Aspects Of Neuroinflammation Research Articles

Glioneuronal apoptosis and neuroinflammation in drug resistant temporal lobe epilepsy

The study of glioneuronal apoptosis and neuroinflammation is extremely important for understanding the causes of epilepsy. Currently, the focus is on neuronal apoptosis and certain aspects of neuroinflammation, while glial apoptosis remains poorly understood. Objective : to evaluate neuronal and glial apoptosis in conjunction with neuroinflammation in the area of the epileptic focus in patients with focal drug-resistant epilepsy (DRE). Material and methods . Biopsy specimens of the cortex and white matter of the temporal lobe of the brain from 30 patients with focal DRE due to focal cortical dysplasia were studied. We evaluated pathological changes and structural signs of apoptosis, levels of apoptotic and pro-inflam-matory factors such as caspase-3, caspase-9, FAS, FAS ligand (FAS-L), tumor necrosis factor α (TNFα), p53, nuclear factor κB (NF-κB). Histological methods, transmission electron microscopy (TEM), immunohistochemical study (IHC), and Western blot (WB) were used. The comparison group consisted of 21 people without epilepsy and brain involvement. Results . In DRE patients IHC revealed the expression of active caspase-3 in single neurons (20% of cases) and in gliocytes of the cerebral cortex and white matter (100% of cases). TEM revealed ultrastructural signs of apoptosis in all cases in neurons and oligodendrocytes. The WB of the epileptic focus showed an increased expression of the apoptotic factors caspase-9, FAS, p53 and pro-inflammatory factors TNFα, NF-κB. Conclusion . The results obtained indicate the presence of associated apoptosis and neuroinflammation processes of in DRE. Glial apoptosis is actively involved in epileptogenesis. The main part of apoptotic glia is oligodendrocytes, which explains the well-known phenomenon of myelin damage in epilepsy. Along with neuronal apoptosis, oligodendrocyte apoptosis together with neuroinflammation forms a self-sustaining pathological focus, which contributes to the progression of the disease and the occurrence of relapses.

Differences in in vitro microglial accumulation of the energy metabolism tracers [18F]FDG and [18F]BCPP-EF during LPS- and IL4 stimulation

The positron emission tomography probes 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and 2-tert-butyl-4-chloro-5-{6-[2-(2-[18F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF) are designed to evaluate glycolysis and oxidative phosphorylation, respectively, and are both used to estimate neuronal activity. However, previous studies have shown a discrepancy in these probes’ accumulation in the compromised region, possibly due to the presence of activated microglia acting like deleterious or neuroprotective phenotypes. Hence, we evaluated lipopolysaccharide (LPS)- and interleukin 4 (IL4)-stimulated microglial uptake of [14C]2DG and [18F]BCPP-EF to give a new insight into the hypothesis that different uptake of [18F]FDG and [18F]BCPP-EF can be ascribed to the different metabolic pathways activated during microglial activation. LPS or IL4 stimulation increased the proinflammatory or anti-inflammatory marker gene expression in microglial cells. In LPS-stimulated cells, [14C]2DG uptake and glycolysis related gene expression were elevated, and [18F]BCPP-EF uptake was reduced. In IL4-stimulated cells, [18F]BCPP-EF uptake was increased, and [14C]2DG uptake was decreased. The expression of genes involved in glycolysis and mitochondrial complex I subunits was not changed by IL4 stimulation. The uptake of [14C]2DG and [18F]BCPP-EF differs in LPS- and IL4-stimulated polarized microglial cells. The present results suggest that the in vivo accumulation of metabolic tracers [18F]FDG and [18F]BCPP-EF can be influenced by the different aspects of neuroinflammation.

Corrigendum: Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods.

[This corrects the article DOI: 10.3389/fneur.2018.01033.].

Bicuculline Reduces Neuroinflammation in Hippocampus and Improves Spatial Learning and Anxiety in Hyperammonemic Rats. Role of Glutamate Receptors.

Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) with mild cognitive impairment. Hyperammonemia is a main contributor to cognitive impairment in MHE, which is mediated by neuroinflammation. GABAergic neurotransmission is altered in hyperammonemic rats. We hypothesized that, in hyperammonemic rats, (a) enhanced GABAergic tone would contribute to induce neuroinflammation, which would be improved by reducing GABAergic tone by chronic bicuculline treatment; (b) this would improve spatial learning and memory impairment; and (c) modulation of glutamatergic neurotransmission would mediate this cognitive improvement. The aim of this work was to assess the above hypotheses. Bicuculline was administrated intraperitoneally once a day for 4 weeks to control and hyperammonemic rats. The effects of bicuculline on microglia and astrocyte activation, IL-1β content, on membrane expression of AMPA and NMDA glutamate receptors subunits in the hippocampus and on spatial learning and memory as well as anxiety were assessed. Treatment with bicuculline reduces astrocyte activation and IL-1β but not microglia activation in the hippocampus of hyperammonemic rats. Bicuculline reverses the changes in membrane expression of AMPA receptor subunits GluA1 and GluA2 and of the NR2B (but not NR1 and NR2A) subunit of NMDA receptors. Bicuculline improves spatial learning and working memory and decreases anxiety in hyperammonemic rats. In hyperammonemia, enhanced activation of GABAA receptors in the hippocampus contributes to some but not all aspects of neuroinflammation, to altered glutamatergic neurotransmission and to impairment of spatial learning and memory as well as anxiety, all of which are reversed by reducing activation of GABAA receptors with bicuculline.

Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the label given to a syndrome that can include long-term flu-like symptoms, profound fatigue, trouble concentrating, and autonomic problems, all of which worsen after exertion. It is unclear how many individuals with this diagnosis are suffering from the same condition or have the same underlying pathophysiology, and the discovery of biomarkers would be clarifying. The name “myalgic encephalomyelitis” essentially means “muscle pain related to central nervous system inflammation” and many efforts to find diagnostic biomarkers have focused on one or more aspects of neuroinflammation, from periphery to brain. As the field uncovers the relationship between the symptoms of this condition and neuroinflammation, attention must be paid to the biological mechanisms of neuroinflammation and issues with its potential measurement. The current review focuses on three methods used to study putative neuroinflammation in ME/CFS: (1) positron emission tomography (PET) neuroimaging using translocator protein (TSPO) binding radioligand (2) magnetic resonance spectroscopy (MRS) neuroimaging and (3) assays of cytokines circulating in blood and cerebrospinal fluid. PET scanning using TSPO-binding radioligand is a promising option for studies of neuroinflammation. However, methodological difficulties that exist both in this particular technique and across the ME/CFS neuroimaging literature must be addressed for any results to be interpretable. We argue that the vast majority of ME/CFS neuroimaging has failed to use optimal techniques for studying brainstem, despite its probable centrality to any neuroinflammatory causes or autonomic effects. MRS is discussed as a less informative but more widely available, less invasive, and less expensive option for imaging neuroinflammation, and existing studies using MRS neuroimaging are reviewed. Studies seeking to find a peripheral circulating cytokine “profile” for ME/CFS are reviewed, with attention paid to the biological and methodological reasons for lack of replication among these studies. We argue that both the biological mechanisms of cytokines and the innumerable sources of potential variance in their measurement make it unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered.

New aspects of neuroinflammation and neuroimmune crosstalk in the airways

Neuroimmune interaction has long been discussed in the pathogenesis of allergic airway diseases, such as allergic asthma. Mediators released during inflammation can alter the function of both sensory and parasympathetic neurons innervating the airways. Evidence has been provided that the inflammatory response can be altered by various mediators that are released by sensory and parasympathetic neurons and vice versa. Our aim is to demonstrate recent developments in the reciprocal neuroimmune interaction and to include, if available, data from invivo and clinical studies.

Nuclear receptor agonist-driven modification of inflammation and amyloid pathology enhances and sustains cognitive improvements in a mouse model of Alzheimer\u2019s disease

BackgroundAlzheimer’s disease (AD) is a highly prevalent neurodegenerative disorder characterized by pathological hallmarks of beta-amyloid plaque deposits, tau pathology, inflammation, and cognitive decline. Treatment remains a clinical obstacle due to lack of effective therapeutics. Agonists targeting nuclear receptors, such as bexarotene, reversed cognitive deficits regardless of treatment duration and age in murine models of AD. While bexarotene demonstrated marked efficacy in decreasing plaque levels following short-term treatment, prolonged treatment did not modulate plaque burden. This suggested that plaques might reform in mice treated chronically with bexarotene and that cessation of bexarotene treatment before plaques reform might alter amyloid pathology, inflammation, and cognition in AD mice.MethodsWe utilized one-year-old APP/PS1 mice that were divided into two groups. We treated one group of mice for 2 weeks with bexarotene. The other group of mice was treated for 2 weeks with bexarotene followed by withdrawal of drug treatment for an additional 2 weeks. Cognition was evaluated using the novel-object recognition test either at the end of bexarotene treatment or the end of the withdrawal period. We then analyzed amyloid pathology and microgliosis at the conclusion of the study in both groups.ResultsBexarotene treatment enhanced cognition in APP/PS1 mice similar to previous findings. Strikingly, we observed sustained cognitive improvements in mice in which bexarotene treatment was discontinued for 2 weeks. We observed a sustained reduction in microgliosis and plaque burden following drug withdrawal exclusively in the hippocampus.ConclusionsOur findings demonstrate that bexarotene selectively modifies aspects of neuroinflammation in a region-specific manner to reverse hippocampal-dependent cognitive deficits in AD mice and may provide insight to inform future studies with nuclear receptor agonists.

The Role of Mast Cells in Alzheimer's Disease.

Immunity and inflammation are deeply involved in Alzheimer's disease. The most important properties of pathological Alzheimer's disease are the extracellular deposits of amyloid â-protein plaque aggregates along with other unknown mutated proteins, which are implicated in immunity and inflammation. Mast cells are found in the brain of all mammalian species and in the periphery, and their biological mediators, including cytokines/chemokines, arachidonic acid products and stored enzymes, play an import role in Alzheimer's disease. Cytokines/chemokines, which are generated mostly by microglia and astrocytes in Alzheimer's disease, contribute to nearly every aspect of neuroinflammation and amyloid â-protein plaque aggregates may induce in mast cells the release of a plethora of mediators, including pro-inflammatory cytokines/chemokines such as interleukin-1, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-alpha, vascular endothelial growth factor, transforming growth factor beta, CXCL8 and CCL2-3-4. These proinflammatory cytokines/chemokines are prominent mediators of neuroinflammation in brain disorders such as Alzheimer's disease, and their inhibition may be associated with improved recovery. In this review, we summarize the current knowledge regarding the roles of mast cell mediators (stored and de novo synthesis) in the pathogenesis of Alzheimer's disease.

The plasminogen activation system in neuroinflammation

The plasminogen activation (PA) system consists in a group of proteases and protease inhibitors regulating the activation of the zymogen plasminogen into its proteolytically active form, plasmin. Here, we give an update of the current knowledge about the role of the PA system on different aspects of neuroinflammation. These include modification in blood–brain barrier integrity, leukocyte diapedesis, removal of fibrin deposits in nervous tissues, microglial activation and neutrophil functions. Furthermore, we focus on the molecular mechanisms (some of them independent of plasmin generation and even of proteolysis) and target receptors responsible for these effects. The description of these mechanisms of action may help designing new therapeutic strategies targeting the expression, activity and molecular mediators of the PA system in neurological disorders involving neuroinflammatory processes. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.

SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation

Methamphetamine (METH) exposure results in dopaminergic neurotoxicity in striatal regions of the brain, an effect that has been linked to an increased risk of Parkinson's disease. Various aspects of neuroinflammation, including astrogliosis, are believed to be contributory factors in METH neurotoxicity. METH interacts with sigma receptors at physiologically relevant concentrations and treatment with sigma receptor antagonists has been shown to mitigate METH-induced neurotoxicity in rodent models. Whether these compounds alter the responses of glial cells within the central nervous system to METH however has yet to be determined. Therefore, the purpose of the current study was to determine whether the sigma receptor antagonist, SN79, mitigates METH-induced striatal reactive astrogliosis. Male, Swiss Webster mice treated with a neurotoxic regimen of METH exhibited time-dependent increases in striatal gfap mRNA and concomitant increases in GFAP protein, indicative of astrogliosis. This is the first report that similar to other neurotoxicants that induce astrogliosis through the activation of JAK2/STAT3 signaling by stimulating gp-130-linked cytokine signaling resulting from neuroinflammation, METH treatment also increases astrocytic oncostatin m receptor (OSMR) expression and the phosphorylation of STAT3 (Tyr-705) in vivo. Pretreatment with SN79 blocked METH-induced increases in OSMR, STAT3 phosphorylation and astrocyte activation within the striatum. Additionally, METH treatment resulted in striatal cellular degeneration as measured by Fluoro-Jade B, an effect that was mitigated by SN79. The current study provides evidence that sigma receptor antagonists attenuate METH-induced astrocyte activation through a pathway believed to be shared by various neurotoxicants.

Chronic treatment with a CNTF-derived peptide reverses dendritic and synaptic plasticity deficits, cognitive impairment and tau pathology in an Alzheimer's disease mouse model

suggested to impair hippocampal neurogenesis, which can be linked to cognitive decline in aging and AD. The a 7 nAChRs play an important role in modulating synaptic plasticity in the hippocampus and we have previously reported an increased expression of a 7 nAChRs on reactive astrocytes in AD postmortem brain (Yu et al., 2005). Here we propose that stimulating a 7 nAChR signaling induces a favorable brain microenvironment, which could enhance repair processes and ameliorate cognitive impairment. Methods: Different aspects of neuroinflammation in relation to AD pathogenesis were investigated. i) First, human microglia cells were exposed to beta-amyloid 42 at nM concentrations and we studied how the secretion of pro-inflammatory cytokines released in cell media affected human stem cell neuronal differentiation in vitro. ii) Later, to evaluate astroglial processes in relation to neurogenesis in vivo, we used AD Tg2576 mice, which were treated with daily i.p. injections for 5 weeks with the partial a 7 nAChR agonist JN403 (0.03 mg/kg) in combination with bilateral human neural stem cell (hNSC) transplantation in the hippocampus. Results: Surprisingly, microglia exposed to fibrillary beta-amyloid 42, decreased secretion of cytokines TNF a, IL-1 band IL-2, which in turn impaired human stem cells differentiation(p<0.05). Tg2576 mice treated with JN403 displayed a decreased number of a 7 nAChR expressing astrocytes that correlated with an impairment of hippocampal neurogenesis (r1⁄40.7, p<0.01).Conclusions:Both our in vitro and in vivo findings suggest that low-graded inflammatory processes involving a 7 nAChRs are important for devising tissue remodeling and repair strategies in the brain.

Human T Lymphotropic Virus Type 1 Increases T Lymphocyte Migration by Recruiting the Cytoskeleton Organizer CRMP2

Recruitment of virus-infected T lymphocytes into the CNS is an essential step in the development of virus-associated neuroinflammatory diseases, notably myelopathy induced by retrovirus human T leukemia virus-1 (HTLV-1). We have recently shown the key role of collapsin response mediator protein 2 (CRMP2), a phosphoprotein involved in cytoskeleton rearrangement, in the control of human lymphocyte migration and in brain targeting in animal models of virus-induced neuroinflammation. Using lymphocytes cloned from infected patients and chronically infected T cells, we found that HTLV-1 affects CRMP2 activity, resulting in an increased migratory potential. Elevated CRMP2 expression accompanies a higher phosphorylation level of CRMP2 and its more pronounced adhesion to tubulin and actin. CRMP2 forms, a full length and a shorter, cleaved one, are also affected. Tax transfection and extinction strategies show the involvement of this viral protein in enhanced full-length and active CRMP2, resulting in prominent migratory rate. A role for other viral proteins in CRMP2 phosphorylation is suspected. Full-length CRMP2 confers a migratory advantage possibly by preempting the negative effect of short CRMP2 we observe on T lymphocyte migration. In addition, HTLV-1-induced migration seems, in part, supported by the ability of infected cell to increase the proteosomal degradation of short CRMP2. Finally, gene expression in CD69(+) cells selected from patients suggests that HTLV-1 has the capacity to influence the CRMP2/PI3K/Akt axis thus to positively control cytoskeleton organization and lymphocyte migration. Our data provide an additional clue to understanding the infiltration of HTLV-1-infected lymphocytes into various tissues and suggest that the regulation of CRMP2 activity by virus infection is a novel aspect of neuroinflammation.

The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia

Neuroinflammation is a key element in the ischemic cascade after cerebral ischemia that results in cell damage and death in the subacute phase. However, anti-inflammatory drugs do not improve outcome in clinical settings suggesting that the neuroinflammatory response after an ischemic stroke is not entirely detrimental. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. Because of its inhibitory influence on several pathways of the ischemic cascade, hypothermia has been introduced as a promising neuroprotective strategy. This review also discusses the influence of hypothermia on the neuroinflammatory response. We conclude that hypothermia exerts both stimulating and inhibiting effects on different aspects of neuroinflammation and hypothesize that these effects are key to neuroprotection.

11C]-DPA-713 and [18F]-DPA-714 as New PET Tracers for TSPO: A Comparison with [11C]-(R)-PK11195 in a Rat Model of Herpes Encephalitis

BackgroundActivation of microglia cells plays an important role in neurological diseases. Positron emission tomography (PET) with [11C]-(R)-PK11195 has already been used to visualize activated microglia cells in neurological diseases. However, [11C]-(R)-PK11195 may not possess the required sensitivity to visualize mild neuroinflammation. In this study, we evaluated the PET tracers [11C]-DPA-713 and [18F]-DPA-714 as agents for imaging of activated microglia in a rat model of herpes encephalitis.Materials and MethodsRats were intranasally inoculated with HSV-1. On day 6 or 7 after inoculation, small animal PET studies were performed to compare [11C]-(R)-PK11195, [11C]-DPA-713, and [18F]-DPA-714.ResultsUptake of [11C]-DPA-713 in infected brain areas was comparable to that of [11C]-(R)-PK11195, but [11C]-DPA-713 showed lower non-specific binding. Non-specific uptake of [18F]-DPA-714 was lower than that of [11C]-(R)-PK11195. In the infected brain, total [18F]-DPA-714 uptake was lower than that of [11C]-(R)-PK11195, with comparable specific uptake.Conclusions[11C]-DPA-713 may be more suitable for visualizing mild inflammation than [11C]-(R)-PK11195. In addition, the fact that [18F]-DPA-714 is an agonist PET tracer opens new possibilities to evaluate different aspects of neuroinflammation. Therefore, both tracers warrant further investigation in animal models and in a clinical setting.