The Effect of Erythropoietin on Neurotrophic Factors in

Aim: In this study, we investigated whether interferon gamma (IFNγ), lipopolysaccharides (LPS) and amyloid beta (AMYβ), as toxic stimulator agents, and erythropoietin (EPO), as a neurotrophic agent, have an effect on the production of the following neurotrophic factors in the N9 murine microglia cell line: neurotrophin 3 (NT3), neurotrophin 4 (NT4), and brain-derived neurotrophic factor (BDNF). Materials and Methods: Microglial cells were incubated with 50 μg/ml AMYβ, or 1 μg/ml of LPS plus 100 U/ml recombinant murine IFNγ, and/or one of three different concentrations (0.1, 1.0, and 5.0 U/ml) of recombinant mouse EPO for 24 h. Results: EPO 0.1 U/ml dose significantly increased NT4 levels compared to EPO 5.0 U/ml dose (P < 0.05). EPO, in all doses, and AMYβ significantly induced NT4 secretion in microglias, while BDNF and NT3 were not changed by AMYβ or EPO. LPS + IFNγ alone did not change neurotrophic factor levels in any group. However, EPO with LPS and IFNγ induced NT4 secretion, especially the 5.0 U/ml dose of EPO.

Inhibition Motif Signaling in Neuroinflammation

Copyright © 2010 Bettina Linnartz et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Elimination of extracellular aggregates and apoptotic neural membranes without inflammation is crucial for brain tissue homeostasis. In the mammalian central nervous system, essential molecules in this process are the Fc receptors and the DAP12associated receptors which both trigger the microglial immunoreceptor tyrosine-based activation motif- (ITAM-) Syk-signaling cascade. Microglial triggering receptor expressed on myeloid cells-2 (TREM2), signal regulatory protein-β1, and complement receptor-3 (CD11b/CD18) signal via the adaptor protein DAP12 and activate phagocytic activity of microglia. Microglial ITAMsignaling receptors are counter-regulated by immunoreceptor tyrosine-based inhibition motif- (ITIM-) signaling molecules such as sialic acid-binding immunoglobulin superfamily lectins (Siglecs). Siglecs can suppress the proinflammatory and phagocytic activity of microglia via ITIM signaling. Moreover, microglial neurotoxicity is alleviated via interaction of Siglec-11 with sialic acids on the neuronal glycocalyx. Thus, ITAM- and ITIM-signaling receptors modulate microglial phagocytosis and cytokine expression during neuroinflammatory processes. Their dysfunction could lead to impaired phagocytic clearance and neurodegeneration triggered by chronic inflammation. 1. Microglia and Alzheimer’s Diseas

New Venues for Potential Therapeutic Approaches

The last decade has witnessed an increasing interest for the role played by the peroxisome proliferator-activated receptor-γ (PPARγ) in controlling inflammation in peripheral organs as well as in the brain. Activation of PPAR-γ has been shown to control the response of microglial cells, the main macrophage population found in brain parenchyma, and limit the inflammation. The antiinflammatory capacity of PPAR-γ agonists has led to the hypothesis that PPAR-γ might be targeted to modulate degenerative brain diseases in which inflammation has been increasingly recognized as a significant component. Recent experimental evidence suggests that PPAR-γ agonists could be exploited to treat ocular diseases such as diabetic retinopathy, age-related macular degeneration, autoimmune uveitis, and optic neuritis where inflammation has relevant role. Additional PPAR-γ agonist beneficial effects could involve amelioration of retinal microcirculation and inhibition of neovascularization. However, PPAR-γ activation could, in some instances, aggravate the ocular pathology, for example, by increasing the synthesis of vascular endothelial growth factor, a proangiogenic factor that could trigger a vicious circle and further deteriorate retinal perfusion. The development of new in vivo and in vitro models to study ocular inflammation and how to modulate for the eye benefit will be instrumental for the search of effective therapies. Copyright © 2008 Fiorella Malchiodi-Albedi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1

FLUPENTIXOL AND TRIFLUPERIDOL REDUCE INTERLEUKIN-1 � AND INTERLEUKIN-2 RELEASE BY RAT MIXED GLIAL AND

Flupentixol and trifluperidol reduce interleukin-1β and interleukin-2 release by rat mixed glial and microglial cell cultures. J. KOWALSKI, K. LABUZEK, Z.S. HERMAN. Pol. J. Pharmacol., 2004, 56, 563–570. Neuroleptics penetrate into the brain, where they act not only on neurons but probably also on glial cells. In the available literature, there are no reports on the effect of neuroleptics on cytokine release in glia cultures. The aim of this study was to evaluate the effect of neuroleptics on the release of proinflammatory cytokines (IL-1 � and IL-2) by mixed glial and microglial cell cultures. Trifluperidol at 20 and 2 �M reduced IL- � secretion by mixed glial cultures after 3 days of exposure. Trifluperidol at 20, 2 and 0.2 �M diminished IL- � secretion after 1 day of incubation. Trifluperidol at 20 and 2 �M reduced IL-2 release after 1 and 3 days of exposure. Flupentixol at 20 and 2 �M reduced IL-1 � by mixed glial cell cultures after 3 days of exposure. Flupentixol at 20, 2 and 0.2 �M caused diminution of IL-1 � release after 1 day of exposure. Flupentixol at 20 and 2 �M reduced IL-2 release after 1 day of incubation. Flupentixol at 20, 2 and 0.2 �M diminished IL-2 release after 3 days of exposure. Flupentixol at 20, 10, 2 and 0.2 �M reduced IL-1� release by microgial cell cultures. Flupentixol at 20, 10 and 2 �M reduced release of IL-2 by microglial cells after 1 day of exposure. The results of the present study suggest that neuroleptics have an inhibiting effect on the release of glial cytokines, but clinical significance this results remains to be elucidated

�-Chemokine Synthesis in Human Microglial Cells and

The understanding of immune surveillance and inflammation regulation in cerebral tissue is essential in the therapy of neuroimmunological disorders. We demonstrate here that primary human glial cells were able to produce �- and �-chemokines (IL-8> growth related protein � (GRO�) ��� � RANTES> microphage inflammatory protein (MIP)-1 � and MIP-1�) in parallel to PGs (PGE2 and PGF2�) after proinflammatory cytokine stimulation: TNF- � � IL-1 � induced all except RANTES, which was induced by TNF- � � IFN-�. Purified cultures of astrocytes and microglia were also induced by the same combination of cytokines, to produce all these mediators except MIP-1 � and MIP-1�, which were produced predominantly by astrocytes. The inhibition of PG production by indomethacin led to a 37–60 % increase in RANTES, MIP-1�, and MIP-1 � but not in GRO � and IL-8 secretion. In contrast, inhibition of IL-8 and GRO activities using neutralizing Abs resulted in a specific 6-fold increase in PGE2 but not in PGF2 � production by stimulated microglial cells and astrocytes, whereas Abs to �-chemokines had no effect. Thus, the production of PGs in human glial cells down-regulates their �-chemokine secretion, whereas �-chemokine production in these cells control

Development/Plasticity/Repair Palmitoylethanolamide Increases after Focal Cerebral

Focal cerebral ischemia (FCI) induces rapid neuronal death in the ischemic core, which gradually expands toward the penumbra, partly as the result of a neuroinflammatory response. It is known that propagation of neuroinflammation involves microglial cells, the resident macrophages of the brain, which are highly motile when activated by specific signals. However, the signals that increase microglial cell motility in response to FCI remain mostly elusive. Here, we tested the hypothesis that endocannabinoids mediate neuroinflammation propagation by increasing microglial cell motility. We found that, in mouse cerebral cortex, FCI greatly increases palmitoylethanolamide (PEA), only moderately increases anandamide [arachidonylethanolamide (AEA)], and does not affect 2-arachidonoylglycerol levels. We also found that PEA potentiates AEA-induced microglial cell migration, without affecting other steps of microglial activation, such as proliferation, particle engulfment, and nitric oxide production. This potentiation of microglial cell migration by PEA involves reduction in cAMP levels. In line with this, we provide evidence that PEA acts through Gi/o-coupled receptors. Interestingly, these receptors engaged by PEA are pharmacologically distinct from CB1 and CB2 cannabinoid receptors, as well as from the WIN and abn-CBD (abnormal-cannabidiol) receptors, two recently identified cannabinoid receptors. Our results show that PEA and AEA increase after FCI and synergistically enhance microglial cell motility. Because such a response could participate in the propagation of the FCI-induced neuroinflammation within the CNS, and because PEA is likely to act through its own receptor, a better understanding of the receptor engaged by PEA may help guide the search for improved therapies against neuroinflammation. Key words: stroke; neuroinflammation; marijuana; lipids; nitric oxide; phagocytosi

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The Journal of Immunology System xc and Glutamate Transporter Inhibition Mediates

Elevated levels of extracellular glutamate cause excitotoxic oligodendrocyte cell death and contribute to progressive oligodendrocyte loss and demyelination in white matter disorders such as multiple sclerosis and periventricular leukomalacia. However, the mechanism by which glutamate homeostasis is altered in such conditions remains elusive. We show here that microglial cells, in their activated state, compromise glutamate homeostasis in cultured oligodendrocytes. Both activated and resting microglial cells release glutamate by the cystine-glutamate antiporter system xc. In addition, activated microglial cells act to block glutamate transporters in oligodendrocytes, leading to a net increase in extracellular glutamate and subsequent oligodendrocyte death. The blocking of �-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors or the system xc antiporter prevented the oligodendrocyte injury produced by exposure to LPS-activated microglial cells in mixed glial cultures. In a whole-mount rat optic nerve, LPS exposure produced wide-spread oligodendrocyte injury that was prevented by AMPA/kainate receptor block and greatly reduced by a system xc antiporter block. The cell death was typified by swelling and disruption of mitochondria, a feature that was not found in closely associated axonal mitochondria. Our results reveal a novel mechanism by which reactive microglia can contribute to altering glutamate homeostasis and to the pathogenesis of white matter disorders. The Journal of Immunology, 2007, 178: 6549–6556. Activation of microglia is a natural response to CNS infection to eliminate cell debris after injury and to suppor

Naegleria fowleri Lysate Induces Strong Cytopathic Effects and Pro-inflammatory Cytokine Release

Abstract: Naegleria fowleri, a ubiquitous free-living ameba, causes fatal primary amebic meningoencephalitis in humans. N. fowleri trophozoites are known to induce cytopathic changes upon contact with microglial cells, including necrotic and apoptotic cell death and pro-inflammatory cytokine release. In this study, we treated rat microglial cells with amebic lysate to probe contact-independent mechanisms for cytotoxicity, determining through a combination of light microscopy and scanning and transmission electron microscopy whether N. fowleri lysate could effect on both necrosis and apoptosis on microglia in a time- as well as dose-dependent fashion. A 51 Cr release assay demonstrated pronounced lysate induction of cytotoxicity (71.5%) toward microglial cells by 24 hr after its addition to cultures. In an assay of pro-inflammatory cytokine release, microglial cells treated with N. fowleri lysate produced TNF-α, IL-6, and IL-1β, though generation of the former 2 cytokines was reduced with time, and that of the last increased throughout the experimental period. In summary, N. fowleri lysate exerted strong cytopathic effects on microglial cells, and elicited pro-inflammatory cytokine release as a primary immune response. Key words: Naegleria fowleri, microglial cell, pro-inflammatory cytokine, cytotoxicity Free-living N. fowleri is a ubiquitous, soil- and water-borne ameba that can cause fatal primary amebic meningoencephalitis (PAM) in both humans and animal models. PAM occur