Prenatal stress aggravates age-dependent cognitive decline, insulin signaling dysfunction, and the pro-inflammatory response in the APPNL-F/NL-F mouse model of Alzheimer's disease.

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 Aß42/Aß40 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.

Emerging Molecular Targets for Anti-Epileptogenic and Epilepsy Modifying Drugs.

The pharmacological treatment of epilepsy is purely symptomatic. Despite many decades of intensive research, causal treatment of this common neurologic disorder is still unavailable. Nevertheless, it is expected that advances in modern neuroscience and molecular biology tools, as well as improved animal models may accelerate designing antiepileptogenic and epilepsy-modifying drugs. Epileptogenesis triggers a vast array of genomic, epigenomic and transcriptomic changes, which ultimately lead to morphological and functional transformation of specific neuronal circuits resulting in the occurrence of spontaneous convulsive or nonconvulsive seizures. Recent decades unraveled molecular processes and biochemical signaling pathways involved in the proepileptic transformation of brain circuits including oxidative stress, apoptosis, neuroinflammatory and neurotrophic factors. The "omics" data derived from both human and animal epileptic tissues, as well as electrophysiological, imaging and neurochemical analysis identified a plethora of possible molecular targets for drugs, which could interfere with various stages of epileptogenetic cascade, including inflammatory processes and neuroplastic changes. In this narrative review, we briefly present contemporary views on the neurobiological background of epileptogenesis and discuss the advantages and disadvantages of some more promising molecular targets for antiepileptogenic pharmacotherapy.

Carnosic Acid Shows Higher Neuroprotective Efficiency than Edaravone or Ebselen in In Vitro Models of Neuronal Cell Damage.

This study compared the neuroprotective efficacy of three antioxidants-the plant-derived carnosic acid (CA), and two synthetic free radical scavengers: edaravone (ED) and ebselen (EB)-in in vitro models of neuronal cell damage. Results showed that CA protected mouse primary neuronal cell cultures against hydrogen peroxide-induced damage more efficiently than ED or EB. The neuroprotective effects of CA were associated with attenuation of reactive oxygen species level and increased mitochondrial membrane potential but not with a reduction in caspase-3 activity. None of the tested substances was protective against glutamate or oxygen-glucose deprivation-evoked neuronal cell damage, and EB even increased the detrimental effects of these insults. Further experiments using the human neuroblastoma SH-SY5Y cells showed that CA but not ED or EB attenuated the cell damage induced by hydrogen peroxide and that the composition of culture medium is the critical factor in evaluating neuroprotective effects in this model. Our data indicate that the neuroprotective potential of CA, ED, and EB may be revealed in vitro only under specific conditions, with their rather narrow micromolar concentrations, relevant cellular model, type of toxic agent, and exposure time. Nevertheless, of the three compounds tested, CA displayed the most consistent neuroprotective effects.

Targeting the NLRP3 Inflammasome-Related Pathways via Tianeptine Treatment-Suppressed Microglia Polarization to the M1 Phenotype in Lipopolysaccharide-Stimulated Cultures.

An increasing body of evidence postulates that microglia are the main mediators of inflammation-related disorders, including depression. Since activated microglia produce a wide range of pro- and anti-inflammatory factors, the modulation of M1/M2 microglial polarization by antidepressants may be crucial in the treatment of depression. The current paper aimed to investigate the impact of tianeptine on the microglia's viability/death parameters, and on M1/M2 microglial activation in response to lipopolysaccharide (LPS) stimulation. Furthermore, the molecular mechanisms via which tianeptine affected the LPS-evoked changes were investigated. The results revealed that tianeptine had partially protective effects on the changes in microglia viability/death evoked by LPS. Tianeptine attenuated microglia activation by decreasing the expression of cluster of differentiation 40 (CD40), and major histocompatibility complex class II (MHC II) markers, as well as the release of pro-inflammatory factors: interleukin (IL)-1ß, IL-18, IL-6, tumor necrosis factor alpha (TNF-α), and chemokine CC motif ligand 2 (CCL2), and the production of nitric oxide and reactive oxygen species. In contrast, we did not observe an impact of tianeptine on M2 microglia measured by IL-4, IL-10, TGF-ß, and insulin-like growth factor 1 (IGF-1) expression. Moreover, we demonstrated an inhibitory effect of tianeptine on the LPS-induced activation of the nucleotide-binding oligomerization domain-like (NOD-like) receptor pyrin-containing 3 inflammasome (NLRP3) inflammasome subunits, NLRP3 and caspase-1, as well as the ability of tianeptine to reduce Toll-like receptor 4 (TLR4) levels, as well as the phosphorylation of extracellular signal-related kinases 1 and 2 (ERK1/2) and of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Collectively, we demonstrated that tianeptine has protective properties and inhibits M1 polarization, thus attenuating the production of inflammatory mediators. Moreover, we found that M1 microglia suppression may be related to the NLRP3 inflammasome and TLR4 signaling. These findings suggest that a better understanding of the multifaceted mechanisms of tianeptine action on microglia may increase the effectiveness of therapy, where inflammation is a central hallmark.

Anti-inflammatory properties of tianeptine on lipopolysaccharide-induced changes in microglial cells involve toll-like receptor-related pathways.

Accumulating evidence suggests that activation of microglia plays a key role in the pathogenesis of depression. Activated microglia produce a wide range of factors whose prolonged or excessive release may lead to brain disorders. Thus, the inhibition of microglial cells may be beneficial in the treatment of depressive diseases. Tianeptine is an atypical antidepressant drug with proven clinical efficacy, but its mechanism of action remains still not fully understood. In the present study, using microglial cultures we investigated whether tianeptine modifies microglial activation after lipopolysaccharide (LPS) stimulation and which intracellular pathways are involved in the activity of this antidepressant. Our study shows that tianeptine attenuated the LPS-evoked inflammatory activation of microglia by decreasing the expression of proinflammatory cytokines such as IL-1ß, IL-18, IL-6 and tumor necrosis factor α (TNF-α), the release of nitric oxide (NO) and reactive oxygen species (ROS) as well as the expression of inducible nitric oxide synthase. Analyses of signaling pathways demonstrate that tianeptine led to the suppression of LPS-induced TLR4 expression and ERK1/2 phosphorylation. Furthermore, our study reveals the inhibitory impact of tianeptine on caspase-3-induced PKCδ degradation and consequently on the activation of NF-κB factor in microglial cells. Taken together, present results show anti-inflammatory properties of tianeptine in microglial cultures stimulated by LPS. This study provides evidence that the inhibition of microglial activation may underlie the therapeutic activity of tianeptine. Our findings show the anti-inflammatory effect of tianeptine (TIA) in lipopolisaccharide (LPS)-stimulated microglial cells. The beneficial tianeptine action is mediated through the inhibition of Toll-like receptor 4 (TLR4) expression as well as the TLR4-related pathways: extracellular signal-regulated kinase 1/2 (ERK1/2), caspase-3-dependent protein kinase δ (PKCδ) cleavage and the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These findings may provide a new therapeutic strategy for treatment of disorders based on neuroinflammation, including depression.

The impact of mitochondrial aldehyde dehydrogenase (ALDH2) activation by Alda-1 on the behavioral and biochemical disturbances in animal model of depression.

The etiology of depression remains still unclear. Recently, it has been proposed, that mitochondrial dysfunction may be associated with development of mood disorders, such as depression, bipolar disorder and anxiety disorders. Mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme responsible for the detoxification of reactive aldehydes, is considered to exert protective function in mitochondria. We investigated the influence of Alda-1, a small-molecule activator of ALDH2, on depressive- and anxiety-like behaviors in an animal model of depression - the prenatally stressed rats - using behavioral, molecular and proteomic methods. Prolonged Alda-1 administration significantly increased the climbing time, tended to reduce the immobility time and increased the swimming time of the prenatally stressed rats in the forced swim test. Moreover, treatment of prenatally stressed rats with Alda-1 significantly increased number of entries into the open arms of the maze and the time spent therein, as assessed by elevated plus-maze test. Such actions were associated with reduction of plasma 4-HNE-protein content, decrease of TNF-α mRNA and increase of PGC-1α (regulator of mitochondrial biogenesis) mRNA level in the frontal cortex and hippocampus of the prenatally stressed rats as well as with normalization of peripheral immune parameters and significant changes in expression of 6 and 4 proteins related to mitochondrial functions in the frontal cortex and hippocampus, respectively. Collectively, ALDH2 activation by Alda-1 led to a significant attenuation of depressive- and anxiety-like behaviors in the prenatally stressed rats. The pattern of changes suggested mitoprotective effect of Alda-1, however the exact functional consequences of the revealed alterations require further investigation.

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.

An Involvement of PI3-K/Akt Activation and Inhibition of AIF Translocation in Neuroprotective Effects of Undecylenic Acid (UDA) Against Pro-Apoptotic Factors-Induced Cell Death in Human Neuroblastoma SH-SY5Y Cells.

Undecylenic acid (UDA), a naturally occurring 11-carbon unsaturated fatty acid, has been used for several years as an economical antifungal agent and a nutritional supplement. Recently, the potential usefulness of UDA as a neuroprotective drug has been suggested based on the ability of this agent to inhibit µ-calpain activity. In order to verify neuroprotective potential of UDA, we tested protective efficacy of this compound against cell damage evoked by pro-apoptotic factors (staurosporine and doxorubicin) and oxidative stress (hydrogen peroxide) in human neuroblastoma SH-SY5Y cells. We showed that UDA partially protected SH-SY5Y cells against the staurosporine- and doxorubicin-evoked cell death; however, this effect was not connected with its influence on caspase-3 activity. UDA decreased the St-induced changes in mitochondrial and cytosolic AIF level, whereas in Dox-model it affected only the cytosolic AIF content. Moreover, UDA (1-40 µM) decreased the hydrogen peroxide-induced cell damage which was connected with attenuation of hydrogen peroxide-mediated necrotic (PI staining, ADP/ATP ratio) and apoptotic (mitochondrial membrane potential, caspase-3 activation, AIF translocation) changes. Finally, we demonstrated that an inhibitor of PI3-K/Akt (LY294002) but not MAPK/ERK1/2 (U0126) pathway blocked the protection mediated by UDA in all tested models of SH-SY5Y cell injury. These in vitro data point to UDA as potentially effective neuroprotectant the utility of which should be further validated in animal studies.

Elevated brain glucose and glycogen concentrations in an animal model of depression.

INTRODUCTION: Recent data indicate that there is a link between depression and diabetes and that excess glucocorticoids may play an underlying role in the pathogenesis of both of these diseases. The aim of the present study was to determine whether there are any alterations in glucose, glycogen, glucose transporters, insulin, insulin receptors or corticosterone concentrations in the hippocampus and frontal cortex in a prenatal stress rat model of depression. METHODS: Male rats whose mothers had been subjected to stress and control animals were subjected to the Porsolt test to verify the experimental model. Next, some of the rats were subjected to acute stress and/or were administered glucose. Glucose, glycogen, corticosterone, insulin, insulin receptor, phospho-insulin receptor and glucose transporter (GLUT1, GLUT3 and GLUT4) concentrations were assayed. RESULTS: Prenatally stressed rats exhibited glucose and glycogen concentrations in both investigated brain structures that exceeded those of the control animals. Prenatal stress also increased the levels of glucose transporters - GLUT1 in both tissues and GLUT4 in the frontal cortex. The changes in the prenatally stressed rats were more prominent in the animals that were subjected to stress or glucose loading in adulthood. CONCLUSION: The increase in carbohydrate brain concentrations evoked by prenatal stress may result from changes in the amounts of glucose transporters, especially GLUT1. Moreover, the obtained results support the hypothesis that stress during the perinatal period permanently increases the sensitivity of brain tissue to factors that act in adulthood. © 2014 S. Karger AG, Basel.

[The role of ATM kinase in neurodegeneration]. / Znaczenie kinazy ATM w procesach neurodegeneracyjnych.

Neurodegenerative diseases represent a major challenge for modern medicine. Despite many years of research, no effective neuroprotective therapy has been proposed. Ataxia telangiectasia (A-T) is rare disease, which is caused by a mutation of the ATM protein. Cerebellar degeneration is the main symptom of the A-T. The kinase ATM, inter alia is involved in the repair of DNA damage, cell cycle regulation and the control of apoptosis. In recent years the presence of that kinase in the cytoplasm has been demonstrated. This led to the discovery of its participation in the regulation of metabolic processes, homeostasis mitochondrial oxidative stress response or modulation of synaptic function. The pleiotropic effect of ATM kinase requires effective control exercised by, inter alia, proteins having specific binding motifs this kinase, such as ATMIN and NBS1. The regulation of prosurvival processes which are controlled by ATM kinase, may prove an attractive therapeutic strategy in treatment of neurodegenerative diseases.

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.

Presynaptic antiseizure medications - basic mechanisms and clues for their rational combinations.

Among clinically highly efficient antiseizure medications (ASMs) there are modifiers of the presynaptic release machinery. Of them, levetiracetam and brivaracetam show a high affinity to the synaptic vesicle protein type 2 A (SV2A), whereas pregabalin and gabapentin are selective ligands for the α2δ1 subunits of the voltage-gated calcium channels. In this paper, we present recent progress in understanding the significance of presynaptic release machinery in the neurochemical mechanisms of epilepsy and ASMs. Furthermore, we discuss whether the knowledge of the basic mechanisms of the presynaptically acting ASMs might help establish a rational polytherapy for drug-resistant epilepsy.

A new animal model of (chronic) depression induced by repeated and intermittent lipopolysaccharide administration for 4 months.

Chronic activation of immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways plays an important role in the pathophysiology of clinical depression. Increased IgA responses directed against LPS of gram-negative bacteria, indicating increased bacterial translocation, may be one of the drivers underpinning these pathways. There is a strong association between signs of bacterial translocation and chronicity of depression and O&NS, but not pro-inflammatory cytokines. The aims of the present study were to: (1) develop a new neurobehavioral model of (chronic) depression (anhedonic behavior) that may reflect chronic LPS stimulation and is associated with increased oxidative stress, and (2) to delineate the effects of fluoxetine on this new depression model. We established that in female mice repeated LPS injections once daily for 5 days (from 750 µg/kg to a maximal dose 1250 µg/kg; increasing doses for the first three days which were then gradually decreased on day 4 and 5) at a one-month interval and this repeated for 4 consecutive months induced chronic anhedonia (estimated by the preference to drink a 1% sucrose) lasting for at least 7 weeks. Chronic LPS administration significantly decreased thymus weight, proliferative activity of splenocytes, production of interferon (IFN)γ and interleukin-(IL)10, and increased superoxide and corticosterone production. Treatment with fluoxetine for 3 weeks abolished the neurobehavioral effects of LPS. The antidepressant effect of fluoxetine was accompanied by increased production of IL-10 and reduced superoxide and corticosterone production. Our results suggest that repeated intermittent LPS injections to female mice may be a useful model of chronic depression and in particular for the depressogenic effects of long standing activation of the toll-like receptor IV complex.

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.

Effects of cocaine-kindling on the expression of NMDA receptors and glutamate levels in mouse brain.

In the present study we examined the effects of cocaine seizure kindling on the expression of NMDA receptors and levels of extracellular glutamate in mouse brain. Quantitative autoradiography did not reveal any changes in binding of [³H] MK-801 to NMDA receptors in several brain regions. Likewise, in situ hybridization and Western blotting revealed no alteration in expression of the NMDA receptor subunits, NR1 and NR2B. Basal overflow of glutamate in the ventral hippocampus determined by microdialysis in freely moving animals also did not differ between cocaine-kindled and control groups. Perfusion with the selective excitatory amino acid transporter inhibitor, pyrrolidine-2,4-dicarboxylic acid (tPDC, 0.6 mM), increased glutamate overflow confirming transport inhibition. Importantly, KCl-evoked glutamate overflow under tPDC perfusion was significantly higher in cocaine-kindled mice than in control mice. These data suggest that enhancement of depolarization stimulated glutamate release may be one of the mechanisms underlying the development of increased seizure susceptibility after cocaine kindling.

Preclinical Evidence for the Interplay between Oxidative Stress and RIP1-Dependent Cell Death in Neurodegeneration: State of the Art and Possible Therapeutic Implications.

Neurodegenerative diseases are the most frequent chronic, age-associated neurological pathologies having a major impact on the patient's quality of life. Despite a heavy medical, social and economic burden they pose, no causative treatment is available for these diseases. Among the important pathogenic factors contributing to neuronal loss during neurodegeneration is elevated oxidative stress resulting from a disturbed balance between endogenous prooxidant and antioxidant systems. For many years, it was thought that increased oxidative stress was a cause of neuronal cell death executed via an apoptotic mechanism. However, in recent years it has been postulated that rather programmed necrosis (necroptosis) is the key form of neuronal death in the course of neurodegenerative diseases. Such assumption was supported by biochemical and morphological features of the dying cells as well as by the fact that various necroptosis inhibitors were neuroprotective in cellular and animal models of neurodegenerative diseases. In this review, we discuss the relationship between oxidative stress and RIP1-dependent necroptosis and apoptosis in the context of the pathomechanism of neurodegenerative disorders. Based on the published data mainly from cellular models of neurodegeneration linking oxidative stress and necroptosis, we postulate that administration of multipotential neuroprotectants with antioxidant and antinecroptotic properties may constitute an efficient pharmacotherapeutic strategy for the treatment of neurodegenerative diseases.

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

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-1ß, Il-6, Arg1, Il-4, Cd74, Fizz and Cx3cr1) and TNF-α, IL-1ß 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.

[Immunological and endocrinological pattern in ADHD etiopathogenesis]. / Udzial czynników immunologicznych i endokrynnych w etiopatogenezie ADHD.

Attention-Deficit Hyperactivity Disorder (ADHD) is the most prevalent neurodevelopmental disorder among children. There are 3 subtypes of ADHD: (1) with prevalent inattentive symptoms (2) with prevalent hyperactive-impulsive symptoms and (3) the combined subtype. It typically manifests itself before age 7 years and occurs more frequently in boys than in girls. It is diagnosed when the hyperactivity, impulsiveness and inattention last long, appear at least in two environments and their intensity impairs the functioning of the child. The etiology of ADHD is not well-known but recent studies have shown that genetic factors are of big importance. Also several environmental influences that raise the risk for ADHD development have been identified. Recently, it has been postulated that the reduced activity of the dopaminergic and noradrenergic systems play a crucial role in ADHD pathogenesis. It is evidenced by the fact that drugs intensifying the noradrenergic and dopaminergic transmission are the most successful for ADHD treatment. At present, it has been also postulated that the disturbances in endocrine and immune systems are involved in the ADHD pathogenesis. Interconnections between functions of these systems and function of neurotransmitters are better recognized now and show that disturbances in their cooperation can be involved in some psychiatric disorders. In the case of ADHD, most data are related to disturbances in the activity of the hypothalamus-pituitary-adrenal (HPA) axis activity. In particular, the lower level of cortisol in children with ADHD, especially in the hyperactive-impulsive type ADHD, the disturbance in the circadian rhythm of this steroid and the lack of its inhibition by the dexamethasone have been documented. Many clinical data indicate that in children with ADHD, the psychological stress evokes a weaker activation of the HPA axis than in the control group. Epidemiological and preclinical investigations have shown that the disturbance in the HPA axis in ADHD can result from an excessive exposure to glucocorticoids in the fetal and early postnatal periods. Glucocorticoid administration in this period of life can provoke permanent changes in the level of brain glucocorticoid receptors and, in consequence, dysregulation of HPA axis activity, disturbances in biosynthesis of the neurotransmitters and their receptors and changes in the intracellular pathways. Glucocorticoids are known to intensify the dopaminergic system activity, so the decrease in their expression in ADHD can cause the hypofunction of this system. Since the attention and motor activity disorders often occur in children with generalized resistance to thyroid hormones, their role in ADHD pathogenesis was evaluated. However, most of the studies indicated that the levels of triiodothyronine (T3), thyroxine (T4), the free thyroxine, and the thyroid stimulating hormone (TSH) did not change in ADHD. Preclinical data concerning the role of androgens in the ADHD pathogenesis suggest that the elevated testosterone level can diminish the brain blood flow in the frontal cortex, via lowering of the level of estrogen receptor-alpha and the vascular endothelial growth factor (VEGF), and in consequence disturb processes of the memory. The association between ADHD and the polymorphism of the gene coding for androgen receptor, which leads to its higher expression has been found, however, the issue of the androgen participation in the ADHD pathogenesis is still poorly recognized. Frequent co-occurrence of ADHD and allergic diseases and correlation between ADHD and streptococcus-mediated neuropsychiatric disorders suggest the participation of the immune system in the ADHD pathogenesis. Also experimental data from an animal model of ADHD showed changes in the expression in at least several essential genes for the immune system function. However, on the other hand, the lack of the association between asthma and immunoglobulin E- dependent athopic reaction and the lack of the elevated anti-ganglia antibodies in ADHD speaks against the implication of autoimmunity in ADHD pathogenesis. Since psychostimulants, the most therapeutically efficient drugs in ADHD, not only increase the level of the dopamine and norepinephrines but also increase the activity of the HPA axis and reduce the concentration of androgens, it cannot be excluded that their beneficial effect can partly issue from a normalizing action on hormonal levels. However, currently available clinical and experimental data do not permit precise estimation of the role of endocrine and immune systems in the pathogenesis of ADHD and in therapeutic action of psychostimulants.

Developments in the discovery and design of intranasal antidepressants.

INTRODUCTION: Depression remains a major cause of morbidity worldwide; consequently, there is a need in neuropsychiatry for new antidepressants with a rapid onset of action. Intranasal administration of antidepressants is an attractive and promising approach to the treatment of mental disorders, as this route is noninvasive, offers a fast onset of action and improved drug bioavailability, allows a drug dose reduction, as well as gives the possibility to bypass the blood-brain barrier and reduce the number of systemic side effects. AREAS COVERED: This review is a comprehensive discussion of the available intranasal drugs that have found application as antidepressants. The results of relevant clinical studies are presented. Additionally, the use of nanotechnology-based formulations for enhancing the intranasal delivery of antidepressants is briefly described. EXPERT OPINION: Intranasal drug delivery has a huge potential for antidepressant administration, but its use in the treatment of central nervous system disorders is currently very limited. The nasal route of antidepressant delivery is noninvasive, improves drug bioavailability, as well as allows to overcome the problem with the blood-brain barrier, gastrointestinal absorption, and first-pass metabolism. In our opinion, fast-acting intranasal antidepressants will be widely used in the treatment of mental disorders in the future.