Search

Microglia are the primary innate immune cells of the central nervous system and extensively contribute to brain homeostasis. Dysfunctional or excessive activity of microglia may be associated with several neuropsychiatric disorders, including schizophrenia. Therefore, we examined whether aripiprazole and risperidone could influence the expression of the Cd200–Cd200r and Cx3cl1–Cx3cr1 axes, which are crucial for the regulation of microglial activity and interactions of these cells with neurons. Additionally, we evaluated the impact of these drugs on microglial pro- and anti-inflammatory markers (Cd40, Il-1β, Il-6, Cebpb, Cd206, Arg1, Il-10 and Tgf-β) and cytokine release (IL-6, IL-10). The research was executed in organotypic cortical cultures (OCCs) prepared from the offspring of control rats (control OCCs) or those exposed to maternal immune activation (MIA OCCs), which allows for the exploration of schizophrenia-like disturbances in animals. All experiments were performed under basal conditions and after additional stimulation with lipopolysaccharide (LPS), following the “two-hit” hypothesis of schizophrenia. We found that MIA diminished the mRNA level of Cd200r and affected the OCCs’ response to additional LPS exposure in terms of this parameter. LPS downregulated the Cx3cr1 expression and profoundly changed the mRNA levels of pro- and anti-inflammatory microglial markers in both types of OCCs. Risperidone increased Cd200 expression in MIA OCCs, while aripiprazole treatment elevated the gene levels of the Cx3cl1–Cx3cr1 dyad in control OCCs. The antipsychotics limited the LPS-generated increase in the expression of proinflammatory factors (Il-1β and Il-6) and enhanced the mRNA levels of anti-inflammatory components (Cd206 and Tgf-β) of microglial polarization, mostly in the absence of the MIA procedure. Finally, we observed a more pronounced modulating impact of aripiprazole on the expression of pro- and anti-inflammatory cytokines when compared to risperidone in MIA OCCs. In conclusion, our data suggest that MIA might influence microglial activation and crosstalk of microglial cells with neurons, whereas aripiprazole and risperidone could beneficially affect these changes in OCCs.

Accumulating evidence indicates that early adverse life experiences may be involved in the pathogenesis of Alzheimer's disease (AD). Prenatal stress (PS) can affect brain maturation and neuroimmune and metabolic interactions, leading to age-dependent cognitive deficits in offspring. However, a multi-faceted cause-and-effect impact of PS on the development of cognitive deficits in the process of physiological ageing and in the APPNL-F/NL-F mouse model of Alzheimer's disease has not yet been evaluated.We have identified age-dependent cognitive learning and memory deficits using male C57BL/6 J (wild type, WT) and the knock-in APPNL-F/NL-F (KI) aged 12, 15, and 18 months. An increase in the Aβ42/Aβ40 ratio and mouse ApoE levels in the hippocampus and frontal cortex preceded the onset of cognitive deficits in the KI mice. Moreover, dysfunction in insulin signaling, including increased IRS-1 serine phosphorylation in both brain areas and the tyrosine phosphorylation deficit in the frontal cortex, suggested age-dependent insulin/IGF-1 resistance. Resistance was reflected by disturbances in mTOR or ERK1/2 kinase phosphorylation and excessive pro-inflammatory (TNF-α, IL-6, and IL-23) status in the KI mice. Importantly, our study has provided insights into the higher vulnerability to PS-induced exacerbation of age-dependent cognitive deficits and biochemical dysfunction in KI mice than in WT animals.We anticipate our study will lead to future investigation of a multi-faceted cause-and-effect relationship between stress during neurodevelopment and the onset of AD pathology, distinguishing it from changes in the course of dementia during normal ageing.

The dental pulp is the inner part of the tooth responsible for properly functioning during its lifespan. Apart from the very big biological heterogeneity of dental cells, tooth microenvironments differ a lot in the context of mechanical properties—ranging from 5.5 kPa for dental pulp to around 100 GPa for dentin and enamel. This physical heterogeneity and complexity plays a key role in tooth physiology and in turn, is a great target for a variety of therapeutic approaches. First of all, physical mechanisms are crucial for the pain propagation process from the tooth surface to the nerves inside the dental pulp. On the other hand, the modulation of the physical environment affects the functioning of dental pulp cells and thus is important for regenerative medicine. In the present review, we describe the physiological significance of biomechanical processes in the physiology and pathology of dental pulp. Moreover, we couple those phenomena with recent advances in the fields of bioengineering and pharmacology aiming to control the functioning of dental pulp cells, reduce pain, and enhance the differentiation of dental cells into desired lineages. The reviewed literature shows great progress in the topic of bioengineering of dental pulp—although mainly in vitro. Apart from a few positions, it leaves a gap for necessary filling with studies providing the mechanisms of the mechanical control of dental pulp functioning in vivo.

Microglial cells have been demonstrated to be significant resident immune cells that maintain homeostasis under physiological conditions. However, prolonged or excessive microglial activation leads to disturbances in the resolution of inflammation (RoI). Formyl peptide receptor 2 (FPR2) is a crucial player in the RoI, interacting with various ligands to induce distinct conformational changes and, consequently, diverse biological effects. Due to the poor pharmacokinetic properties of endogenous FPR2 ligands, the aim of our study was to evaluate the pro-resolving effects of a new ureidopropanamide agonist, compound AMS21, in hippocampal organotypic cultures (OHCs) stimulated with lipopolysaccharide (LPS). Moreover, to assess whether AMS21 exerts its action via FPR2 specifically located on microglial cells, we conducted a set of experiments in OHCs depleted of microglial cells using clodronate. We demonstrated that the protective and anti-inflammatory activity of AMS21 manifested as decreased levels of lactate dehydrogenase (LDH), nitric oxide (NO), and proinflammatory cytokines IL-1β and IL-6 release evoked by LPS in OHCs. Moreover, in LPS-stimulated OHCs, AMS21 treatment downregulated NLRP3 inflammasome-related factors (CASP1, NLRP3, PYCARD) and this effect was mediated through FPR2 because it was blocked by the FPR2 antagonist WRW4 pre-treatment. Importantly this beneficial effect of AMS21 was only observed in the presence of microglial FPR2, and absent in OHCs depleted with microglial cells using clodronate. Our results strongly suggest that the compound AMS21 exerts, at nanomolar doses, protective and anti-inflammatory properties and an FPR2 receptor located specifically on microglial cells mediates the anti-inflammatory response of AMS21. Therefore, microglial FPR2 represents a promising target for the enhancement of RoI.

Atypical antipsychotics currently constitute the first-line medication for schizophrenia, with quetiapine being one of the most commonly prescribed representatives of the group. Along with its specific affinity for multiple receptors, this compound exerts other biological characteristics, among which anti-inflammatory effects are strongly suggested. Simultaneously, published data indicated that inflammation and microglial activation could be diminished by stimulation of the CD200 receptor (CD200R), which takes place by binding to its ligand (CD200) or soluble CD200 fusion protein (CD200Fc). Therefore, in the present study, we sought to evaluate whether quetiapine could affect certain aspects of microglial activity, including the CD200-CD200R and CX3CL1-CX3CR1 axes, which are involved in the regulation of neuron–microglia interactions, as well as the expression of selected markers of the pro- and anti-inflammatory profile of microglia (Cd40, Il-1β, Il-6, Cebpb, Cd206, Arg1, Il-10 and Tgf-β). Concurrently, we examined the impact of quetiapine and CD200Fc on the IL-6 and IL-10 protein levels. The abovementioned aspects were investigated in organotypic cortical cultures (OCCs) prepared from the offspring of control rats (control OCCs) or those subjected to maternal immune activation (MIA OCCs), which is a widely implemented approach to explore schizophrenia-like disturbances in animals. The experiments were performed under basal conditions and after additional exposure to the bacterial endotoxin lipopolysaccharide (LPS), according to the “two-hit” hypothesis of schizophrenia. The results of our research revealed differences between control and MIA OCCs under basal conditions and in response to treatment with LPS in terms of lactate dehydrogenase and nitric oxide release as well as Cd200r, Il-1β, Il-6 and Cd206 expression. The additional stimulation with the bacterial endotoxin resulted in a notable change in the mRNA levels of pro- and anti-inflammatory microglial markers in both types of OCCs. Quetiapine diminished the influence of LPS on Il-1β, Il-6, Cebpb and Arg1 expression in control OCCs as well as on IL-6 and IL-10 levels in MIA OCCs. Moreover, CD200Fc reduced the impact of the bacterial endotoxin on IL-6 production in MIA OCCs. Thus, our results demonstrated that quetiapine, as well as the stimulation of CD200R by CD200Fc, beneficially affected LPS-induced neuroimmunological changes, including microglia-related activation.

Ischaemic stroke is characterized by a sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. As a result of this process, neurons in the ischaemic core are deprived of oxygen and trophic substances and are consequently destroyed. Tissue damage in brain ischaemia results from a complex pathophysiological cascade comprising various distinct pathological events. Ischaemia leads to brain damage by stimulating many processes, such as excitotoxicity, oxidative stress, inflammation, acidotoxicity, and apoptosis. Nevertheless, less attention has been given to biophysical factors, including the organization of the cytoskeleton and the mechanical properties of cells. Therefore, in the present study, we sought to evaluate whether the oxygen-glucose deprivation (OGD) procedure, which is a commonly accepted experimental model of ischaemia, could affect cytoskeleton organization and the paracrine immune response. The abovementioned aspects were examined ex vivo in organotypic hippocampal cultures (OHCs) subjected to the OGD procedure. We measured cell death/viability, nitric oxide (NO) release, and hypoxia-inducible factor 1α (HIF-1α) levels. Next, the impact of the OGD procedure on cytoskeletal organization was evaluated using combined confocal fluorescence microscopy (CFM) and atomic force microscopy (AFM). Concurrently, to find whether there is a correlation between biophysical properties and the immune response, we examined the impact of OGD on the levels of crucial ischaemia cytokines (IL-1β, IL-6, IL-18, TNF-α, IL-10, IL-4) and chemokines (CCL3, CCL5, CXCL10) in OHCs and calculated Pearsons’ and Spearman’s rank correlation coefficients. The results of the current study demonstrated that the OGD procedure intensified cell death and nitric oxide release and led to the potentiation of HIF-1α release in OHCs. Moreover, we presented significant disturbances in the organization of the cytoskeleton (actin fibers, microtubular network) and cytoskeleton-associated protein 2 (MAP-2), which is a neuronal marker. Simultaneously, our study provided new evidence that the OGD procedure leads to the stiffening of OHCs and a malfunction in immune homeostasis. A negative linear correlation between tissue stiffness and branched IBA1 positive cells after the OGD procedure suggests the pro-inflammatory polarization of microglia. Moreover, the negative correlation of pro- and positive anti-inflammatory factors with actin fibers density indicates an opposing effect of the immune mediators on the rearrangement of cytoskeleton induced by OGD procedure in OHCs. Our study constitutes a basis for further research and provides a rationale for integrating biomechanical and biochemical methods in studying the pathomechanism of stroke-related brain damage. Furthermore, presented data pointed out the interesting direction of proof-of-concept studies, in which follow-up may establish new targets for brain ischemia therapy.

Abstract 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 animals. Moreover, we visualized the localization of ligand-receptor systems in the hippocampal regions (CA1, CA3 and DG) and the frontal cortex of young rats exposed to MIA. The differences between groups were analysed using Student’s t test. Results We observed that MIA altered developmental trajectories in neuron-microglia communication in the brains of young offspring, as evidenced by the disruption of CX3CL1-CX3CR1 and/or CD200-CD200R axes. Our data demonstrated the presence of abnormalities after LPS-induced MIA in levels of Cd40, Il-1β, Tnf-α, Arg1, Tgf-β and Il-10, as well as IBA1, IL-1β and IL-4, while after Poly I:C-generated MIA in levels of Cd40, iNos, Il-6, Tgf-β, Il-10, and IBA1, IL-1β, TNF-α, IL-6, TGF-β and IL-4 early in the life of male animals. In adult male rats that experienced prenatal exposure to MIA, we observed behavioural changes resembling a schizophrenia-like phenotype. Conclusions Our study provides evidence that altered CX3CL1-CX3CR1 and/or CD200-CD200R pathways, emerging after prenatal immune challenge with LPS and Poly I:C, might be involved in the aetiology of schizophrenia.

The vitamin D receptor (VDR) belongs to the nuclear receptor superfamily of transcription factors. The VDR is expressed in diverse brain regions and has been implicated in the neuroprotective, antiaging, prosurvival, and anti-inflammatory action of vitamin D. Accordingly, a relationship between vitamin D insufficiency and susceptibility to neurodegenerative diseases has been suggested. However, due to the multitargeted mechanisms of vitamin D and its often overlapping genomic and nongenomic effects, the role of the VDR in brain pathologies remains obscure. In this narrative review, we present progress in deciphering the molecular mechanism of nuclear VDR-mediated vitamin D effects on prosurvival and anti-inflammatory signaling pathway activity within the central nervous system. In line with the concept of the neurovascular unit in pathomechanisms of neurodegenerative diseases, a discussion of the role of the VDR in regulating the immune and vascular brain systems is also included. Next, we discuss the results of preclinical and clinical studies evaluating the significance of vitamin D status and the efficacy of vitamin D supplementation in the treatment of Parkinson’s and Alzheimer’s diseases, emphasizing the possible role of the VDR in these phenomena. Finally, the associations of some VDR polymorphisms with higher risks and severity of these neurodegenerative disorders are briefly summarized.

Ischemic stroke is one of the major causes of death and permanent disability worldwide. The only efficient treatment to date is anticoagulant therapy and thrombectomy, which enable restitution of blood flow to ischemic tissues. Numerous promising neuroprotectants have failed in clinical trials. Given the complex pathomechanism of stroke, a multitarget pharmacotherapy seems a more rational approach in stroke prevention and treatment than drugs acting on single molecular targets. Recently, vitamin D3 has emerged as a potential treatment adjunct for ischemic stroke, as it interferes with the key prosurvival pathways and shows neuroprotective, anti-inflammatory, regenerative and anti-aging properties in both neuronal and vascular tissue. Moreover, the stimulatory effect of vitamin D3 on brain-derived neurotrophic factor (BDNF) signaling and neuroplasticity may play a role not only in the recovery of neurological functions, but also in ameliorating post-stroke depression and anxiety. This narrative review presents advances in research on the biochemical mechanisms of stroke-related brain damage, and the genomic and non-genomic effects of vitamin D3 which may interfere with diverse cell death signaling pathways. Next, we discuss the results of in vitro and in vivo experimental studies on the neuroprotective potential of 1alpha,25-dihydroxyvitamin D3 (calcitriol) in brain ischemia models. Finally, the outcomes of clinical trials on vitamin D3 efficiency in ischemic stroke patients are briefly reviewed. Despite the mixed results of the clinical trials, it appears that vitamin D3 still holds promise in preventing or ameliorating neurological and psychiatric consequences of ischemic stroke and certainly deserves further study.

The maternal immune activation produced by the systemic administration of lipopolysaccharide (LPS) in rats provides valuable insights into the basis of behavioural schizophrenia-like disturbances and biochemical changes in the brains of the offspring, such as microglial activation. Regarding therapy, antipsychotics continually constitute the cornerstone of schizophrenia treatment. To their various efficacy and side effects, as well as not fully recognised mechanisms of action, further characteristics have been suggested, including an anti-inflammatory action via the impact on neuron–microglia axes responsible for inhibition of microglial activation. Therefore, in the present study, we sought to determine whether chronic treatment with chlorpromazine, quetiapine or aripiprazole could influence schizophrenia-like behavioural disturbances at the level of sensorimotor gating in male offspring prenatally exposed to LPS. Simultaneously, we wanted to explore if the chosen antipsychotics display a positive impact on the neuroimmunological parameters in the brains of these adult animals with a special focus on the ligand-receptor axes controlling neuron–microglia communication as well as pro- and anti-inflammatory factors related to the microglial activity. The results of our research revealed the beneficial effect of quetiapine on deficits in sensorimotor gating observed in prenatally LPS-exposed offspring. In terms of axes controlling neuron–microglia communication and markers of microglial reactivity, we observed a subtle impact of quetiapine on hippocampal Cx3cl1 and Cx3cr1 levels, as well as cortical Cd68 expression. Hence, further research is required to fully define and explain the involvement of quetiapine and other antipsychotics in Cx3cl1-Cx3cr1 and/or Cd200-Cd200r axes modulation and inflammatory processes in the LPS-based model of schizophrenia-like disturbances.

Here we present comparative data on the inhibition of lipid peroxidation by a variety of tocochromanols in liposomes. We also show for the first time the potential neuroprotective role of all the vitamin E homologues investigated on the neuronally differentiated human neuroblastoma SH-SY5Y cell line. α-Tocopherol had nearly no effect in the inhibition of lipid peroxidation, while β-, γ-, and δ-tocopherols inhibited the reaction completely when it was initiated in a lipid phase. Similar effects were observed for tocotrienol homologues. Moreover, in this respect plastochromanol-8 was as effective as β-, γ-, and δ-tocochromanols. When the prenyllipids were investigated in a 1,1-diphenyl-2-picrylhydrazyl (DPPH) test and incorporated into different lipid carriers, the radical oxidation was most pronounced in liposomes, followed by mixed micelles and the micellar system. When the reaction of tocochromanols was examined in niosomes, the oxidation was most pronounced for α-tocopherol and plastochromanol-8, followed by α-tocotrienol. Next, using retinoic acid-differentiated SH-SY5Y cells, we tested the protective effects of the compounds investigated on hydrogen peroxide (H2O2)-induced cell damage. We showed that tocotrienols were more active than tocopherols in the oxidative stress model. Plastochromanol-8 had a strong inhibitory effect on H2O2-induced lactate dehydrogenase (LDH) release and H2O2-induced decrease in cell viability. The water-soluble α-tocopherol phosphate had neuroprotective effects at all the concentrations analyzed. The results clearly indicate that structural differences between vitamin E homologues reflect their different biological activity and indicate their potential application in pharmacological treatments for neurodegenerative diseases. In this respect, the application of optimal tocochromanol-carrying structures might be critical.

Major depressive disorder and a major depressive episode (MDD/MDE) are characterized by activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). In MDD/MDE, recent precision nomothetic psychiatry studies discovered a new endophenotype class, namely major dysmood disorder (MDMD), a new pathway phenotype, namely reoccurrence of illness (ROI), and a new model of the phenome of depression. The aim of the present study is to examine the association between ROI, the phenome of depression, and MDMD’s features and IRS, CIRS, macrophages (M1), T helper (Th)1, Th2, Th17, T regulatory, and growth factor (GF) profiles. Culture supernatants of unstimulated and stimulated (5 μg/mL of PHA and 25 μg/mL of LPS) diluted whole blood of 30 MDD/MDE patients and 20 controls were assayed for cytokines/GF using the LUMINEX assay. MDMD was characterized by increased M1, Th1, Th2, Th17, Treg, IRS, CIRS, neurotoxicity, and GF profiles. Factor analysis shows that ROI features and immune-GF profiles may be combined into a new pathway phenotype (an extracted latent vector). ROI, lifetime and recent suicidal behaviors, and severity of depression are significantly associated with immunotoxicity and GF profiles. Around 80.0% of the variance in the phenome is predicted by ROI and neurotoxicity or the IRS/CIRS ratio. The molecular pathways underpinning ROI-associated sensitization of immune/growth networks are transmembrane receptor protein kinase-triggered STAT protein phosphorylation, TLR/NF-κB, JAK-STAT, and the main proliferation/survival PI3K/Akt/RAS/MAPK pathway. In conclusion, MDMD’s heightened immune responses are the consequence of ROI-associated sensitization combined with immunostimulatory triggers.

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 after 24 h of stimulation by endotoxin. MR-39 was the only FPR2 ligand that attenuated LPS-evoked changes in the mitochondrial membrane potential and diminished the ROS and NO release. Moreover, the LPS-induced alterations in the microglial phenotype were modulated by LXA4, AT-LXA4, and MR-39. The anti-inflammatory effect of MR-39 on the IL-1β release was mediated through FPR2. All tested ligands inhibited TNF-α production, while AT-LXA4 and MR-39 also diminished IL-6 levels in LPS-stimulated microglia. The favorable action of LXA4 and MR-39 was mediated through the inhibition of ERK1/2 phosphorylation. AT-LXA4 and MR39 diminished the phosphorylation of the transcription factor NF-κB, while AT-LXA4 also affected p38 kinase phosphorylation. Our results suggest that new pro-resolving synthetic mediators can represent an attractive treatment option for the enhancement of RoI, and that FPR2 can provide a perspective as a target in immune-related brain disorders.

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 age, control and prenatally LPS-treated rats were decapitaded and hippocampi and frontal cortices were dissected. Immunohistofluorescent staining was performed using primary antibodies: anti-CX3CL1, anti-OX2 and anti-CX3CR1 as well as anti-OX2R. Moreover proteins were co-stained with neuronal (anti-MAP2), astroglial (anti-GFAP) and microglial markers (anti-Iba1), to clearly demonstrate the co-localization of CX3CL1, CD200, CD200R and CX3CR1 with brain cells in selected areas of hippocampus and frontal cortex of young offspring. Results: First we demonstrated the localization of CX3CL1 and CD200 mainly on neuronal cells, while CX3CR1 and CD200R on microglial cells in hippocampus and frontal cortex of young offspring. Analyzing both ligands localization we observed that maternal LPS administration tender to increase the expression of neuronal CX3CL1 in hippocampus, while CD200 in both examined brain areas. On the other hand, maternal immune challenge in the opposite way affects the microglial expression of CX3CR1 and CD200R. Prenatal exposure to LPS have been found to increase the CX3CR1 expression in hippocampus regions, while decrease a staining of CD200R in hippocampus and also in the frontal cortex of young offspring. Conclusions: These immunohistofluorescent data provide evidence that maternal exposure to immune challenges induce malfunction of neuron-microglia proteines staining in brain areas of young offspring. Thus phenomenon, termed prenatal neuroinflammatory priming, via disruption of homeostatic mechanisms regulating brain immune system, may be a key factor leading to the occurrence of schizophrenia-like behavioral deficits observed in adult animals in commonly accepted neurodevelopmental model of this disease.

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 tissue derived from WT but not KO mice. Receptor specificity was confirmed by adding the FPR2 antagonist WRW4, which abolished the abovementioned effects of MR-39. Further biochemical data showed an increase in the phospho-p65/total p65 ratio after LPS stimulation in hippocampal tissues from both WT and KO mice, and MR-39 only reversed this effect on WT OHCs. LPS also increased TRAF6 levels, which are critical for the TLR4-mediated NF-κB pro-inflammatory responses. MR-39 attenuated the LPS-evoked increase in the levels of the NLRP3 and caspase-1 proteins in WT but not KO hippocampal cultures. Since NLRP3 may be involved in the pyroptosis, a lytic type of programmed cell death in which the main role is played by Gasdermin D (GSDMD), we examined the effects of LPS and/or MR-39 on the GSDMD protein level. LPS only increased GSDMD production in the WT tissues, and this effect was ameliorated by MR-39. Collectively, this study indicates that the new FPR2 agonist efficiently abrogates LPS-induced neuroinflammation in an ex vivo model, as evidenced by a decrease in pro-inflammatory cytokine expression and release as well as the downregulation of NLRP3 inflammasome-related pathways.

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 and anxiety-like behaviours. The most intriguing finding was observed in the prepulse inhibition (PPI) test, where the deficit in the sensorimotor gating was age-dependent and present only in part of the rats. We were able to distinguish the occurrence of two groups: responsive and non-responsive (without the deficit). Concurrently, based on the results of the biochemical studies, MIA disrupted mainly the CD200–CD200R system, while the changes of the CX3CL1–CX3CR1 axis were less evident in the frontal cortex of adult non-responsive offspring. MIA markedly affected the immune regulators of the CD200–CD200R pathway as we observed an increase in cortical IL-6 release in the responsive group and IL-4 in the non-responsive offspring. Importantly, the “second hit” generated disturbances at the behavioural and biochemical levels mostly in the non-responsive adult animals. Those offspring were characterized both by disturbed PPI and “priming” microglia. Altogether, the exposure to MIA altered the immunomodulatory mechanisms, including the CD200–CD200R axis, in the brain and sensitized animals to subsequent immunological challenges, leading to the manifestation of schizophrenia-like alterations.

An increasing number of studies indicate that the chemokine system may be the third major communication system of the brain. Therefore, the role of the chemokine system in the development of brain disorders, including depression, has been recently proposed. However, little is known about the impact of the administration of various antidepressant drugs on the brain chemokine – chemokine receptor axis. In the present study, we used an animal model of depression based on the prenatal stress procedure. We determined whether chronic treatment with tianeptine, venlafaxine, or fluoxetine influenced the evoked by prenatal stress procedure changes in the mRNA and protein levels of the homeostatic chemokines, CXCL12 (SDF-1α), CX3CL1 (fractalkine) and their receptors, in the hippocampus and frontal cortex. Moreover, the impact of mentioned antidepressants on the TGF-β, a molecular pathway related to fractalkine receptor (CX3CR1), was explored. We found that prenatal stress caused anxiety and depressive-like disturbances in adult offspring rats, which were normalized by chronic antidepressant treatment. Furthermore, we showed the stress-evoked CXCL12 upregulation while CXCR4 downregulation in hippocampus and frontal cortex. CXCR7 expression was enhanced in frontal cortex but not hippocampus. Furthermore, the levels of CX3CL1 and CX3CR1 were diminished by prenatal stress in the both examined brain areas. The mentioned changes were normalized with various potency by chronic administration of tested antidepressants. All drugs in hippocampus, while tianeptine and venlafaxine in frontal cortex normalized the CXCL12 level in prenatally stressed offspring. Moreover, in hippocampus only fluoxetine enhanced CXCR4 level, while fluoxetine and tianeptine diminished CXCR7 level in frontal cortex. Additionally, the diminished by prenatal stress levels of CX3CL1 and CX3CR1 in the both examined brain areas were normalized by chronic tianeptine and partially fluoxetine administration. Tianeptine modulate also brain TGF-β signaling in the prenatal stress-induced animal model of depression. Our results provide new evidence that not only prenatal stress-induced behavioral disturbances but also changes of CXCL12 and their receptor and at less extend in CX3CL1–CX3CR1 expression may be normalized by chronic antidepressant drug treatment. In particular, the effect on the CXCL12 and their CXCR4 and CXCR7 receptors requires additional studies to elucidate the possible biological consequences.

Cocaine addiction is known to impair immune system function, but the effects of repeated treatment with cocaine in a self-administration model, its withdrawal as well as reinstatement of cocaine-seeking behavior on cell-mediated immunity are not well known. Cocaine self-administered for 18 days induced a significant increase in spleen weight, plasma corticosterone levels, interleukin (IL)-10, and tumor necrosis factor-α production, while concanavalin A–stimulated proliferation responses of peripheral blood T-lymphocytes and interferon-γ production by splenic lymphocytes were not altered. After 10 days withdrawal from cocaine, reinstatement of cocaine seeking behavior induced either by a priming dose of the drug (unconditioned stimulus), by cue previously associated with cocaine self-administration (conditioned stimuli), or by both these stimuli evoked similar changes in several immunological parameters, for example, a decrease in relative spleen weight, proliferative activity of splenocytes, and their ability to produce IL-10. The results showed that the cue previously associated with cocaine suppressed some parameters of cell-mediated immunity to the same degree as reexposure to cocaine. The present study provides the first evidence that alterations of immune status can be conditioned by environmental stimuli paired with cocaine administration. Keywords:: cocaine, extinction, relapse, self-administration, immune system

The potential contribution of inflammation to the development of neuropsychiatric diseases has recently received substantial attention. In the brain, the main immune cells are the microglia. As they are the main source of inflammatory factors, it is plausible that the regulation of their activation may be a potential therapeutic target. Fractalkine (CX3CL1) and its receptor CX3CR1 play a crucial role in the control of the biological activity of the microglia. In the present study, using microglial cultures we investigated whether fractalkine is able to reverse changes in microglia caused by a prenatal stress procedure. Our study found that the microglia do not express fractalkine. Prenatal stress decreases the expression of the fractalkine receptor, which in turn is enhanced by the administration of exogenous fractalkine. Moreover, treatment with fractalkine diminishes the prenatal stress-induced overproduction of proinflammatory factors such as IL-1β, IL-18, IL-6, TNF-α, CCL2, or NO in the microglial cells derived from prenatally stressed newborns. In conclusion, the present results revealed that the pathological activation of microglia in prenatally stressed newborns may be attenuated by fractalkine administration. Therefore, understanding of the role of the CX3CL1-CX3CR1 system may help to elucidate the mechanisms underlying the neuron-microglia interaction and its role in pathological conditions in the brain.

The effects of prenatal stress procedure were investigated in 3 months old male rats. Prenatally stressed rats showed depressive-like behavior in the forced swim test, including increased immobility, decreased mobility and decreased climbing. In ex vivo frontal cortex slices originating from prenatally stressed animals, the amplitude of extracellular field potentials (FPs) recorded in cortical layer II/III was larger, and the mean amplitude ratio of pharmacologically-isolated NMDA to the AMPA/kainate component of the field potential--smaller than in control preparations. Prenatal stress also resulted in a reduced magnitude of long-term potentiation (LTP). These effects were accompanied by an increase in the mean frequency, but not the mean amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in layer II/III pyramidal neurons. These data demonstrate that stress during pregnancy may lead not only to behavioral disturbances, but also impairs the glutamatergic transmission and long-term synaptic plasticity in the frontal cortex of the adult offspring.