Protective Effects of Cannabidiol (CBD) against Qxidative Stress, but Not Excitotoxic-Related Neuronal Cell Damage-An In Vitro Study.

Cannabidiol (CBD) appears to possess some neuroprotective properties, but experimental data are still inconsistent. Therefore, this in vitro study aimed to compare the effects of CBD in a wide range of concentrations on oxidative stress and excitotoxic-related cell damage. Results showed that low concentrations of CBD ameliorated the H2O2-evoked cell damage of primary cortical neuronal cell culture. However, higher concentrations of CBD alone (5-25 µM) decreased the viability of cortical neurons in a concentration-dependent manner and aggravated the toxic effects of hydrogen peroxide (H2O2). Neuroprotection mediated by CBD in primary neurons against H2O2 was not associated with a direct influence on ROS production nor inhibition of caspase-3, but we found protective effects of CBD at the level of mitochondrial membrane potential and DNA fragmentation. However, CBD had no protective effect on the glutamate-induced cell damage of cortical neurons, and in higher concentrations, it enhanced the toxic effects of this cell-damaging factor. Likewise, CBD, depending on its concentration, at least did not affect or even enhance cortical cellular damage exposed to oxygen-glucose deprivation (OGD). Finally, we showed that CBD in submicromolar or low micromolar concentrations significantly protected human neuronal-like SH-SY5Y cells against H2O2- and 6-hydroxydopamine (6-OHDA)-induced cell damage. Our data indicate that CBD has a dual effect on oxidative stress-induced neuronal death-in low concentrations, it is neuroprotective, but in higher ones, it may display neurotoxic activity. On the other hand, in excitotoxic-related models, CBD was ineffective or enhanced cell damage. Our data support the notion that the neuroprotective effects of CBD strongly depend on its concentration and experimental model of neuronal death.

Insights into the Potential Impact of Quetiapine on the Microglial Trajectory and Inflammatory Response in Organotypic Cortical Cultures Derived from Rat Offspring.

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-1ß, Il-6, Cebpb, Cd206, Arg1, Il-10 and Tgf-ß). 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-1ß, 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-1ß, 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.

The Vitamin D Receptor as a Potential Target for the Treatment of Age-Related Neurodegenerative Diseases Such as Alzheimer's and Parkinson's Diseases: A Narrative Review.

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.

Vitamin D3 and Ischemic Stroke: A Narrative Review.

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.

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.

Formyl peptide receptor 2 (FPR2) agonists can boost the resolution of inflammation and can offer alternative approaches for the treatment of pathologies with underlying chronic neuroinflammation, including neurodegenerative disorders. Starting from the FPR2 agonist 2 previously identified in our laboratory and through fine-tuning of FPR2 potency and metabolic stability, we have identified a new series of ureidopropanamide derivatives endowed with a balanced combination of such properties. Computational studies provided insights into the key interactions of the new compounds for FPR2 activation. In mouse microglial N9 cells and in rat primary microglial cells stimulated with lipopolysaccharide, selected compounds inhibited the production of pro-inflammatory cytokines, counterbalanced the changes in mitochondrial function, and inhibited caspase-3 activity. Among the new agonists, (S)-11l stands out also for the ability to permeate the blood-brain barrier and to accumulate in the mouse brain in vivo, thus representing a valuable pharmacological tool for studies in vivo.

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

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-1ß 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.

Formyl peptide receptor 2, as an important target for ligands triggering the inflammatory response regulation: a link to brain pathology.

Formyl peptide receptors (FPRs) belong to the family of seven-transmembrane G protein-coupled receptors. Among them, FPR2 is a low affinity receptor for N-formyl peptides and is considered the most promiscuous member of FPRs. FPR2 is able to recognize a broad variety of endogenous or exogenous ligands, ranging from lipid to proteins and peptides, including non-formylated peptides. Due to this property FPR2 has the ability to modulate both pro- and anti-inflammatory response, depending on the nature of the bound agonist and on the different recognition sites of the receptor. Thus, FPR2 takes part not only in the proinflammatory response but also in the resolution of inflammation (RoI) processes. Recent data have indicated that the malfunction of RoI may be the background for some central nervous system (CNS) disorders. Therefore, much interest is focused on endogenous molecules called specialized pro-resolving mediators (SPMs), as well as on new synthetic FPR2 agonists, which kick-start the resolution of inflammation (RoI) and modulate its course. Here, we shed some light on the general characteristics of the FPR family in humans and in the experimental animals. Moreover, we present a guide to understanding the "double faced" action of FPR2 activation in the context of immune-related diseases of the CNS.

The Emerging Role of the Double-Edged Impact of Arachidonic Acid- Derived Eicosanoids in the Neuroinflammatory Background of Depression.

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.

The Contribution of Formyl Peptide Receptor Dysfunction to the Course of Neuroinflammation: A Potential Role in the Brain Pathology.

Chronic inflammatory processes within the central nervous system (CNS) are in part responsible for the development of neurodegenerative and psychiatric diseases. These processes are associated with, among other things, the increased and disturbed activation of microglia and the elevated production of proinflammatory factors. Recent studies indicated that the disruption of the process of resolution of inflammation (RoI) may be the cause of CNS disorders. It is shown that the RoI is regulated by endogenous molecules called specialized pro-resolving mediators (SPMs), which interact with specific membrane receptors. Some SPMs activate formyl peptide receptors (FPRs), which belong to the family of seven-transmembrane G protein-coupled receptors. These receptors take part not only in the proinflammatory response but also in the resolution of the inflammation process. Therefore, the activation of FPRs might have complex consequences. This review discusses the potential role of FPRs, and in particular the role of FPR2 subtype, in the brain under physiological and pathological conditions and their involvement in processes underlying neurodegenerative and psychiatric disorders as well as ischemia, the pathogenesis of which involves the dysfunction of inflammatory processes.

Protective effects of polydatin in free and nanocapsulated form on changes caused by lipopolysaccharide in hippocampal organotypic cultures.

BACKGROUND: Polydatin (PD) is a compound, originally isolated from the root and rhizome of the Chinese herb Polygonum cuspidatum. To date, various biological properties of this compound, such as analgesic, anti-pyretic or diuretic effects, have been shown. Recently, anti-oxidant and anti-inflammatory properties have been widely postulated, yet PD instability and low bioavailability limit its beneficial actions. Therefore, it has been suggested that an encapsulation process may be a promising strategy for overcoming these limitations and increasing the therapeutic efficacy of PD. METHODS: We examined the effects of PD in two forms, including free and in PD-loaded polymeric nanocapsules, on lipopolysaccharide (LPS)-induced changes in hippocampal organotypic cultures. RESULTS: Our results indicated that free and encapsulated PD diminished cell death processes and attenuated the secretion of pro-inflammatory cytokines induced by LPS administration. Additionally, PD in both forms strongly inhibited the production of nitric oxide and down-regulated the level of iNOS enzyme in LPS-stimulated hippocampal cultures. CONCLUSION: Taken together, our study showed that PD exerts anti-inflammatory and anti-oxidant properties in LPS-treated hippocampal organotypic cultures. Furthermore, we show that the encapsulation procedure preserved the features of the free form of this compound, and therefore, the polymeric nanocapsules containing PD may be used as a novel and promising delivery system in therapeutic strategies.

Correction to: Role of Chronic Administration of Antidepressant Drugs in the Prenatal Stress-Evoked Inflammatory Response in the Brain of Adult Offspring Rats: Involvement of the NLRP3 Inflammasome-Related Pathway.

The original version of this article unfortunately contained mistake in Acknowledgment.

Role of Chronic Administration of Antidepressant Drugs in the Prenatal Stress-Evoked Inflammatory Response in the Brain of Adult Offspring Rats: Involvement of the NLRP3 Inflammasome-Related Pathway.

Evidence indicates that adverse experiences in early life may be a factor for immune disturbances leading to the depression in adulthood. Recently, a pivotal role in the pathogenesis of depression has been assigned to the activation of the brain Nod-like receptor pyrin-containing 3 (NLRP3) inflammasome. We investigated the impact of chronic treatment with antidepressant drugs on the behavioral disturbances and the levels of proinflammatory factors in the hippocampus and frontal cortex of adult male rats after prenatal stress exposure. Next, we explored the involvement of the NLRP3 inflammasome-related pathways in the mechanism of antidepressant action. Our study confirmed that chronic antidepressant treatment attenuated depression-like disturbances and exerted an anxiolytic action. All antidepressants diminished the prenatal stress-induced increase in IL-1ß in both brain areas, while IL-18 only in the hippocampus. Moreover, tianeptine administration diminished the increase in CCR2 levels in both brain areas, while in the hippocampus, tianeptine, along with venlafaxine CCL2 and iNOS levels. Next, we observed that in the hippocampus, tianeptine and fluoxetine suppressed upregulation of TLR4. Furthermore, venlafaxine suppressed NFкB p65-subunit phosphorylation, while fluoxetine enhanced the IкB level. Importantly, in the hippocampus, all antidepressants normalized evoked by stress changes in caspase-1 level, while tianeptine and venlafaxine also affect the levels of ASC and NLRP3 subunits. Our results provide new evidence that chronic administration of antidepressants exerts anti-inflammatory effects more pronounced in the hippocampus, through suppression of the NLRP3 inflammasome activation. These effects are accompanied by an improvement in the behavioral dysfunctions evoked by prenatal stress.

Stimulatory effect of desipramine on lung metastases of adenocarcinoma MADB 106 in stress highly-sensitive and stress non-reactive rats.

The effect of antidepressant drugs on tumor progress is very poorly recognized. The aim of the present study was to examine the effect of individual reactivity to stress and 24-day desipramine (DES) administration on the metastatic colonization of adenocarcinoma MADB 106 cells in the lungs of Wistar rats. Wistar rats were subjected to stress procedure according to the chronic mild stress (CMS) model of depression for two weeks and stress highly-sensitive (SHS) and stress non-reactive (SNR) rats were selected. SHS rats were more prone to cancer metastasis than SNR ones and chronic DES treatment further increased the number of lung metastases by 59% and 50% in comparison to vehicle-treated appropriate control rats. The increase in lung metastases was connected with DES-induced skew macrophage activity towards M2 functional phenotype in SHS and SNR rats. Moreover, during 24h after DES injection in healthy rats, the decreased number of TCD8+ and B cells in SHS and SNR rats as well as NK cell cytotoxic activity in SNR rats could be attributed to the lowered capacity to defend against cancer metastasis observed in chronic DES treated and tumor injected rats.

Prenatal stress affects viability, activation, and chemokine signaling in astroglial cultures.

CXCL12/SDF-1α and CX3CL1/fractalkine are constitutively expressed in the brain, which indicates their significant functions. Emerging evidence highlights the role of astrocytes and the immune system in the pathophysiology of stress-related disorders. The aim of this study was to assess whether prenatal stress affects chemokine signaling, cell viability/activation, and the iNOS pathway in astroglial cultures. Our results showed that prenatal stress lowered astrocyte viability and simultaneously increased GFAP expression. Furthermore, CX3CL1 production and the CXCL12/CXCR4-7 axis were also altered by prenatal stress. Taken together, malfunctions caused by prenatal stress may adversely influence brain development, leading to long-term effects on adult brain function and behavior.

Suppression of pro-inflammatory cytokine expression and lack of anti-depressant-like effect of fluoxetine in lipopolysaccharide-treated old female mice.

Some antidepressants show a significantly lower efficacy in elderly patients, particularly in women. Previous studies have shown that antidepressants administered to young animals reduced depression-like symptoms induced by lipopolysaccharide (LPS). The aim of this study was to find out whether the antidepressant and anti-inflammatory properties of fluoxetine (FLU) can be observed also in old female C57BL/6J mice. A depression-like state was evoked by the administration of LPS (100µg/kg for 4 consecutive days) which was followed by reduction of sucrose preference (anhedonia) and enhancement of immobility-time in the forced swim test (FST). Animals, which received FLU (10mg/kg, 11days) exhibited a decreased LPS-induced expression of some inflammatory cytokines in the hippocampus and spleen but this effect was not accompanied by beneficial changes in animals' behavior. Despite the lack of antidepressant-properties of FLU in this model, our studies have proven significant profound anti-inflammatory properties of chronic FLU treatment which may suggest its suitability for fending off inflammatory processes in the elderly.

Participation of protein kinases in cytotoxic and proapoptotic effects of ethylene glycol ethers and their metabolites in SH-SY5Y cells.

Ethylene glycol ethers (EGEs) are compounds widely used in many branches of industry. Their toxicological profile in the peripheral tissues is relatively well described, but little is known about their action on the central nervous system (CNS). In this study, we evaluated the effect of 2-ethoxyethanol (EE), 2-butoxyethanol (BE), 2-phenoxyethanol (PHE) and their metabolites on necrotic (estimated by cell viability and lactate dehydrogenase release) and apoptotic (caspase-3 activity and mitochondrial membrane potential) processes and reactive oxygen species' (ROS) production in human neuroblastoma (SH-SY5Y) cells. We have shown that, similar to the peripheral tissues, EGE metabolites in most of the performed assays revealed greater potential to damage than the parent compounds in the CNS cells. Subsequently, we investigated the participation of some selected protein kinases in the degenerative activity of PHE and its main metabolite, phenoxyacetic acid (PHA). It has been found that a GSK3ß inhibitor weakened the damaging effects of PHE and PHA in each of the performed assays. Furthermore, the kinases, p38-MAPK, JNK-MAPK and PKC, had a significant role in the cytotoxic and proapoptotic effects of PHA. These results indicate that the neurotoxic effect of EGEs may stem from their impact on many intracellular signal transduction pathways.

Encapsulation of curcumin in polyelectrolyte nanocapsules and their neuroprotective activity.

Poor water solubility and low bioavailability of lipophilic drugs can be potentially improved with the use of delivery systems. In this study, encapsulation of nanoemulsion droplets was utilized to prepare curcumin nanocarriers. Nanosize droplets containing the drug were encapsulated in polyelectrolyte shells formed by the layer-by-layer (LbL) adsorption of biocompatible polyelectrolytes: poly-L-lysine (PLL) and poly-L-glutamic acid (PGA). The size of synthesized nanocapsules was around 100 nm. Their biocompatibility and neuroprotective effects were evaluated on the SH-SY5Y human neuroblastoma cell line using cell viability/toxicity assays (MTT reduction, LDH release). Statistically significant toxic effect was clearly observed for PLL coated nanocapsules (reduction in cell viability about 20%-60%), while nanocapsules with PLL/PGA coating did not evoke any detrimental effects on SH-SY5Y cells. Curcumin encapsulated in PLL/PGA showed similar neuroprotective activity against hydrogen peroxide (H2O2)-induced cell damage, as did 5 µM curcumin pre-dissolved in DMSO (about 16% of protection). Determination of concentration of curcumin in cell lysate confirmed that curcumin in nanocapsules has cell protective effect in lower concentrations (at least 20 times) than when given alone. Intracellular mechanisms of encapsulated curcumin-mediated protection engaged the prevention of the H2O2-induced decrease in mitochondrial membrane potential (MMP) but did not attenuate Reactive Oxygen Species (ROS) formation. The obtained results indicate the utility of PLL/PGA shell nanocapsules as a promising, alternative way of curcumin delivery for neuroprotective purposes with improved efficiency and reduced toxicity.

Nanocapsules with Polyelectrolyte Shell as a Platform for 1,25-dihydroxyvitamin D3 Neuroprotection: Study in Organotypic Hippocampal Slices.

Calcitriol (1,25-dihydroxyvitamin D3), an active metabolite of vitamin D3, besides the role in calcium and phosphorus metabolism, plays a role in maintaining the functions of the brain. Active forms of vitamin D3 stimulate neurotrophic factors' expression, regulate brain immune processes, and prevent neuronal damage. Therefore, a potential utility of vitamin D3 in a therapy of neurodegenerative disorders should be taken into account. On the other hand, systemic vitamin D3 treatment carries the risk of undesirable effects, e.g., hypercalcemia. Thus, 1,25-dihydroxyvitamin D3 targeting delivery by nanoparticles would be a tremendous advancement in treatment of brain disorders. Calcitriol was enclosed in emulsion-templated nanocapsules with different polymeric shells: PLL (Poly(L-lysine hydrobromide)), PLL/PGA (/Poly(L-glutamic acid)), and PLL/PGA-g-PEG (Poly(L-glutamic acid) grafted with polyethylene glycol). The average size of all synthesized nanocapsules ranged from -80 to -100 nm. Biocompatibilities of synthesized nanocarriers were examined in hippocampal organotypic cultures in basal conditions and after treatment with lipopolysaccharide (LPS) using various biochemical tests. We demonstrated that nanocapsules coated with PLL were toxic, while PLL/PGA- and PLL/PGA-g-PEG-covered ones were nontoxic and used for further experiments. Our study demonstrated that in LPS-treated hippocampal slices, both types of loaded nanoparticles have protective ability. Our findings underlined that the neuroprotective action of vitamin D3 in both free and nanoparticle forms seems to be related to the suppression of LPS-induced nitric oxide release.

The Effect of Chronic Mild Stress and Imipramine on the Markers of Oxidative Stress and Antioxidant System in Rat Liver.

Liver abnormalities have been reported to occur in up to 20 % of patients on a long-term therapy with the tricyclic antidepressant drug imipramine (IMI). The mechanism involved in this IMI-induced process is unknown but a contribution of oxidative stress is highly likely. Chronic mild stress (CMS) is widely used for modeling depressive-like behavior in rats. In the present study, we examined the effects of CMS and chronic IMI treatment, applied alone or in combination, on the levels of oxidative stress markers, such as reactive oxygen species (ROS), malondialdehyde (MDA), non-protein sulfhydryl groups, and sulfane sulfur as well as on activities of key antioxidant enzymes: catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase in the rat liver. Administration of IMI for 5 weeks to rats subjected to CMS resulted in a gradual significant reduction of anhedonia measured by sucrose intake, in a majority of animals (CMS IMI-reactive, CMS IMI-R), although about 20 % of rats did not respond to the IMI treatment (CMS IMI non-reactive, CMS IMI-NR). CMS-induced hepatic oxidative stress, estimated by increased ROS and MDA concentrations, was not prevented by the IMI administration, moreover, in CMS IMI-NR animals, the level of the marker of lipid peroxidation, i.e., MDA was increased in comparison to CMS-subjected rats and activity of antioxidant enzymes (GPx and CAT) was decreased compared to IMI-treated rats. The clinical significance of this observation remains to be established.

Inhibitory effect of antidepressant drugs on contact hypersensitivity reaction is connected with their suppressive effect on NKT and CD8(+) T cells but not on TCR delta T cells.

BACKGROUND: Contact hypersensitivity (CHS) reaction induced by a topical application of hapten is a cell-mediated antigen-specific type of skin inflammation mediated by interaction of several subtypes of T cell subpopulations. Recently, it has been shown that antidepressant drugs inhibit CHS reaction, although the mechanism of this effect remains unknown. The aim of the present study was to investigate the effect of 2-week desipramine or fluoxetine administration on the CHS reaction induced by picryl chloride (PCL) application in B10.PL mice and in knock-out mice established on B10.PL background: TCRδ(-/-) mice lacking TCRγδ T lymphocytes; ß2m(-/-) mice lacking CD8(+) T lymphocytes and CD1d(-/-) mice lacking CD1d dependent natural killer T (NKT) lymphocytes. METHODS: B10.PL, TCRδ(-/-), ß2m(-/-) and CD1d(-/-) mice were divided into six groups: 1) vehicle-treated negative control group; 2) desipramine-treated negative control group; 3) fluoxetine-treated negative control group; 4) vehicle and PCL-treated group (positive control group); 5) desipramine and PCL-treated group; and 6) fluoxetine and PCL-treated group. CHS to PCL was tested by evaluation of ear swelling. Metabolic activity of spleen and lymph node cells were estimated by MTT test. RESULTS: The antidepressants significantly suppressed the CHS reaction in B10.PL mice: desipramine by 55% and fluoxetine by 42% compared to the positive control. This effect was even stronger in TCRδ(-/-) mice, in which fluoxetine reduced the ear swelling by 73% in comparison with the vehicle-treated positive control group. On the other hand, desipramine and fluoxetine did not inhibit CHS reaction in ß2m(-/-) and CD1d(-/-) mice. Moreover, PCL increased metabolic and/or proliferative activity of splenocytes in all four strains of mice whereas the antidepressants decreased this activity of splenocytes in B10.PL, TCRδ(-/-) and CD1d(-/-) mice. CONCLUSION: The results of the present study show that lack of CD8(+) T cells or NKT cells abolishes the immunosuppressive effect of antidepressant drugs on PCL-induced CHS reaction in mice. These results suggest that antidepressant drug-induced inhibition of CHS reaction is connected with their inhibitory effect on ability of CD8(+) T cells and NKT cells to induce and/or escalate CHS reaction. TCRγδ cells seem not to be involved in antidepressant-induced suppression of CHS.