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While the detrimental impact of inflammation on adult hippocampal neurogenesis and associated behaviors has recently gained credence, the effects of inflammation on the developing brain is an area of research which is quickly gaining momentum, and a growing number of research articles on this topic have been published in recent years. Indeed, we now know that pro-inflammatory mediators negatively influence both hippocampal neurogenesis and neuronal cytoarchitecture during brain development. Here we present a comprehensive review of the current literature on inflammation-induced changes in hippocampal neurogenesis during early life and the consequent behavioral deficits which may ensue in later life. We also offer insights into the cellular and molecular mechanisms underlying the hippocampal-dependant behavioral changes observed in neurodevelopmental disorders, particularly in those where cognitive dysfunction plays a major role. We further consider whether early-life inflammation-induced changes in hippocampal neurogenesis may contribute to the onset of mood and cognitive deficits in later life., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Multicellular spheroids are useful models of mammalian tissue for studies of cell proliferation, differentiation, replacement therapies and drug action. Having a size of 100-500 μm they mimic in vivo micro-environment and characteristic gradients of O2, pH and nutrients. We describe the use of cell-penetrating O2 probes based on phosphorescent Pt-porphyrins to perform high-resolution 2D and 3D mapping of O2 in spheroid structures by live cell fluorescence imaging technique. Optimised procedures for preparation of neurospheres from cortical neural cells isolated from embryonic rat brain, their staining with the phosphorescent O2 probes NanO2 and MM2 and subsequent analysis of oxygenation on different live cell imaging platforms, including widefield and confocal phosphorescence lifetime imaging microscopy (PLIM), conventional confocal and two-photon ratiometric intensity based O2 detection are presented. This is followed by a series of physiological experiments in which oxygenation patterns of the neurospheres are correlated with culturing conditions (atmospheric hypoxia and hyperoxia, size, growth factors), distribution of stem cells, mature neurons and astrocytes, HIF-2α stabilisation and responses to metabolic stimulation. The O2 imaging method allows multiplexing with many conventional fluorescent probes to perform multi-parametric imaging analysis of cells in 3D microenvironment. It can be applied to other types of spheroids and 3D tissue models., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Adult hippocampal neurogenesis is modulated by a number of intrinsic and extrinsic factors including local signalling molecules, exercise, aging and inflammation. Inflammation is also a major contributor to several hippocampal-associated disorders. Interleukin-1beta (IL-1β) is the most predominant pro-inflammatory cytokine in the brain, and an increase in its concentration is known to decrease the proliferation of both embryonic and adult hippocampal neural precursor cells (NPCs). Recent research has focused on the role of nuclear receptors as intrinsic regulators of neurogenesis, and it is now established that the orphan nuclear receptor TLX is crucial in maintaining the NPC pool in neurogenic brain regions. To better understand the involvement of TLX in IL-1β-mediated effects on hippocampal NPC proliferation, we examined hippocampal NPC proliferation and TLX expression in response to IL-1β treatment in an adult rat hippocampal neurosphere culture system. We demonstrate that IL-1β reduced the proliferation of hippocampal NPCs and TLX expression in a dose and time-dependent manner and that co-treatment with IL-1β receptor antagonist or IL-1 receptor siRNA prevented these effects. We also report a dose-dependent effect of IL-1β on the composition of cell phenotypes in the culture and on expression of TLX in these cells. This study thus provides evidence of an involvement of TLX in IL-1β-induced changes in adult hippocampal neurogenesis, and offers mechanistic insight into disorders in which neuroinflammation and alterations in neurogenesis are characteristic features., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A greater understanding of the mechanisms that promote the survival and growth of dopaminergic neurons is essential for the advancement of cell replacement therapies for Parkinson's disease (PD). Evidence supports a role for the mitogen-activated protein kinase p38 in the demise of dopaminergic neurons, while mitogen-activated protein kinase phosphatase-1 (MKP-1), which negatively regulates p38 activity, has not yet been investigated in this context. Here, we show that MKP-1 is expressed in dopaminergic neurons cultured from E14 rat ventral mesencephalon (VM). When dopaminergic neurons were transfected to overexpress MKP-1, they displayed a more complex morphology than their control counterparts in vitro. Specifically, MKP-1-transfection induced significant increases in neurite length and branching with a maximum increase observed in primary branches. We demonstrate that inhibition of dopaminergic neurite growth induced by treatment of rat VM neurons with the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in vitro is mediated by p38 and is concomitant with a significant and selective decrease in MKP-1 expression in these neurons. We further show that overexpression of MKP-1 in dopaminergic neurons contributes to neuroprotection against the effects of 6-OHDA. Collectively, we report that MKP-1 can promote the growth and elaboration of dopaminergic neuronal processes and can help protect them from the neurotoxic effects of 6-OHDA. Thus, we propose that strategies aimed at augmenting MKP-1 expression or activity may be beneficial in protecting dopaminergic neurons and may provide potential therapeutic approaches for PD.

Chronic neuroinflammation is associated with the pathophysiology of Parkinson's disease, a movement disorder characterised by deterioration of the nigrostriatal system of the brain. Recent studies have yielded important insights into the regulation of inflammation by nuclear receptors, a superfamily of ligand-activated transcription factors. Certain nuclear receptors are also emerging as regulators of neurodegeneration, including the degeneration of dopaminergic neurons in Parkinson's disease, and the importance of transcriptional control in this process is becoming increasingly apparent. Here, we discuss the role of Nurr1, peroxisome proliferator-activated receptors (PPARs), retinoic acid receptors, and glucocorticoid receptors in neuroinflammatory processes that contribute to dopaminergic neuronal degeneration. We examine current evidence providing insight into the potential of these important players as therapeutic targets for Parkinson's disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Glycogen synthase kinase-3β (GSK-3β) and the orphan nuclear receptor tailless homolog (TLX) are key regulators of hippocampal neurogenesis, which has been reported to be dysregulated in both neurodegenerative and psychiatric disorders. Inflammation is also implicated in the neuropathology of these disorders because of increased levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the brain. At elevated levels, IL-1β signaling through the IL-1 receptor type 1 has been shown to be detrimental to hippocampal neurogenesis. TLX is required to maintain neural stem/progenitor cells (NSPCs) in an undifferentiated state and is involved in NSPC fate determination, while GSK-3β negatively regulates Wnt signaling, a vital pathway promoting neurogenesis. This study shows that GSK-3β inhibition using a small-molecule inhibitor and the mood stabilizer lithium restores the IL-1β-induced decrease in NSPC proliferation and neuronal differentiation of embryonic rat hippocampal NSPCs to control levels. The IL-1β-induced effect on NSPCs is paralleled by a decrease in TLX expression that can be prevented by GSK-3β inhibition. The present results suggest that GSK-3β ameliorates the anti-proliferative and pro-gliogenic effects of IL-1β, and that TLX is vulnerable to inflammatory insult. Strategies to reduce GSK-3β activity or to increase TLX expression may facilitate the restoration of hippocampal neurogenesis in neuroinflammatory conditions where neurogenesis is impaired.

Neuroinflammation has been shown to contribute to neurodegenerative and psychiatric disorders such as Alzheimer's disease and major depression due to the inappropriate release of pro-inflammatory cytokines from activated microglia. The precise molecular events that mediate cytokine release from glia remain unknown but we suggest that the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) may be involved. The aim of this study therefore was to investigate the effect of lipopolysaccharide (LPS) on expression and activity of the GSK-3β isoform in glia, and to assess if GSK-3 mediates the LPS-induced change in inflammatory cytokine levels in culture medium from rat glial-enriched cortical cultures. GSK-3β was expressed in microglia and astrocytes, and stimulation of these cultures with LPS induced an increase in GSK-3β expression and activity, and in pro-inflammatory cytokine levels in culture media. We show that GSK-3 inhibition using a small molecule inhibitor SB216763 or the mood stabiliser lithium chloride reduced the LPS-induced elevated levels of pro-inflammatory cytokines present in culture media from rat glial-enriched cortical cultures. These results demonstrate a role for GSK-3 as a modulator of inflammatory cytokine levels in the brain, and contribute to a mechanistic insight into neurological disorders in which neuroinflammation is a characteristic feature., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Idiopathic Parkinson's disease (PD) represents a complex interaction between the inherent vulnerability of the nigrostriatal dopaminergic system, a possible genetic predisposition, and exposure to environmental toxins including inflammatory triggers. Evidence now suggests that chronic neuroinflammation is consistently associated with the pathophysiology of PD. Activation of microglia and increased levels of pro-inflammatory mediators such as TNF-α, IL-1β and IL-6, reactive oxygen species and eicosanoids has been reported after post-mortem analysis of the substantia nigra from PD patients and in animal models of PD. It is hypothesised that chronically activated microglia secrete high levels of pro-inflammatory mediators which damage neurons and further activate microglia, resulting in a feed forward cycle promoting further inflammation and neurodegeneration. Moreover, nigrostriatal dopaminergic neurons are more vulnerable to pro-inflammatory and oxidative mediators than other cell types because of their low intracellular glutathione concentration. Systemic inflammation has also been suggested to contribute to neurodegeneration in PD, as lymphocyte infiltration has been observed in brains of PD patients and in animal models of PD, substantiating the current theory of a fundamental role of inflammation in neurodegeneration. We will examine the current evidence in the literature which offers insight into the premise that both central and systemic inflammation may contribute to neurodegeneration in PD. We will discuss the emerging possibility of the use of diagnostic tools such as imaging technologies for PD patients. Finally, we will present the immunomodulatory therapeutic strategies that are now under investigation and in clinical trials as potential neuroprotective drugs for PD., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Neurogenesis occurs in the hippocampus of the developing and adult brain due to the presence of multipotent stem cells and restricted precursor cells at different stages of differentiation. It has been proposed that they may be of potential benefit for use in cell transplantation approaches for neurodegenerative disorders and trauma. Prolonged release of interleukin-1β (IL-1β) from activated microglia has a deleterious effect on hippocampal neurons and is implicated in the impaired neurogenesis and cognitive dysfunction associated with aging, Alzheimer's disease and depression. This study assessed the effect of IL-1β on the proliferation and differentiation of embryonic rat hippocampal NPCs in vitro. We show that IL-1R1 is expressed on proliferating NPCs and that IL-1β treatment decreases cell proliferation and neurosphere growth. When NPCs were differentiated in the presence of IL-1β, a significant reduction in the percentages of newly-born neurons and post-mitotic neurons and a significant increase in the percentage of astrocytes was observed in these cultures. These effects were attenuated by IL-1 receptor antagonist. These data reveal that IL-1β exerts an anti-proliferative, anti-neurogenic and pro-gliogenic effect on embryonic hippocampal NPCs, which is mediated by IL-1R1. The present results emphasise the consequences of an inflammatory environment during NPC development, and indicate that strategies to inhibit IL-1β signalling may be necessary to facilitate effective cell transplantation approaches or in conditions where endogenous hippocampal neurogenesis is impaired., (Copyright © 2012 Elsevier Inc. All rights reserved.)

During pregnancy, activation of the maternal immune system results in inflammation in the foetal nervous system. The causative agents are pro-inflammatory cytokines like interleukin-1β (IL-1β), produced by the foetus. In this study, we examine the effect of IL-1β on the proliferation and differentiation of neural progenitor cells (NPCs) to better understand its potential effects on the developing brain. We find that the IL-1β receptor (IL-1R1) is expressed in the ventral mesencephalon of the developing brain. Furthermore, IL-1R1 is expressed on Nestin-positive, Sox-2-positive NPCs. IL-1β treatment reduced the numbers of proliferating NPCs, an effect prevented by the IL-1R1 receptor antagonist. LDH and MTT assays, and western blot analysis for cleaved caspase 3 and poly(ADP-ribose) polymerase, confirmed that this was not due to an increase in cell death but rather an induction of differentiation. To further study the effects of IL-1β on cell fate determination, we differentiated NPCs in the presence and absence of IL-1β. Il-1β promoted gliogenesis and inhibited neurogenesis, an effect that required p38-MAPK kinase signalling. In summary, these data show that exposure of NPCs to IL-1β affects their development. This necessitates an examination of the consequences that maternal immune system activation during pregnancy has on the cellular architecture of the developing brain., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

Several secreted proteins facilitate the growth and guidance of sympathetic axons to their target organs during development. Here we show that IL-1β, a key regulator of inflammation in the immune system, inhibits axonal growth and branching from cultured sympathetic neurons at a stage in development when their axons are ramifying within their targets in vivo. IL-1β is synthesised in sympathetic ganglia and its targets at this stage, and IL-1β protein is detectable in the axons and perikarya of the innervating neurons. It acts directly on developing axons to inhibit their growth via NF-κB signalling. These findings show that IL-1β is a novel locally, and target-derived factor that can regulate the extent of sympathetic axon growth during the late embryonic and early postnatal period in developing rat sympathetic neurons., (Copyright © 2011 Elsevier Inc. All rights reserved.)

It is well established that neuroinflammation contributes to brain aging, and that cortical cells are particularly vulnerable. Lipopolysaccharide stimulates the release of the pro-inflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta from glial cells which consequently induces an impairment in neuronal cell function. The food supplement, Aquamin, is a natural, multi-mineral derived from the red algae Lithothamnion corallioides, rich in calcium, magnesium and 72 other trace minerals. The aim of this study was to evaluate the anti-inflammatory potential of Aquamin in lipopolysaccharide-stimulated, glial-enriched primary cultures of rat cortex. It is reported that Aquamin prevented lipopolysaccharide-induced secretion of tumor necrosis factor-alpha and interleukin-1beta from cortical glia. These data suggest that nutritional supplements such as Aquamin may play an important role in impeding the detrimental effects of excessive inflammation in the brain., (Copyright © 2010 John Wiley & Sons, Ltd.)

Inflammation is involved in the pathology of Parkinson's disease, a disorder characterised by degeneration of dopaminergic neurons. This study demonstrates that conditioned medium (CM) from lipopolysaccharide (LPS)-treated rat glial-enriched cortical cultures induced death of embryonic rat dopaminergic neurons in vitro, an effect which was additive to the toxicity of the neurotoxin 6-hydroxydopamine. Interleukin-1β (IL-1β) in the CM may mediate this neuronal death. IL-1R1 was found to be expressed on dopaminergic neurons. Blockade of IL-1R1 prevented CM-induced dopaminergic neuronal death. This study suggests that IL-1β in CM from LPS-stimulated glia contributes to dopaminergic neuronal death induced by glia-conditioned medium., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Tumour necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine, which influences neuronal survival and function yet there is limited information available on its effects on hippocampal neural precursor cells (NPCs). We show that TNFalpha treatment during proliferation had no effect on the percentage of proliferating cells prepared from embryonic rat hippocampal neurosphere cultures, nor did it affect cell fate towards either an astrocytic or neuronal lineage when cells were then allowed to differentiate. However, when cells were differentiated in the presence of TNFalpha, significantly reduced percentages of newly born and post-mitotic neurons, significantly increased percentages of astrocytes and increased expression of TNFalpha receptors, TNF-R1 and TNF-R2, as well as expression of the anti-neurogenic Hes1 gene, were observed. These data indicate that exposure of hippocampal NPCs to TNFalpha when they are undergoing differentiation but not proliferation has a detrimental effect on their neuronal lineage fate, which may be mediated through increased expression of Hes1., (Copyright 2009 Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is characterised by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Inflammation may be associated with the neuropathology of PD due to the following accumulating evidence: excessive microglial activation and increased levels of the pro-inflammatory cytokines tumour necrosis factor-alpha and interleukin-1beta in the SNpc of patients with PD; the emergence of PD-like symptoms following influenza infection; the increased susceptibility to PD associated with bacterial vaginosis; the presence of inflammatory mediators and activators in animal models of PD; the ability of anti-inflammatory drugs to decrease susceptibility to PD; and the emerging possibility of the use of microglial activation inhibitors as a therapy in PD. In this review, we will discuss the role of inflammation in PD. We will focus on the influence of microglia in the pathogenesis of PD and discuss potential therapeutic interventions for PD, that target microglia.

Deficits in cognitive function are associated with neuroinflammatory changes, typified by activation of glial cells and an alteration of the pro- and anti-inflammatory cytokine balance in the brain. Although there is evidence to suggest that activation of microglia is regulated by interaction with other cell types in the brain, the mechanism(s) involved is poorly understood. Here, we provide evidence that interaction between CD200 and its receptor plays a role in modulating microglial activation under conditions of chronic and acute inflammation of the brain. We report that interleukin-4 (IL-4) plays a central role in modulating expression of CD200 and identify a mechanism by which IL-4 directly controls microglial cell activation. Our findings provide the first demonstration of a role for IL-4 in modulating CD200 expression and suggest a mechanism for regulation of microglial activation in the intact CNS under inflammatory conditions.