Neuroinflammatory Factors Research Articles

Probiotics modify body weight together with anxiety states via pro-inflammatory factors in HFD-treated Syrian golden hamster

Emerging studies are beginning to suggest that emotional states together with healthful measures constitute pertinent features of our lifestyle in which bad eating habits but more importantly what our gut has to host are causing great concern. It is well known that humans have established mutual relationships with a wide array of colonized microbes (collectively called gut microbiota) consisting of bacteria, fungi, eukaryotic parasites and viruses. The gut microbiota has exhibited a notable ability of communicating with the brain via a two-way system that includes the vagus nerve, immune sites, and a number of neurotransmitters. Interestingly, stressful along with obesity, cognitive, and brain developmental states are strongly influenced by microbiota homeostatic conditions. It was our aim to investigate behavioral and obesity effects evoked by treatment with probiotics via neuroinflammatory factors and namely IL-1β, NLRP3, Caspase-1 and NF-kB levels in the Syrian golden hamster. Following treatment with a high-fat diet (HFD), in the presence or absence of a multi-species probiotic formulation, hamsters were exposed to an unpredictable chronic mild stress (UCMS) test for 4 weeks. Independently of the diet, probiotics treatment markedly reduced stress-like behaviors in the different mazes. Moreover, probiotics decreased hypothalamic expression levels of the pro-neuroinflammatory factors like IL-1β, NLRP3, Caspase-1 and NF-kB, whereas HFD increased them. Contextually, they decreased plasmatic levels of IL-1β, NLRP3 and caspase-1 but not NF-kB. Our findings clearly support probiotics as a potentially valuable treatment strategy in obesity and anxiety, thereby proposing them for clinical treatments in patients with metabolic and mood disorders.

DNA binding protein HMGB1 secreted by activated microglia promotes the apoptosis of hippocampal neurons in diabetes complicated with OSA

Type 2 diabetes mellitus (T2DM) complicated with obstructive sleep apnea (OSA) may cause neuronal apoptosis and cognitive deficits, but the underlying mechanisms remain unclear. We aimed to determine the relationship between the activation of microglia and the apoptosis of hippocampal neurons, specifically in terms of high mobility group box-1 (HMGB1), after high glucose (HG) and intermittent hypoxia (IH) exposure. Diabetic KK-Ay mice and non-diabetic C57BL/6J mice (C57 mice) underwent IH or normoxia (control) exposure for 4 weeks. Cognitive function, microglial activation and hippocampal neuronal apoptosis were assessed after IH or normoxia exposure. Compared with C57 control mice, KK-Ay control mice exhibited increased cognitive dysfunction, microglial activation and hippocampal neuronal apoptosis. There were no differences between untreated KK-Ay control mice and C57 mice that had been exposed to IH. The abovementioned responses were aggravated in IH-exposed KK-Ay mice compared with control KK-Ay mice. In vitro, a cellular co-culture experiment showed that HG combined with IH could activate BV2 microglia, leading to the release of neuroinflammatory factors (ROS, TNF-α, IL-1β) and mediating the apoptosis of HT22 cells via the PI3K/Akt/GSK-3β signaling pathway. Meanwhile, HMGB1 was actively secreted into the extracellular environment from activated BV2 microglia. As a proinflammatory factor, it was able to sustain microglial activation by directly acting on those cells. The activation promoted positive feedback and aggravated neuronal damage further. In a cellular monoculture or co-culture system, HMGB1 siRNA was able to alleviate the activation of BV2 cells and the apoptosis of HT22 cells induced by HG combined with IH. Our object is to show that inhibition of HMGB1 may break the vicious cycle to prevent or treat neuroinflammation and hippocampal neuronal apoptosis caused by T2DM complicated with OSA.

Correlation between hypertension and brain neuroinflammatory factors in the spontaneously hypertensive rat

Correlation between hypertension and brain neuroinflammatory factors in the spontaneously hypertensive rat

AMPK/Nrf2 signaling is involved in the anti-neuroinflammatory action of Petatewalide B from Petasites japonicus against lipopolysaccharides in microglia

Objectives: Abnormal microglia secrete neuroinflammatory factors that play a pivotal role in neurodegenerative-disorder development. Thus, regulating abnormal microglia-activation could be a promising therapeutic strategy. The purposes of this study included investigating the effect of Petatewalide B on lipopolysaccharide- (LPS-) stimulated microglia and exploring the role of the AMPK/Nrf2- (adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor 2) signaling pathway in the anti-neuroinflammatory function of Petatewalide B.Methods: We divided the microglia into four groups: a control group, a Petatewalide B-treated group, an LPS-treated group, and an LPS and Petatewalide B-treated group. The four groups of microglia were experimented with, using the NO, ELISA, and promoter assays, and western blotting was conducted to determine LPS-stimulated neuroinflammatory responses.Results: We found that pretreatment with Petatewalide B strongly alleviates interleukin- (IL-) 1β, IL-6, and tumor-necrosis-factor-α (TNF-α) production, and suppresses iNOS and nitric oxide (NO) overexpression in LPS-stimulated microglia. The AMPK/Nrf2-signaling pathway is important for inducing anti-neuroinflammatory responses. Mechanistic studies report that Petatewalide B increases nuclear-Nrf2 translocation, and heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) expression in a dose-dependent manner. Furthermore, Petatewalide B significantly up-regulates HO-1 and NQO1 by specifically improving antioxidant-response-elements-transcription activity. We then investigated whether Nrf2/HO-1/NQO1 contribute to the anti-neuroinflammatory properties of Petatewalide B. Nrf2, HO-1, and NQO1 small-integrating-ribonucleic-acids (siRNAs) significantly blocked Petatewalide B-attenuated iNOS-promoter-activity in LPS-stimulated microglia. Furthermore, Petatewalide B also up-regulated AMPK-phosphorylation in a dose-dependent manner. We next evaluated whether blocking AMPK-phosphorylation using an inhibitor (compound C) would critically affect anti-neuroinflammatory responses. We found that the AMPK-phosphorylation is associated with nuclear-Nrf2 translocation and elevated HO-1 and NQO1 expression levels. Our data also showed that AMPK-inhibitor pretreatment significantly reverses Petatewalide B-attenuated iNOS-promoter-activity in LPS-stimulated microglia.Conclusions: Our findings provide the possible mechanism of the anti-neuroinflammatory properties of Petatewalide B that result from beneficial responses in the AMPK/Nrf2-signaling pathway.

Role of Brain Neuroinflammatory Factors on Hypertension in the Spontaneously Hypertensive Rat

It is already widely known that the different brain areas involved in blood pressure control, are highly vulnerable to the deleterious effects of this condition. Of particular concern are hypertensive and neuroinflammatory-dependent injuries that by modifying blood flow account for artery structural and functional alterations. It was thus our intention to establish if expression changes of some key brain neuroinflammatory factors like caspase-1,3, NF-kB, IL-1β and NLRP3, which are known to control blood pressure, are actively involved with inflammation regulatory events in a highly valuable spontaneously hypertensive rat (SHR) model. Indeed, notably increased (p < 0.001) caspase-1, NLRP3 and IL-1β mRNA levels were detected in amygdalar plus hypothalamic areas of SHR. Contextually, similar up-regulated levels of these factors were also reported in brainstem nuclei with respect to the few hippocampal areas. This trend was supported by moderate increases (p < 0.05) of NLRP3 in amygdalar and brainstem sites, while notably greater expression differences of NF-kB protein were observed in hippocampal and hypothalamic areas of SHR. At the same time, moderately increased levels of iNOS were typical of all of the above brain areas with the exception of the consistently (p < 0.01) increased levels featured in the brainstem. Moreover, even immunohistochemical evaluations supplied notably and moderately increased cleaved caspase-3 cell levels in hippocampus and hypothalamus areas, respectively. Overall, evident hypertensive bouts correlated to neuroinflammatory events, especially in brain areas controlling blood pressure, tend to underlie the value of novel therapeutic approaches designed to improve brain blood flow and subsequently reduce hypertensive-dependent cerebral complications.

Exosomes secreted by stem cells from human exfoliated deciduous teeth contribute to functional recovery after traumatic brain injury by shifting microglia M1/M2 polarization in rats

BackgroundTraumatic brain injury (TBI) is one of the major causes of mortality and disability for all ages worldwide. Mesenchymal stem cells (MSCs)-originated exosomes have provided therapeutic effects. However, as an indispensable component of MSCs, whether odontogenic stem cell-generated exosomes could benefit TBI is still unclear. Thus we aimed to explore the potential of stem cells from human exfoliated deciduous teeth-originated exosomes (SHED-Ex) for the management of TBI.MethodsFirst, a transwell system was used to co-culture activated BV-2 microglia cells with SHED. The secretion levels of neuroinflammatory factors and nitrite were evaluated by enzyme-linked immunosorbent assay (ELISA) and Griess assay. Furthermore, purified SHED-Ex were co-cultured with activated BV-2. ELISA, Griess assay, flow cytometry, immunofluorescence, and qRT-PCR were performed to test the levels of inflammatory factors as well as the microglia phenotype. Finally, SHED and SHED-Ex were locally injected into TBI rat models. Basso, Beattie, and Bresnahan (BBB) scores were chosen to evaluate the motor functional recovery. Histopathology and immunofluorescence were performed to measure the lesion volume and neuroinflammation.ResultsAs a result, SHED-Ex could reduce neuroinflammation by shifting microglia polarization. The administration of SHED-Ex improves rat motor functional recovery and reduces cortical lesion compared with the control group 2 weeks post-injury (P < 0.05).ConclusionsThe current study demonstrates for the first time that SHED-Ex contribute a therapeutic benefit to TBI in rats, at least in part by shifting microglia polarization to reduce neuroinflammation. The use of odontogenic stem cells, and indeed their exosomes, may be expanded for the treatment of TBI or other neurological disorders.

Cafeteria diet induces neuroplastic modifications in the nucleus accumbens mediated by microglia activation.

High-palatable and caloric foods are widely overconsumed due to hedonic mechanisms that prevail over caloric necessities leading to overeating and overweight. The nucleus accumbens (NAc) is a key brain area modulating the reinforcing effects of palatable foods and is crucially involved in the development of eating disorders. We describe that prolonged exposure to high-caloric chocolate cafeteria diet leads to overeating and overweight in mice. NAc functionality was altered in these mice, presenting structural plasticity modifications in medium spiny neurons, increased expression of neuroinflammatory factors and activated microglia, and abnormal responses after amphetamine-induced hyperlocomotion. Chronic inactivation of microglia normalized these neurobiological and behavioural alterations exclusively in mice exposed to cafeteria diet. Our data suggest that prolonged exposure to cafeteria diet produces neuroplastic and functional changes in the NAc that can modify feeding behaviour. Microglia activation and neuroinflammation play an important role in the development of these neurobiological alterations.

COMPUTATIONAL APPROACHES IN PRECLINICAL DIAGNOSTICS AND PROGNOSIS FOR ALZHEIMER’S DISEASE

Alzheimer's disease (AD) is referred to as “disease with many faces”, biggest reason being that variability in the phenotypic manifestations are consequence of different molecular pathways underlying what is known as single, consensus prototype pathology. This variability represents one of the biggest challenges in developing specific diagnostic test. Alternative is identification of multiple biomarkers that in synchrony, accurately predict and track AD. Technologies that enable screening for complex disease markers (CDM) with high-throughput capabilities are of particular interest. We use MathWorks MATLAB to explore accuracy and usefulness of computational approaches in AD diagnostics. Experimentation is initiated by “sketching” broad mechanism of AD pathogenesis, and identifying most significant neuroinflammatory and neuro-apoptotic factors, then connecting with factors of interest. Comprehensive PubMed search allows accumulation of cumulative knowledge about molecular pathway, maximizing the output accuracy. Figure shows schematic diagram for applying computational methods in elucidation of AD pathogenesis. It consists of: 1) Identifying the functional diagram or sub-set of intermolecular signal transaction interactions; 2) Biochemical equations for the molecular mechanism under study are created; 3) Conversion to the differential equations. The parameter values are then assigned based on quantitative literature information, or are otherwise “assumed”; 4) MAT LAB computations. We have demonstrated 100% accuracy of the computational results by comparison with Western and ELISA quantitative time-course measurements for inflammatory factors such as IL-1a, TNF-a, MAPK, JNK and neurotrophic factors, such as BDNF and NF-kB. Time-course graphic allows signaling progression to be determined when and whether two factors of interest are connected in signaling pathway. Using this approach we have identified (IIAC 2011) critical importance for small factor, MyD88 in signal transmission along IL-1α/TRAF/TNFα/NF-κB pathway.

Vitamin D administration, cognitive function, BBB permeability and neuroinflammatory factors in high-fat diet-induced obese rats.

The purpose of this research was to investigate the effects of vitamin D administration on cognitive function, nuclear factor-κB (NF-κB), brain-derived neurotrophic factor (BDNF) concentration in the hippocampus and blood-brain barrier (BBB) permeability in high-fat diet (HFD)-induced obese rats. Male Wistar rats were fed either a control diet or HFD for 16 weeks (n=20); then, each group was randomized into two subgroups supplemented orally with 500 IU kg-1 vitamin D for 5 weeks. A Morris water maze (MWM) test was performed at the 21st week to examine cognitive function. BBB permeability was characterized by Evans blue dye in the hippocampus. BDNF and NF-κB concentrations in the hippocampus and serum vitamin D concentrations were also measured. HFD led to a significant delay in escape latency time and reduced time of MWM probe test because of increased NF-κB and decreased BDNF concentrations in the hippocampus. Vitamin D supplementation in the HFD group significantly reduced body weight, NF-κB concentrations, BBB permeability and increased BDNF concentrations in the hippocampus. Vitamin D reversed HFD-induced cognitive impairments by reduction of the NF-κB and elevation of BDNF concentrations and modulation of the BBB permeability in rats' hippocampus.

A Multimodal Approach For Studying Pathways Leading To Psychosis In 22Q11 Deletion Syndrome

Overall Abstract 22q11 deletion syndrome (22q11DS), also known as velo-cardio-facial syndrome has been the focus of intensive research over the last 15 years. The syndrome is the most commonly known microdeletion syndrome, occurring in at least 1 to 4,000 live births, and is the most commonly known genetic syndrome associated with schizophrenia, with approximately one-thirds of individuals developing schizophrenia by young adulthood. Thus, 22q11DS provides a homogeneous model from which to learn about the effects of decreased dosage of genes on the development of brain structure and function and consequently on the emergence of schizophrenia-like psychotic disorder. The proposed symposium consists of leading 22q11DS international researchers and clinicians and young Israeli scientists. The presenters study longitudinally large cohorts of children, adolescents and young adults with 22q11.2DS. Dr. Gothelf will provide an introduction on the genetic and medical characteristics of 22q11DS. He will also present data on the genotype-neuropsychiatric phenotype associations in 22q11DS and preliminary findings of elevated levels of neuroinflammatory factors in psychotic 22q11DS individuals. Dr. Gur will describe the common psychiatric comorbidities occurring in two-thirds of individuals with 22q11DS including ADHD, anxiety disorders and psychotic disorders. She will also present longitudinal data following the developmental trajectories of attenuated psychotic symptoms in 22q11DS. Dr. Kates will summarize a twelve-year longitudinal study of neuroanatomic, neurofunctional and neuropsychological development in youth with 22q11.2 deletion syndrome (22q11DS). Dr. Kates identified aberrant longitudinal alterations in cortical thickness / connectivity, as well as neurocognitive deficits that may represent biomarkers for the eventual onset of prodromal psychosis in 22q11DS. Finally Dr. Michaelovsky will present the results of bioinformatics analyses on DNA samples of a unique 22q11.2DS multigeneration family (mother and her four children), including psychotic and non-psychotic subjects.

The Potential Role Of Genetic And Immunological Pathways In 22Q11 Deletion Syndrome Psychosis

The 22q11 deletion syndrome (22q11DS) is a neurodevelopmental condition associated with medical diseases, cognitive deficits and psychiatric morbidity. The common 3Mb 22q11 deletion contains ~40 genes. The 22q11DS has multiple potential medical manifestations including cardiovascular and cleft anomalies, hypocalcemia and thymic hypoplasia resulting in an increased risk for recurrent infections and autoimmune disorders. The most common and debilitating manifestations in 22q11DS are the cognitive deficits and psychiatric morbidity. The average IQ in 22q11DS is 75, within the borderline range. Psychiatric rate of psychiatric comorbidities in 22q11DS is ~70% with up to one-third of individuals fulfilling criteria for schizophrenia by adulthood.We will present data from our group exploring the potential association between 22q11DS-psychosis and its related cognitive and neurophysiological deficits and variants of the COMT and PRODH, two genes from the 22q11-deleted region. These findings will be discussed in the context of the data reported from other laboratories on the genotype-schizophrenia phenotype in 22q11DS.We will also report preliminary findings on the potential role of neuroinflammatory factors in 22q11DS psychosis. We found elevated levels of the neuroinflammatory factors CRP and IL-6 in 22q11DS psychotic patients. Taken together with recent promising genetic-immunological pathways from schizophrenia in the general population, our findings suggest that 22q11DS is a promising model to test the genetic-immunological pathways leading to schizophrenia.

Early-life stress lastingly alters the neuroinflammatory response to amyloid pathology in an Alzheimer’s disease mouse model

Exposure to stress during the sensitive period of early-life increases the risk to develop cognitive impairments and psychopathology later in life. In addition, early-life stress (ES) exposure, next to genetic causes, has been proposed to modulate the development and progression of Alzheimer’s disease (AD), however evidence for this hypothesis is currently lacking. We here tested whether ES modulates progression of AD-related neuropathology and assessed the possible contribution of neuroinflammatory factors in this.We subjected wild-type (WT) and transgenic APP/PS1 mice, as a model for amyloid neuropathology, to chronic ES from postnatal day (P)2 to P9. We next studied how ES exposure affected; 1) amyloid β (Aβ) pathology at an early (4month old) and at a more advanced pathological (10month old) stage, 2) neuroinflammatory mediators immediately after ES exposure as well as in adult WT mice, and 3) the neuroinflammatory response in relation to Aβ neuropathology.ES exposure resulted in a reduction of cell-associated amyloid in 4month old APP/PS1 mice, but in an exacerbation of Aβ plaque load at 10months of age, demonstrating that ES affects Aβ load in the hippocampus in an age-dependent manner. Interestingly, ES modulated various neuroinflammatory mediators in the hippocampus of WT mice as well as in response to Aβ neuropathology. In WT mice, immediately following ES exposure (P9), Iba1-immunopositive microglia exhibited reduced complexity and hippocampal interleukin (IL)-1β expression was increased. In contrast, microglial Iba1 and CD68 were increased and hippocampal IL-6 expression was decreased at 4months, while these changes resolved by 10months of age. Finally, Aβ neuropathology triggered a neuroinflammatory response in APP/PS1 mice that was altered after ES exposure. APP/PS1 mice exhibited increased CD68 expression at 4months, which was further enhanced by ES, whereas the microglial response to Aβ neuropathology, as measured by Iba1 and CD11b, was less prominent after ES at 10months of age. Finally, the hippocampus appears to be more vulnerable for these ES-induced effects, since ES did not affect Aβ neuropathology and neuroinflammation in the entorhinal cortex of adult ES exposed mice.Overall, our results demonstrate that ES exposure has both immediate and lasting effects on the neuroinflammatory response. In the context of AD, such alterations in neuroinflammation might contribute to aggravated neuropathology in ES exposed mice, hence altering disease progression. This indicates that, at least in a genetic context, ES could aggravate AD pathology.

Inflammatory Cytokines and Alzheimer's Disease: A Review from the Perspective of Genetic Polymorphisms.

Neuroinflammatory processes are a central feature of Alzheimer's disease (AD) in which microglia are over-activated, resulting in the increased production of pro-inflammatory cytokines. Moreover, deficiencies in the anti-inflammatory system may also contribute to neuroinflammation. Recently, advanced methods for the analysis of genetic polymorphisms have further supported the relationship between neuroinflammatory factors and AD risk because a series of polymorphisms in inflammation-related genes have been shown to be associated with AD. In this review, we summarize the polymorphisms of both pro- and anti-inflammatory cytokines related to AD, primarily interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha, IL-4, IL-10, and transforming growth factor beta, as well as their functional activity in AD pathology. Exploration of the relationship between inflammatory cytokine polymorphisms and AD risk may facilitate our understanding of AD pathogenesis and contribute to improved treatment strategies.

Wheel running reduces ethanol seeking by increasing neuronal activation and reducing oligodendroglial/neuroinflammatory factors in the medial prefrontal cortex

The therapeutic effects of wheel running (WR) during abstinence on reinstatement of ethanol seeking behaviors in rats that self-administered ethanol only (ethanol drinking, ED) or ED with concurrent chronic intermittent ethanol vapor experience (CIE-ED) were investigated. Neuronal activation as well as oligodendroglial and neuroinflammatory factors were measured in the medial prefrontal cortex (mPFC) tissue to determine cellular correlates associated with enhanced ethanol seeking. CIE-ED rats demonstrated escalated and unregulated intake of ethanol and maintained higher drinking than ED rats during abstinence. CIE-ED rats were more resistant to extinction from ethanol self-administration, however, demonstrated similar ethanol seeking triggered by ethanol contextual cues compared to ED rats. Enhanced seeking was associated with reduced neuronal activation, and increased number of myelinating oligodendrocyte progenitors and PECAM-1 expression in the mPFC, indicating enhanced oligodendroglial and neuroinflammatory response during abstinence. WR during abstinence enhanced self-administration in ED rats, indicating a deprivation effect. WR reduced reinstatement of ethanol seeking in CIE-ED and ED rats, indicating protection against relapse. The reduced ethanol seeking was associated with enhanced neuronal activation, reduced number of myelinating oligodendrocyte progenitors, and reduced PECAM-1 expression. The current findings demonstrate a protective role of WR during abstinence in reducing ethanol seeking triggered by ethanol contextual cues and establish a role for oligodendroglia-neuroinflammatory response in ethanol seeking. Taken together, enhanced oligodendroglia-neuroinflammatory response during abstinence may contribute to brain trauma in chronic alcohol drinking subjects and be a risk factor for enhanced propensity for alcohol relapse.

The Lyme Disease Spirochete Borrelia Burgdorferi Induces Increased Expression of Multiple Neuroinflammatory Factors in Human Microglial Cells In Vitro

Many microorganisms can cause inflammation in the central nervous system (CNS) by damaging or penetrating the protective blood‐brain and blood‐cerebral spinal fluid barriers that sequester the brain from the periphery. Breakdown of the blood‐brain barrier (BBB) or blood‐cerebral spinal fluid (blood‐CSF) barrier could facilitate entry of both B. burgdorferi and activated immune cells into the CNS leading to multiple neurological complications, collectively termed neuroborreliosis. Indeed, B. burgdorferi has an affinity for the CNS and can be isolated from the CSF of humans as early as 18 days after the bite of an infected tick. However, the mechanism by which the bacterium initiates neuroinflammation leading to neural disfunction remains unknown. The ensuing neurological symptoms are likely a result of a glial‐driven, host inflammatory response to the bacterium. However, the specific contributions of human microglial cells to the pathogenesis of neuroborreliosis have not yet been elucidated.We hypothesize that dead B. burgdorferi and debris persist in the CNS after antibiotic treatment and contribute to an ongoing inflammatory response in the CNS. To begin characterization of this response, highly pure cultures of primary human microglia were incubated with live virulent B. burgdorferi and the membrane lipoprotein Pam3Cys to elucidate the cell‐ and lipoprotein‐specific responses to the bacterium. Cultures were analyzed by immuncytochemistry, real time PCR array and ELISA analysis. Array results were confirmed with individual sets of PCR primers. Our results demonstrate a robust increase in numerous inflammatory chemokines, cytokines and related genes in all treatment conditions examined. Most prominent was an increase in the neurophil chemoattractants IL‐8, IL‐6, CXCL1, CXCL10 and LIF. These data suggest that, in addition to B. burgdorferi, infiltrating phagocytic cells, particularly potentially neurotoxic neutrophils, may be important additional contributors to the early inflammatory events associated with the onset of neuroborreliosis.Our continuing studies are now focused on elucidating microglial phagocytosis of B. burgdorferi using real time PCR arrays and culture monolayers coupled with confocal microscopy and trans emission microscopy. Interestingly, initial data has demonstrated that although no there is no phagocytosis of live bugs in vitro, primary human microglia highly up regulate numerous genes associated with phagocytosis and associated cell signaling when exposed to dead and/or dead‐sonicated forms of B. burgdorferi. More specifically, in microglia exposed to dead and/or dead‐sonicated B. burgdorferi, there was a significant increase in expression of genes known to be involved in recognition of Bb (TLRs, NOD1, CD14); Fc receptors; kinases (LYN, MAPK); and things involved in uptake/phagolysosomes (GULP‐1, members of the Rac/Rho family, phospholipases, VAMP, syntaxin). Taken together, these results suggest that primary human microglia continue to mount a pro‐inflammatory response in the absence of viable Borrelia burgdorferi.Support or Funding InformationThis study was funded by a grant from the University of North Dakota Office of Research Development and Compliance (2014).

The effect of resveratrol on beta amyloid-induced memory impairment involves inhibition of phosphodiesterase-4 related signaling.

Resveratrol, a natural polyphenol found in red wine, has wide spectrum of pharmacological properties including antioxidative and antiaging activities. Beta amyloid peptides (Aβ) are known to involve cognitive impairment, neuroinflammatory and apoptotic processes in Alzheimer's disease (AD). Activation of cAMP and/or cGMP activities can improve memory performance and decrease the neuroinflammation and apoptosis. However, it remains unknown whether the memory enhancing effect of resveratrol on AD associated cognitive disorders is related to the inhibition of phosphodiesterase 4 (PDE4) subtypes and subsequent increases in intracellular cAMP and/or cGMP activities. This study investigated the effect of resveratrol on Aβ1-42-induced cognitive impairment and the participation of PDE4 subtypes related cAMP or cGMP signaling. Mice microinfused with Aβ1-42 into bilateral CA1 subregions displayed learning and memory impairment, as evidenced by reduced memory acquisition and retrieval in the water maze and retention in the passive avoidance tasks; it was also significant that neuroinflammatory and pro-apoptotic factors were increased in Aβ1-42-treated mice. Aβ1-42-treated mice also increased in PDE4A, 4B and 4D expression, and decreased in PKA level. However, PKA inhibitor H89, but not PKG inhibitor KT5823, prevented resveratrol's effects on these parameters. Resveratrol also reversed Aβ1-42-induced decreases in phosphorylated cAMP response-element binding protein (pCREB), brain derived neurotrophic factor (BDNF) and anti-apoptotic factor BCl-2 expression, which were reversed by H89. These findings suggest that resveratrol reversing Aβ-induced learning and memory disorder may involve the regulation of neuronal inflammation and apoptosis via PDE4 subtypes related cAMP-CREB-BDNF signaling.

Excessive Iron and α-Synuclein Oligomer in Brain are Relevant to Pure Apathy in Parkinson Disease.

To investigate the demographic features, clinical features, and potential mechanism in patients with Parkinson disease (PD) with pure apathy. A total of 145 patients with PD without depression and dementia and 30 age-matched controls were consecutively recruited. Patients with PD were evaluated by Apathy Scale (AS), scales for motor symptoms and quality of life. The levels of iron, oxidative and neuroinflammatory factors, α-synuclein oligomer, and dopamine in cerebrospinal fluid (CSF) from patients with PD and controls were detected by enzyme-linked immunosorbent assay, chemical colorimetric method, and high-performance liquid chromatography. Comparisons between PD with pure apathy and with no pure apathy groups and correlation between AS score and the levels of above factors were analyzed. There were 64 (44.14%) cases in PD-apathy group. The PD-apathy group had older age, (97.81 ± 10.82) years versus (61.86 ± 10.80) years, and severer quality of life (P < .05). The PD-apathy and PD without apathy groups presented no remarkable differences in motor symptoms (P > .05). The levels of iron, hydroxyl radical (·OH), hydrogen peroxide (H2O2), and α-synuclein oligomer in CSF in PD-apathy group were significantly higher than that in PD without the apathy group (P < .05). In patients with PD, the AS score was positively correlated with the levels of iron, ·OH, H2O2 and α-synuclein oligomer in CSF (r = 19.838, .063, 1.046, and 0.498, respectively, P < .05). In PD-apathy group, iron level was positively correlated with ·OH level (r = .011, P < .05), and H2O2 level was positively correlated with α-synuclein oligomer level in CSF (r = .045, P < .05). Patients with PD had high prevalence of pure apathy. Patients with PD having pure apathy had older age. Pure apathy reduced quality of life for patients without worsening motor function. Excessive iron and α-synuclein oligomer in brain commonly contributed to pure apathy of PD through potential mechanism of oxidative stress.

Pharmacological Tools to Study the Role of Astrocytes in Neural Network Functions.

Despite that astrocytes and microglia do not communicate by electrical impulses, they can efficiently communicate among them, with each other and with neurons, to participate in complex neural functions requiring broad cell-communication and long-lasting regulation of brain function. Glial cells express many receptors in common with neurons; secrete gliotransmitters as well as neurotrophic and neuroinflammatory factors, which allow them to modulate synaptic transmission and neural excitability. All these properties allow glial cells to influence the activity of neuronal networks. Thus, the incorporation of glial cell function into the understanding of nervous system dynamics will provide a more accurate view of brain function. Our current knowledge of glial cell biology is providing us with experimental tools to explore their participation in neural network modulation. In this chapter, we review some of the classical, as well as some recent, pharmacological tools developed for the study of astrocyte's influence in neural function. We also provide some examples of the use of these pharmacological agents to understand the role of astrocytes in neural network function and dysfunction.

Importance of neurobiological mechanisms in depression

We have read the article titled “Association between Socioeconomic Factors and Depression among Cardiovascular Patients Living in Rich Resourced Middle Eastern Country” written by Tam Truong Donnelly with great interest [1]. This article highlights the impact of heterogeneous socioeconomic factors on cardiovascular patients with depression as well as the importance of collaborative management to improve both mental and physical conditions in this population. The author reported that some socioeconomic and demographic factors like unemployment, being full-time homemaker, female sex, and lowmonthly incomewere associatedwith depression in cardiovascular patients. Depression is among the most debilitating disorders worldwide while it is associated with significant disability and low quality of life by its own apart from comorbidities. Although association between socioeconomic factors and depression has been demonstrated, endogenous factors also play a role in the pathophysiology of the disease. According to some authors, endogenous depression is classified as a subtype of depression. Recent studies showed that depression has been associated with neuroendocrinological and neuroinflammatory factors such as immune system dysregulation with increased activity of proinflammatory cytokines, hypothalamic-pituitary–adrenal axis activation resulting in hypercortisolemia, and autonomic system

Maternal separation induces neuroinflammation and long-lasting emotional alterations in mice

Early life experiences play a key role in brain function and behaviour. Adverse events during childhood are therefore a risk factor for psychiatric disease during adulthood, such as mood disorders. Maternal separation is a validated mouse model for maternal neglect, producing negative early life experiences that result in subsequent emotional alteration. Mood disorders have been found to be associated with neurochemical changes and neurotransmitter deficits such as reduced availability of monoamines in discrete brain areas. Emotional alterations like depression result in reduced serotonin availability and enhanced kynurenine metabolism through the action of indoleamine 2, 3-dioxygenase in response to neuroinflammatory factors. This mechanism involves regulation of the neurotransmitter system by neuroinflammatory agents, linking mood regulation to neuroinmunological reactions. In this context, the aim of this study was to investigate the effects of maternal separation with early weaning on emotional behaviour in mice. We investigated neuroinflammatory responses and the state of the tryptophan–kynurenine metabolic pathway in discrete brain areas following maternal separation. We show that adverse events during early life increase risk of long-lasting emotional alterations during adolescence and adulthood. These emotional alterations are particularly severe in females. Behavioural impairments were associated with microglia activation and disturbed tryptophan–kynurenine metabolism in brain areas related to emotional control. This finding supports the preeminent role of neuroinflammation in emotional disorders.