Our results showed that LXA4, AT-LXA4, and MR-39 exhibit a protective and pro-resolving potential in LPS-stimulated microglia, even if marked differences were apparent regarding the time dependency and efficacy of inhibiting particular biomarkers. The LXA4 action was found mainly after 3 h of LPS stimulation, and the AT-LXA4 effect was varied in time, while MR-39′s effect was mainly observed...

Research paper thumbnail of The impact of prenatal inflammatory priming on the neuron-microglia proteines expression in young offspring brain: immunohistochemical study in neurodevelopmental model of schizophrenia

Introduction : A number of studies suggest that in brain microglia are held in a surveillant and ... more Introduction : A number of studies suggest that in brain microglia are held in a surveillant and quiescent state of activation through several inhibitory signaling dyads. Recently the fractalkine (CX3CL1) and its receptor (CX3CR1) as well as CD200 and CD200 receptor (CD200R) are particularly noteworthy, because disruption of these networks extended the duration of pro-inflammatory response, mainly via malfunction of a unique communication system between neuron-microglia cells. Objective : To explore the possibility that maternal inflammatory priming based on the bacterial endotoxin (lipopolisaccharide, LPS) administration might serve as a trigger to disturbances in CX3CL1-CX3CR1 and CD200-CD200R signaling in the brain of young offspring. Material and Methods: Pregnant females were injected subcutaneously with LPS at a dose of 2 mg/kg every second day from the seventh day of pregnancy until the delivery. Control pregnant rats were left undisturbed in their homecages. At 7 days of ag...

Research paper thumbnail of Role of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation and Subsequent Immune Challenge in the Behaviour and Microglial Cell Trajectory in Adult Offspring: A Study of the Neurodevelopmental Model of Schizophrenia

International Journal of Molecular Sciences, 2021

Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the... more Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1β, Tnf-α, Il-6, Arg1, Igf-1, Tgf-β and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the “two-hit” hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led...

Research paper thumbnail of The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Improves Ex Vivo and In Vivo Amyloid Beta (1–42)-Induced Neuroinflammation in Mouse Models of Alzheimer’s Disease

Molecular Neurobiology, 2021

The major histopathological hallmarks of Alzheimer’s disease (AD) include β-amyloid (Aβ) plaques,... more The major histopathological hallmarks of Alzheimer’s disease (AD) include β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Aβ 1–42 (Aβ1-42) has been shown to induce neurotoxicity and secretion of proinflammatory mediators that potentiate neurotoxicity. Proinflammatory and neurotoxic activities of Aβ1-42 were shown to be mediated by interactions with several cell surface receptors, including the chemotactic G protein-coupled N-formyl peptide receptor 2 (FPR2). The present study investigated the impact of a new FPR2 agonist, MR-39, on the neuroinflammatory response in ex vivo and in vivo models of AD. To address this question, organotypic hippocampal cultures from wild-type (WT) and FPR2-deficient mice (knockout, KO, FPR2−/−) were treated with fibrillary Aβ1-42, and the effect of the new FPR2 agonist MR-39 on the release of pro- and anti-inflammatory cytokines was assessed. Similarly, APP/PS1 double-transgenic AD mice were treated for 20 weeks with MR-39, and immuno...

Research paper thumbnail of Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200–CD200R and CX3CL1–CX3CR1 Systems

Cells, 2020

Early life challenges resulting from maternal immune activation (MIA) may exert persistent effect... more Early life challenges resulting from maternal immune activation (MIA) may exert persistent effects on the offspring, including the development of psychiatric disorders, such as schizophrenia. Recent evidence has suggested that the adverse effects of MIA may be mediated by neuron–microglia crosstalk, particularly CX3CL1–CX3CR1 and CD200–CD200R dyads. Therefore, the present study assessed the behavioural parameters resembling schizophrenia-like symptoms in the adult male offspring of Sprague-Dawley rats that were exposed to MIA and to an additional acute lipopolysaccharide (LPS) challenge in adulthood, according to the “two-hit” hypothesis of schizophrenia. Simultaneously, we aimed to clarify the role of the CX3CL1–CX3CR1 and CD200–CD200R axes and microglial reactivity in the brains of adult offspring subjected to MIA and the “second hit” wit LPS. In the present study, MIA generated a range of behavioural changes in the adult male offspring, including increased exploratory activity an...

Research paper thumbnail of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Journal of Neuroinflammation, 2020

Background The bidirectional communication between neurons and microglia is fundamental for the h... more Background The bidirectional communication between neurons and microglia is fundamental for the homeostasis and biological function of the central nervous system. Maternal immune activation (MIA) is considered to be one of the factors affecting these interactions. Accordingly, MIA has been suggested to be involved in several neuropsychiatric diseases, including schizophrenia. The crucial regulatory systems for neuron-microglia crosstalk are the CX3CL1-CX3CR1 and CD200-CD200R axes. Methods We aimed to clarify the impact of MIA on CX3CL1-CX3CR1 and CD200-CD200R signalling pathways in the brains of male Wistar rats in early and adult life by employing two neurodevelopmental models of schizophrenia based on the prenatal challenge with lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (Poly I:C). We also examined the effect of MIA on the expression of microglial markers and the profile of cytokines released in the brains of young offspring, as well as the behaviour of adult an...

Research paper thumbnail of The emerging role for the double-edged impact of arachidonic acidderived eicosanoids in the neuroinflammatory background of depression

Current Neuropharmacology, 2020

Eicosanoids are arachidonic acid (AA) derivatives belonging to a family of lipid signalling media... more Eicosanoids are arachidonic acid (AA) derivatives belonging to a family of lipid signalling mediators that are engaged in both physiological and pathological processes in the brain. Recently, their implication in the prolonged inflammatory response has become a focus of particular interest because, in contrast to acute inflammation, chronic inflammatory processes within the central nervous system (CNS) are crucial for the development of brain pathologies including depression. The synthesis of eicosanoids is catalysed primarily by cyclooxygenases (COX), which are involved in the production of pro-inflammatory AA metabolites, including prostaglandins and thromboxanes. Moreover, eicosanoid synthesis is catalysed by lipoxygenases (LOXs), which generate both leukotrienes and anti-inflammatory derivatives such as lipoxins. Thus, AA metabolites have double-edged pro-inflammatory and anti-inflammatory, pro-resolving properties, and an imbalance between these metabolites has been proposed as a contributor or even the basis for chronic neuroinflammatory effects. This review focuses on important evidence regarding eicosanoid-related pathways (with special emphasis on prostaglandins and lipoxins) that has added a new layer of complexity to the idea of targeting the double-edged AA-derivative pathways for therapeutic benefits in depression. We also sought to explore future research directions that can support a pro-resolving response to control the balance between eicosanoids and thus to reduce the chronic neuroinflammation that underlies at least a portion of depressive disorders.

Research paper thumbnail of Influence of the maternal immunoactivation on the neuron-microglia interactions in young offspring

Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2018

Background: Accumulating evidence suggests that microglial activation plays a key role in the pat... more Background: Accumulating evidence suggests that microglial activation plays a key role in the pathogenesis of various brain disorders, including depression. Activated microglia produce a wide range of factors, whose prolonged or excessive release may be crucial for the brain pathogenesis. Recently a growing body of evidence draws attention to the neuron-glia crosstalk as a mechanism of resolution of microglia activation. Among others the role of fractalkine (CX3CL1) and its receptor (CX3CR1) as well as CD200 and CD200 receptor (CD200R) has been identified in these processes. The expression of ligands on neurons and appropriate receptors (CX3CR1 and CD200R) mainly on microglial cells establishes a unique communication system between these cells within the central nervous system. We set out to asses, whether the maternal immune activation, based on the bacterial endotoxin (lipopolisaccharide, LPS) administration affects CX3CL1-CX3CR1 and CD200-CD200R communications in the brain of young offspring. Methods: Pregnant rats were injected subcutaneously with LPS at a dose of 2 mg/kg every second day from the seventh day of pregnancy until the delivery. Control pregnant rats were left undisturbed in their homecages. At 7 days of age, control and prenatally LPS-treated rats were decapitaded and hippocampi and frontal cortices were dissected. Then the protein levels of CX3CL1, CX3CR1, CD200 and CD200R was measured by western blot or ELISA methods. Results: The data showed that LPS treatment increased the CX3CL1 level in cortex, but not in hippocampus of young offspring. On the other hand in hippocampus and frontal cortex of young animals the diminished level of CD200R was observed. Conclusion: Our results provide evidence that prenatal immune activation leads to significant changes in neuronmicroglia axis in young offspring. It may be postulated that the presence of these disturbances during the critical neurodevelopmental period may play important role in the occurrence of schizophrenia-like behavioral deficits, observed in adult animals in this neurodevelopmental model of schizophrenia.

Research paper thumbnail of The Protective Properties of New Agonists of FPR2 on the Evoked by Bacterial Endotoxin Changes in Microglia Cells

Female Sprague-Dawley rats were paired with males. Pregnancy was confirmed the next morning. Prim... more Female Sprague-Dawley rats were paired with males. Pregnancy was confirmed the next morning. Primary microglia cultures were prepared from cortices of 1-2 day old offspring. Microglia cells were pretreated with each compound (1-500 nM) and next exposed to nonspecific immune system activator-LPS in the concentration of 100 ng/ml. Time-dependent (3-24 h) cell death was determined by lactate dehydrogenase release (LDH test).

Research paper thumbnail of Prenatal Priming with Lipopolysaccharide Enhances the Vulnerability to the Infections in the Adulthood in the Neurodevelopmental Model of Schizophrenia

Research paper thumbnail of Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Ureidopropanamides as Formyl Peptide Receptor 2 (FPR2) Agonists to Target the Resolution of Inflammation in Central Nervous System Disorders

Research paper thumbnail of Additional file 7 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 7: Figure S6. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 7: Figure S6. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the CA3 field of the hippocampus of PND7 offspring after MIA induced by Poly I:C treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 4 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 4: Figure S3. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 4: Figure S3. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the CA1 field of the hippocampus of PND7 offspring after MIA induced by LPS treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 3 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 3: Figure S2. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 3: Figure S2. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the DG of the hippocampus of PND7 offspring after MIA induced by Poly I:C treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 5 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 5: Figure S4. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 5: Figure S4. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the CA1 field of the hippocampus of PND7 offspring after MIA induced by Poly I:C treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 6 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 6: Figure S5. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 6: Figure S5. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the CA3 field of the hippocampus of PND7 offspring after MIA induced by LPS treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 2 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 2: Figure S1. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-C... more Additional file 2: Figure S1. Immunohistofluorescent staining of CX3CL1-CX3CR1 (A, B) and CD200-CD200R (C, D) localization on neurons and microglial cells in the DG of the hippocampus of PND7 offspring after MIA induced by LPS treatment. Representative confocal images showing colocalization of CX3CL1/CD200 (red) immunoreactivity with MAP2 (green)-positive neurons and CX3CR1/CD200R (red) immunoreactivity with IBA1 (green)-positive microglial cells. n = 2 in each group. Magnification: 40x for all images. Scale bar (10 μm) is located in the bottom right corner of each image.

Research paper thumbnail of Additional file 1 of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Additional file 1: Table S1. A list of genes (with corresponding catalogue numbers of TaqMan prob... more Additional file 1: Table S1. A list of genes (with corresponding catalogue numbers of TaqMan probes) examined in the hippocampi and the frontal cortices of male offspring at PND7 using qRT-PCR. B2m or Hprt were used as the reference genes.

Research paper thumbnail of The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Exhibits Anti-Inflammatory Activity in LPS-Stimulated Organotypic Hippocampal Cultures

Cells, 2021

Accumulating evidence indicates a pivotal role for chronic inflammatory processes in the pathogen... more Accumulating evidence indicates a pivotal role for chronic inflammatory processes in the pathogenesis of neurodegenerative and psychiatric disorders. G protein-coupled formyl peptide receptor 2 (FPR2) mediates pro-inflammatory or anti-/pro-resolving effects upon stimulation with biased agonists. We aimed to evaluate the effects of a new FPR2 ureidopropanamide agonist, compound MR-39, on neuroinflammatory processes in organotypic hippocampal cultures (OHCs) derived from control (WT) and knockout FPR2−/− mice (KO) exposed to bacterial endotoxin (lipopolysaccharide; LPS). Higher LPS-induced cytokine expression and basal release were observed in KO FPR2 cultures than in WT cultures, suggesting that a lack of FPR2 enhances the OHCs response to inflammatory stimuli. Pretreatment with MR-39 abolished some of the LPS-induced changes in the expression of genes related to the M1/M2 phenotypes (including Il-1β, Il-6, Arg1, Il-4, Cd74, Fizz and Cx3cr1) and TNF-α, IL-1β and IL-4 release in tissu...

Research paper thumbnail of The effect of chronic tianeptine administration on NLRP3 inflammasome pathway - study in an animal model of depression

Endocrine Abstracts, 2017

A growing body of evidence has focused on the impact of mitochondrial disturbances in the develop... more A growing body of evidence has focused on the impact of mitochondrial disturbances in the development of depression, but little data exist regarding the effects of chronic administration of antidepressant drugs on the brain's mitochondrial protein profile. The aim of this study was to investigate the impact of chronic treatment with an atypical antidepressant drug-tianeptine-on the mitochondria-enriched subproteome profile in the hippocampus and the frontal cortex of 3-month-old male rats following a prenatal stress procedure. Rats that were exposed to a prenatal stress procedure displayed depressive-and anxiety-like disturbances based on the elevated plus-maze and Porsolt tests. Moreover, twodimensional electrophoresis coupled with mass spectrometry showed structure-dependent mitoproteome changes in brains of prenatally stressed rats after chronic tianeptine administration. A component of 2-oxoglutarate and succinate flavoprotein subunit dehydrogenases, isocitrate subunit alpha, was upregulated in the hippocampus. In the frontal cortex, there was a striking increase in the expression of glutamate dehydrogenase and cytochrome bc1 complex subunit 2. These findings suggest that mitochondria are underappreciated targets for therapeutic interventions, and mitochondrial function may be crucial for the effective treatment of stress-related diseases.

Research paper thumbnail of Time-Dependent Protective and Pro-Resolving Effects of FPR2 Agonists on Lipopolysaccharide-Exposed Microglia Cells Involve Inhibition of NF-κB and MAPKs Pathways

Cells, 2021

Prolonged or excessive microglial activation may lead to disturbances in the resolution of inflam... more Prolonged or excessive microglial activation may lead to disturbances in the resolution of inflammation (RoI). The importance of specialized pro-resolving lipid mediators (SPMs) in RoI has been highlighted. Among them, lipoxins (LXA4) and aspirin-triggered lipoxin A4 (AT-LXA4) mediate beneficial responses through the activation of N-formyl peptide receptor-2 (FPR2). We aimed to shed more light on the time-dependent protective and anti-inflammatory impact of the endogenous SPMs, LXA4, and AT-LXA4, and of a new synthetic FPR2 agonist MR-39, in lipopolysaccharide (LPS)-exposed rat microglial cells. Our results showed that LXA4, AT-LXA4, and MR-39 exhibit a protective and pro-resolving potential in LPS-stimulated microglia, even if marked differences were apparent regarding the time dependency and efficacy of inhibiting particular biomarkers. The LXA4 action was found mainly after 3 h of LPS stimulation, and the AT-LXA4 effect was varied in time, while MR-39′s effect was mainly observed...

Research paper thumbnail of The impact of prenatal inflammatory priming on the neuron-microglia proteines expression in young offspring brain: immunohistochemical study in neurodevelopmental model of schizophrenia

Introduction : A number of studies suggest that in brain microglia are held in a surveillant and ... more Introduction : A number of studies suggest that in brain microglia are held in a surveillant and quiescent state of activation through several inhibitory signaling dyads. Recently the fractalkine (CX3CL1) and its receptor (CX3CR1) as well as CD200 and CD200 receptor (CD200R) are particularly noteworthy, because disruption of these networks extended the duration of pro-inflammatory response, mainly via malfunction of a unique communication system between neuron-microglia cells. Objective : To explore the possibility that maternal inflammatory priming based on the bacterial endotoxin (lipopolisaccharide, LPS) administration might serve as a trigger to disturbances in CX3CL1-CX3CR1 and CD200-CD200R signaling in the brain of young offspring. Material and Methods: Pregnant females were injected subcutaneously with LPS at a dose of 2 mg/kg every second day from the seventh day of pregnancy until the delivery. Control pregnant rats were left undisturbed in their homecages. At 7 days of ag...

Research paper thumbnail of Role of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation and Subsequent Immune Challenge in the Behaviour and Microglial Cell Trajectory in Adult Offspring: A Study of the Neurodevelopmental Model of Schizophrenia

International Journal of Molecular Sciences, 2021

Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the... more Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1β, Tnf-α, Il-6, Arg1, Igf-1, Tgf-β and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the “two-hit” hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led...

Research paper thumbnail of The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Improves Ex Vivo and In Vivo Amyloid Beta (1–42)-Induced Neuroinflammation in Mouse Models of Alzheimer’s Disease

Molecular Neurobiology, 2021

The major histopathological hallmarks of Alzheimer’s disease (AD) include β-amyloid (Aβ) plaques,... more The major histopathological hallmarks of Alzheimer’s disease (AD) include β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Aβ 1–42 (Aβ1-42) has been shown to induce neurotoxicity and secretion of proinflammatory mediators that potentiate neurotoxicity. Proinflammatory and neurotoxic activities of Aβ1-42 were shown to be mediated by interactions with several cell surface receptors, including the chemotactic G protein-coupled N-formyl peptide receptor 2 (FPR2). The present study investigated the impact of a new FPR2 agonist, MR-39, on the neuroinflammatory response in ex vivo and in vivo models of AD. To address this question, organotypic hippocampal cultures from wild-type (WT) and FPR2-deficient mice (knockout, KO, FPR2−/−) were treated with fibrillary Aβ1-42, and the effect of the new FPR2 agonist MR-39 on the release of pro- and anti-inflammatory cytokines was assessed. Similarly, APP/PS1 double-transgenic AD mice were treated for 20 weeks with MR-39, and immuno...

Research paper thumbnail of Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200–CD200R and CX3CL1–CX3CR1 Systems

Cells, 2020

Early life challenges resulting from maternal immune activation (MIA) may exert persistent effect... more Early life challenges resulting from maternal immune activation (MIA) may exert persistent effects on the offspring, including the development of psychiatric disorders, such as schizophrenia. Recent evidence has suggested that the adverse effects of MIA may be mediated by neuron–microglia crosstalk, particularly CX3CL1–CX3CR1 and CD200–CD200R dyads. Therefore, the present study assessed the behavioural parameters resembling schizophrenia-like symptoms in the adult male offspring of Sprague-Dawley rats that were exposed to MIA and to an additional acute lipopolysaccharide (LPS) challenge in adulthood, according to the “two-hit” hypothesis of schizophrenia. Simultaneously, we aimed to clarify the role of the CX3CL1–CX3CR1 and CD200–CD200R axes and microglial reactivity in the brains of adult offspring subjected to MIA and the “second hit” wit LPS. In the present study, MIA generated a range of behavioural changes in the adult male offspring, including increased exploratory activity an...

Research paper thumbnail of The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Journal of Neuroinflammation, 2020

Background The bidirectional communication between neurons and microglia is fundamental for the h... more Background The bidirectional communication between neurons and microglia is fundamental for the homeostasis and biological function of the central nervous system. Maternal immune activation (MIA) is considered to be one of the factors affecting these interactions. Accordingly, MIA has been suggested to be involved in several neuropsychiatric diseases, including schizophrenia. The crucial regulatory systems for neuron-microglia crosstalk are the CX3CL1-CX3CR1 and CD200-CD200R axes. Methods We aimed to clarify the impact of MIA on CX3CL1-CX3CR1 and CD200-CD200R signalling pathways in the brains of male Wistar rats in early and adult life by employing two neurodevelopmental models of schizophrenia based on the prenatal challenge with lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (Poly I:C). We also examined the effect of MIA on the expression of microglial markers and the profile of cytokines released in the brains of young offspring, as well as the behaviour of adult an...

Research paper thumbnail of The emerging role for the double-edged impact of arachidonic acidderived eicosanoids in the neuroinflammatory background of depression

Current Neuropharmacology, 2020

Eicosanoids are arachidonic acid (AA) derivatives belonging to a family of lipid signalling media... more Eicosanoids are arachidonic acid (AA) derivatives belonging to a family of lipid signalling mediators that are engaged in both physiological and pathological processes in the brain. Recently, their implication in the prolonged inflammatory response has become a focus of particular interest because, in contrast to acute inflammation, chronic inflammatory processes within the central nervous system (CNS) are crucial for the development of brain pathologies including depression. The synthesis of eicosanoids is catalysed primarily by cyclooxygenases (COX), which are involved in the production of pro-inflammatory AA metabolites, including prostaglandins and thromboxanes. Moreover, eicosanoid synthesis is catalysed by lipoxygenases (LOXs), which generate both leukotrienes and anti-inflammatory derivatives such as lipoxins. Thus, AA metabolites have double-edged pro-inflammatory and anti-inflammatory, pro-resolving properties, and an imbalance between these metabolites has been proposed as a contributor or even the basis for chronic neuroinflammatory effects. This review focuses on important evidence regarding eicosanoid-related pathways (with special emphasis on prostaglandins and lipoxins) that has added a new layer of complexity to the idea of targeting the double-edged AA-derivative pathways for therapeutic benefits in depression. We also sought to explore future research directions that can support a pro-resolving response to control the balance between eicosanoids and thus to reduce the chronic neuroinflammation that underlies at least a portion of depressive disorders.

Research paper thumbnail of Influence of the maternal immunoactivation on the neuron-microglia interactions in young offspring

Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2018

Background: Accumulating evidence suggests that microglial activation plays a key role in the pat... more Background: Accumulating evidence suggests that microglial activation plays a key role in the pathogenesis of various brain disorders, including depression. Activated microglia produce a wide range of factors, whose prolonged or excessive release may be crucial for the brain pathogenesis. Recently a growing body of evidence draws attention to the neuron-glia crosstalk as a mechanism of resolution of microglia activation. Among others the role of fractalkine (CX3CL1) and its receptor (CX3CR1) as well as CD200 and CD200 receptor (CD200R) has been identified in these processes. The expression of ligands on neurons and appropriate receptors (CX3CR1 and CD200R) mainly on microglial cells establishes a unique communication system between these cells within the central nervous system. We set out to asses, whether the maternal immune activation, based on the bacterial endotoxin (lipopolisaccharide, LPS) administration affects CX3CL1-CX3CR1 and CD200-CD200R communications in the brain of young offspring. Methods: Pregnant rats were injected subcutaneously with LPS at a dose of 2 mg/kg every second day from the seventh day of pregnancy until the delivery. Control pregnant rats were left undisturbed in their homecages. At 7 days of age, control and prenatally LPS-treated rats were decapitaded and hippocampi and frontal cortices were dissected. Then the protein levels of CX3CL1, CX3CR1, CD200 and CD200R was measured by western blot or ELISA methods. Results: The data showed that LPS treatment increased the CX3CL1 level in cortex, but not in hippocampus of young offspring. On the other hand in hippocampus and frontal cortex of young animals the diminished level of CD200R was observed. Conclusion: Our results provide evidence that prenatal immune activation leads to significant changes in neuronmicroglia axis in young offspring. It may be postulated that the presence of these disturbances during the critical neurodevelopmental period may play important role in the occurrence of schizophrenia-like behavioral deficits, observed in adult animals in this neurodevelopmental model of schizophrenia.

Research paper thumbnail of The Protective Properties of New Agonists of FPR2 on the Evoked by Bacterial Endotoxin Changes in Microglia Cells

Female Sprague-Dawley rats were paired with males. Pregnancy was confirmed the next morning. Prim... more Female Sprague-Dawley rats were paired with males. Pregnancy was confirmed the next morning. Primary microglia cultures were prepared from cortices of 1-2 day old offspring. Microglia cells were pretreated with each compound (1-500 nM) and next exposed to nonspecific immune system activator-LPS in the concentration of 100 ng/ml. Time-dependent (3-24 h) cell death was determined by lactate dehydrogenase release (LDH test).

Research paper thumbnail of Prenatal Priming with Lipopolysaccharide Enhances the Vulnerability to the Infections in the Adulthood in the Neurodevelopmental Model of Schizophrenia