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At least 19 recordsLinked to original sources
PubMed1997

Neuroinflammatory disease. IBC meeting on neuroinflammatory disease: research and treatment strategies. London, UK, 17 and 18 September 1996.

The conference focused on the impact of neuroinflammation in several important neurological illnesses. The similarities between the diseases were clearly brought out. It is unlikely that a single treatment for inflammation will emerge that will be useful in such diverse conditions. However, those who attended the conference felt that emphasizing the common features of these diseases was very useful. This highly successful meeting was organized by Drs V. Hugh Perry and Andy Gearing.

Alzheimer Disease↗
PubMed2004

Molecular analysis of HLA class II-associated susceptibility to neuroinflammatory diseases in Korean children.

The work was done to study immunogenetic peculiarities of neuroinflammatory diseases among Korean children. A total of 13 children with neuroinflammatory diseases (8 males and 5 females; mean age 4.6 +/-2.6 yr) were consecutively recruited. Geno-mic typing was performed on their HLA DRB/HLA DQB genes using PCR-SSOP/SSP techniques with gel immunoelectrophoresis. The frequencies of HLA-DR1 *15 in children with acute disseminated encephalomyelitis (ADEM) (31%) and DQB1 *06 in other neuroinflammatory diseases (38%) were significantly increased compared with control subjects. The frequencies of HLA-DRB3 * 0202 (100%), HLA-DRB1 * 1302 (67%), HLA-DRB3 * 0301 (67%), and HLA-DQB1 * 0301 (67%) were significantly increased in children with multiple sclerosis and the frequencies of HLA-DRB1 * 1501 (40%) and HLA-DRB5 * 0101 (40%) were significantly increased in children with ADEM. HLA-DRB1 * 1401, HLA- DRB3 * 0202, and HLA-DQB1 * 0502 were found in children with acute necrotizing encephalopathy. In conclusion, HLA-DR1 * 15 and DQB1 * 06 may be involved in susceptibility to inflammation in Korean children. The frequencies of HLA-DRB1 * 1501, HLA-DRB5 * 0101, HLA-DRB3 * 0301, and HLA-DQB1* 0602 were not as high in Korean children with multiple sclerosis as in western children. However, HLA-DRB3 * 0202 was seen in all children with multiple sclerosis. Our data may provide further evidence that the immunogenetic background of neuroinflammatory diseases in Korean is distinctly different from the ones in western countries. Further studies are necessary to confirm this finding.

Alleles↗
PubMed2002

The use of cell products for treatment of autoimmune neuroinflammatory diseases.

Cell products are live cells that are given to patients in order to replace or modify the function of missing or dysfunctional cells. Progress in technology and in the understanding of pathobiology may lead to the use of cell products in many areas. This review outlines the use of cell products in the treatment of autoimmune diseases, with focus on neuroinflammatory diseases like multiple sclerosis. Treatment of autoimmune diseases should be selective and specific in order to avoid serious side effects. To achieve this, T lymphocyte regulation has been in focus for several immunomodulatory regimens. One area of great interest is the use of T cell vaccination, when autologous attenuated auto-reactive T cells are given to patients in order to initiate a specific immune response to the pathogenic T cell populations. Phopheresis may be an immunomodulatory treatment related to T cell vaccination. Another promising area involves ex-vivo alteration of the cytokine profile of harmful auto-reactive T cells. This can be achieved by genetic manipulation or by certain cytokine stimulations. A subsequent adoptive cell transfer will, by homing mechanisms, lead to at site specific delivery of the cells, which will have a local down-regulatory effect on the inflammatory process. Although unsolved questions regarding doses, timing, optimal preparing conditions and mechanisms still remain, both T cell vaccination and adoptive transfer of ex-vivo manipulated cytokine secreting cells have proven successful for treatment of neuroinflammation in experimental models. T cell vaccination was shown to be feasible in patients with multiple sclerosis, however, otherwise the experience in humans so far is limited.

Animals↗
PubMed2006

Quantitative analysis of human endogenous retrovirus-W env in neuroinflammatory diseases.

Although human endogenous retroviruses (HERVs) constitute 8% of the human genome, their role(s) in health and disease remain uncertain. Nonetheless, increased HERV gene activity has been reported in neuroinflammatory diseases such as multiple sclerosis (MS). The human endogenous retrovirus (HERV)-W7q envelope gene encodes a glycosylated envelope protein, syncytin-1, which is expressed in many tissues. Analysis of HERV envelopes (env) revealed a selectively increased abundance of syncytin-1 encoding RNA in brains from patients with MS (p<0.01) relative to non-MS patients. However, HERV env expression from blood-derived leukocytes did not differ between groups. A quantitative PCR-based assay for syncytin-1 RNA showed that median viral RNA levels were higher in brains of MS patients (5.0 log10 copies/microg RNA) relative to non-MS patients (4.6 log10 copies/microg RNA) (p<0.05). Median syncytin-1 DNA levels in MS brains (9.8 log10/microg DNA) were higher than non-MS brain tissue (7.9 log10/microg DNA) (p<0.001) without evidence of new integration events. In contrast, there were no differences in syncytin-1 RNA copy numbers between groups in both CSF (non-MS: 5.0 log10/ml versus MS: 3.8 log10/ml) and plasma (non-MS: 5.033 log10/ml versus MS: 2.9 log10/ml). These observations emphasize the selective induction of syncytin-1 in brain tissue of MS patients but also illustrate the complex dynamics of this retroelement in neuroinflammatory processes.

Brain↗
PubMed1992

Cytokines in neuroinflammatory disease: role of myelin autoreactive T cell production of interferon-gamma.

Many cytokines must be considered as effector and immunoregulatory molecules in neuroinflammatory diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). We have studied the potential role of interferon-gamma (IFN-gamma) in the pathogenesis of these diseases, since this cytokine has a number of important effects such as macrophage activation, induction of MHC class I and class I antigens, and T cell homing. An immunospot assay that allows enumeration of single cells secreting IFN-gamma after short-term culture in vitro of mononuclear cell suspensions has been used. In EAE, increased numbers of IFN-gamma-secreting cells (IFN-gamma-sc) appear in the central nervous system shortly before onset of clinical signs. Such cells also increased during pharmacologically induced relapse of EAE. In later stages of EAE, memory T cells that produced IFN-gamma in response to presented antigen, recognized multiple regions of the myelin basic protein (MBP), showing that (i) myelin autoreactive T cells have the functional ability to produce this cytokine, (ii) the concept of immunodominance as to autoantigen peptide reactivity is non-absolute and time-dependent. In multiple sclerosis (MS) there are increased numbers of IFN-gamma-sc among the CSF cells. Also, there are increased numbers of memory T cells, strongly enriched to the cerebrospinal fluid, which upon recognition of several myelin antigens and several MBP peptide stretches, produce IFN-gamma. Taken together, the data are consistent with a role for IFN-gamma as a key mediator in inflammatory demyelinating diseases.

Animals↗
PubMed2006

Block of neural Kv1.1 potassium channels for neuroinflammatory disease therapy.

OBJECTIVE: We asked whether blockade of voltage-gated K+ channel Kv1.1, whose altered axonal localization during myelin insult and remyelination may disturb nerve conduction, treats experimental autoimmune encephalomyelitis (EAE). METHODS: Electrophysiological, cell proliferation, cytokine secretion, immunohistochemical, clinical, brain magnetic resonance imaging, and spectroscopy studies assessed the effects of a selective blocker of Kv1.1, BgK-F6A, on neurons and immune cells in vitro and on EAE-induced neurological deficits and brain lesions in Lewis rats. RESULTS: BgK-F6A increased the frequency of miniature excitatory postsynaptic currents in neurons and did not affect T-cell activation. EAE was characterized by ventriculomegaly, decreased apparent diffusion coefficient, and decreased (phosphocreatine + beta-adenosine triphosphate)/inorganic phosphate ratio. Reduced apparent diffusion coefficient and impaired energy metabolism indicate astrocytic edema. Intracerebroventricularly BgK-F6A-treated rats showed attenuated clinical EAE with unexpectedly reduced ventriculomegaly and preserved apparent diffusion coefficient values and (phosphocreatine + beta-adenosine triphosphate)/inorganic phosphate ratio. Thus, under BgK-F6A treatment, brain damage was dramatically reduced and energy metabolism maintained. INTERPRETATION: Kv1.1 blockade may target neurons and astrocytes, and modulate neuronal activity and neural cell volume, which may partly account for the attenuation of the neurological deficits. We propose that Kv1.1 blockade has a broad therapeutic potential in neuroinflammatory diseases (multiple sclerosis, stroke, and trauma).

Animals↗
PubMed1998

Therapeutic approaches to the treatment of neuroinflammatory diseases.

Microglia cells are present in the central nervous system and respond quickly to pathogenic stimuli in order to protect the brain. When these immunological responses activate inappropriately or are prolonged, they can contribute to the neuronal damage observed in many neurodegenerative diseases. A variety of immune system modulators including complement proteins, inflammatory cytokines such IL-1 alpha, IL-1 beta, IL-3, IL-6, TNF-alpha, and S100 beta, colony-stimulating factor-1, coagulation proteins and matrix metalloproteases are made by both microglia and astrocytes. Additionally astrocytes, the predominant glial component of the brain, express cell-adhesion molecules, cytokine receptors and induce nitric oxide synthease. The pathophysiology of Alzheimer's disease, stroke, traumatic brain injury, and multiple sclerosis suggest that a large portion of the irreversible damage observed can be attributed to a neuroinflammatory mechanism. The immunomodulators of these diseases are reviewed and new agents within specific molecular mechanisms are presented and discussed.

Adjuvants, Immunologic↗
PubMed2003

Neural stem cells: a potential source for remyelination in neuroinflammatory disease.

In multiple sclerosis, the central nervous system is lesioned through invasion of plaque-forming inflammatory cells, primarily contributing to immune attack of myelin and oligodendrocytes. In this report we address the possible activation and differentiation of central nervous system stem cells following such immunological insults in a well-characterized rat model of multiple sclerosis characterised by spinal cord pathology. Dye-labeled central nervous system stem cells, residing within the ependymal layer of the central canal responded to the multiple sclerosis-like conditions by proliferation, while some of the migrating stem cell-derived cells expressed markers typical for oligodendrocytes (04) and astrocytes (glial fibrillary acidic protein, GFAP) in the demyelinated area. Our results indicate that regenerative stem cell activation following immunoactivity is different from that after trauma, exemplified by the slower time course of stem cell proliferation and migration of progeny, in addition to the ability of the stem cell-derived cells to express oligodendrocyte markers. Finally, deleterious effects of macrophages on the stem cell population were evident and may contribute to the depletion of the stem cell population in neuroinflammatory disorders.

Animals↗
PubMed2001

Cerebrospinal fluid from patients with neurodegenerative and neuroinflammatory diseases: no evidence for rat glial activation in vitro.

To determine the possible contribution of glial cells via oxidative stress/cytokine secretion in the pathogenesis of Parkinson's disease (PD), Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) the concentration of nitric oxide (NO) (by the Griess method) and Interleukin-6 (IL-6) (by enzyme-linked immunosorbent assay) were measured in resting rat microglial and astrocytic cell culture supernatants stimulated by cerebrospinal fluid (CSF) (dilution 1:4, 1:10) from patients with the aforementioned diseases. Neither the concentration of NO (optical density at 450 nm: control, 0.036+/-0.006; MS, 0.034+/-0.008; AD, 0.031+/-0.006; PD, 0.02+/-0.01; lipopolysaccharide (LPS), 0.26+/-0.018) nor the amount of IL-6 (ng/ml: control, 0.112+/-0.026; PD, 0.12+/-0.027; MS, 0.123+/-0.008; ALS, 0.137+/-0.01; LPS, 1.81+/-0.11) differed in any disease group from those of unaffected controls. These findings suggest that the stimuli for inflammatory activation of glia are quite localized and not present in sufficient concentrations in the CSF of affected patients.

Astrocytes↗
PubMed2005

Drug Insight: using statins to treat neuroinflammatory disease.

Statins, a family of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are used primarily to reduce atherogenesis and cardiovascular morbidity. Surprisingly, they have also been shown to have immunomodulatory properties that might be of benefit for the treatment of autoimmune disorders. Statins can prevent and even reverse ongoing paralysis in experimental autoimmune encephalomyelitis--the mouse model for multiple sclerosis--and on the basis of these findings, statins are now being tested in patients with multiple sclerosis in clinical trials.

Animals↗
PubMed2006

Immunophenotypic patterns of T-cell activation in neuroinflammatory diseases.

OBJECTIVES: We aimed to gain insights into the pathogen-specific differences in early adaptive immune responses following central nervous system infections with Borrelia burgdorferi and viral pathogens by studying the immunophenotypic patterns of T-cell activation. Moreover, we wished to determine whether the expression of T-cell activation markers reflects disease activity in multiple sclerosis (MS). METHODS: Proportions of cerebrospinal fluid T-cells expressing the markers HLA-DR, CD25 and CD38 were determined in patients with MS (n = 40), acute viral meningomyeloradiculoneuritis (VID, n = 26), early neuroborreliosis (NB, n = 23) and non-inflammatory neurologic diseases (n = 51) by using flow cytometry. In relapsing-remitting MS, disease activity was assessed by clinical examination and magnetic resonance imaging. RESULTS: For each of the surface markers that were examined, significant differences in T cell proportions were found between patient groups. The proportion of HLA-DR+ T cells was higher and that of CD25+ T cells lower in NB compared with VID. These differences were attributable only to the early phase of the disease (< or = 6 days after symptom onset). Among MS patients, there was a trend for higher proportions of T cells expressing activation markers in patients with gadolinium-enhancing lesions. CONCLUSIONS: The decreased CD25 expression in NB may reflect immunomodulatory effects of B. burgdorferi facilitating persistent infection. Larger prospective studies of T-cell activation markers for ascertaining the association between cellular markers and clinical surrogates of disease activity in MS are warranted.

ADP-ribosyl Cyclase 1↗
PubMed2004

A novel role of lactosylceramide in the regulation of lipopolysaccharide/interferon-gamma-mediated inducible nitric oxide synthase gene expression: implications for neuroinflammatory diseases.

In the present study a possible role of glycosphingolipids (GSLs) in inducible nitric oxide synthase (iNOS) gene expression and nitric oxide (NO) production after spinal cord injury (SCI) in rats has been established. In primary rat astrocytes lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) treatment increased the intracellular levels of lactosylceramide (LacCer) and induced iNOS gene expression. d-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol.HCI (PDMP), a glucosylceramide synthase and LacCer synthase (galactosyltransferase, GalT-2) inhibitor, inhibited LPS/IFN-gamma induced iNOS expression, which was reversed by exogenously supplied LacCer, but not by other glycosphingolipids. LPS/IFN-gamma caused a rapid increase in the activity of GalT-2 and synthesis of LacCer. Silencing of GalT-2 gene with the use of antisense oligonucleotides resulted in decreased LPS/IFN-gamma-induced iNOS, TNF-alpha, and IL-1beta gene expression. The PDMP-mediated reduction in LacCer production and inhibition of iNOS expression correlated with decreased Ras and ERK1/2 activation along with decreased IkappaB phosphorylation, NF-kappaB DNA binding activity, and NF-kappaB-luciferase reporter activity. LacCer-mediated Ras activation was redox-mediated and was attenuated by antioxidants N-acetyl cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC). In vivo administration of PDMP after SCI resulted in improved functional outcome (Basso, Beattie, Bresnahan score); inhibition of iNOS, TNF-alpha, and IL-1beta expression; decreased neuronal apoptosis; and decreased tissue necrosis and demyelination. The in vivo studies supported the conclusions drawn from cell culture studies and provided evidence for the possible role of GalT-2 and LacCer in SCI-induced inflammation and pathology. To our knowledge this is the first report of a role of LacCer in iNOS expression and the advantage of GSL depletion in attenuating post-SCI inflammation to improve the outcome of SCI.

Acetylcysteine↗
PubMed2006

IL-4-induced peroxisome proliferator-activated receptor gamma activation inhibits NF-kappaB trans activation in central nervous system (CNS) glial cells and protects oligodendrocyte progenitors under neuroinflammatory disease conditions: implication for CNS-demyelinating diseases.

Th2 phenotype cytokine, IL-4, plays an important role in the regulation of Th1 cell responses and spontaneous remission of inflammatory CNS demyelinating diseases such as multiple sclerosis (MS). In this study we demonstrate IL-4-induced down-regulation of inducible NO synthase (iNOS) expression and survival of differentiating oligodendrocyte progenitors (OPs) in proinflammatory cytokine (Cyt-Mix)-treated CNS glial cells, which is a condition similar to that observed in the brain of a patient with MS. IL-4 treatment of Cyt-Mix-treated CNS glial cells significantly decreased iNOS expression/NO release with a parallel increase in survival of differentiating OPs. IL-4 effects were concentration-dependent and could be reversed by anti-IL-4R Abs. The use of inhibitors for Akt, p38 MAPK, and peroxisome proliferator-activated receptor gamma (PPAR-gamma) antagonist revealed that inhibition of Cyt-Mix-induced iNOS expression and survival of differentiating OPs by IL-4 is via PPAR-gamma activation. There was a coordinate increase in the expression of both PPAR-gamma and its natural ligand-producing enzyme 12/15-lipoxygenase (12/15-LOX) in IL-4-treated cells. Next, EMSA, immunoblots, and transient cotransfection studies with reporter plasmids (pNF-kappaB-Luc and pTK-PPREx3-Luc) and 12/15-LOX small interfering RNA revealed that IL-4-induced PPAR-gamma activation antagonizes NF-kappaB transactivation in Cyt-Mix-treated astrocytes. In support of this finding, similarly treated 12/15-LOX(-/-) CNS glial cells further corroborated the result. Furthermore, there was reversal of IL-4 inductive effects in the brain of LPS-challenged 12/15-LOX(-/-) mice when compared with LPS-challenged wild-type mice. Together, these data for the first time demonstrate the inhibition of Cyt-Mix-induced NF-kappaB transactivation in CNS glial cells by IL-4 via PPAR-gamma activation, hence its implication for the protection of differentiating OPs during MS and other CNS demyelinating diseases.

Animals↗
PubMed2005

Microglial activation and dopamine terminal loss in early Parkinson's disease.

Neuroinflammatory glial response may contribute to degenerative processes in Parkinson's disease (PD). To investigate changes in microglial activity associated with changes in the presynaptic dopamine transporter density in the PD brain in vivo, we studied 10 early-stage drug-naive PD patients twice using positron emission tomography with a radiotracer for activated microglia [(11)C](R)-PK11195 and a dopamine transporter marker [(11)C]CFT. Quantitative levels of binding potentials (BPs) of [(11)C](R)-PK11195 and [(11)C]CFT in the nigrostriatal pathway were estimated by compartment analyses. The levels of [(11)C](R)-PK11195 BP in the midbrain contralateral to the clinically affected side were significantly higher in PD than that in 10 age-matched healthy subjects. The midbrain [(11)C](R)-PK11195 BP levels significantly correlated inversely with [(11)C]CFT BP in the putamen and correlated positively with the motor severity assessed by the Unified Parkinson's Disease Rating Scale in PD. In healthy subjects, the [(11)C](R)-PK11195 BP in the thalamus and midbrain showed an age-dependent increase. In vivo demonstration of parallel changes in microglial activation and corresponding dopaminergic terminal loss in the affected nigrostriatal pathway in early PD supports that neuroinflammatory responses by intrinsic microglia contribute significantly to the progressive degeneration process of the disease and suggests the importance of early therapeutic intervention with neuroprotective drugs.

Adult↗
PubMed2004

Molecular regulation of CD40 gene expression in macrophages and microglia.

Inflammatory events in the central nervous system (CNS) contribute to the disease process in a variety of neuroinflammatory diseases such as multiple sclerosis (MS), Alzheimer's Disease (AD), and cerebral ischemia, and activated macrophages/microglia are central to this response. Immunological activation of these cells leads to the production of a wide array of cytokines, chemokines, matrix metalloproteinases and neurotoxins, and ultimately to glial/neuronal injury and death. The CD40 molecule has an important role in promoting inflammatory responses by macrophages/microglia, since interaction with its cognate ligand, CD154, leads to secretion of cytokines and neurotoxins. Aberrant CD40 expression by macrophages/microglia, induced by cytokines such as IFN-gamma and TNF-alpha, contributes to neuroimmunologic cascades in the CNS. Strategies to suppress CD40 expression may attenuate inflammation and neuronal damage within the CNS, which will ultimately be of benefit in neuroinflammatory diseases. The mediators that regulate expression of CD40 in macrophages/microglia (both induction and inhibition) function at the level of gene transcription. In this review, we present an overview of the molecular basis of CD40 expression in macrophages/microglia. The signal transduction pathways and transcription factors employed by IFN-gamma and TNF-alpha to induce CD40 expression are described, as are the cis-elements in the CD40 promoter that are critical for CD40 transcription. Information is provided on the mechanism(s) underlying suppression of CD40 in macrophages/microglia by immunomodulatory agents such as IL-4, TGF-beta, neuropeptides, neurotrophins, and statins. A comprehensive assessment of CD40 production and function in macrophages/microglia will establish the foundation for future therapeutic manipulation of this critical immunoregulatory protein.

Animals↗
PubMed2005

Sodium-mediated axonal degeneration in inflammatory demyelinating disease.

Axonal degeneration is a major cause of permanent neurological deficit in multiple sclerosis (MS). The mechanisms responsible for the degeneration remain unclear, but evidence suggests that a failure to maintain axonal sodium ion homeostasis may be a key step that underlies at least some of the degeneration. Sodium ions can accumulate within axons due to a series of events, including impulse activity and exposure to inflammatory factors such as nitric oxide. Recent findings have demonstrated that partial blockade of sodium channels can protect axons from nitric oxide-mediated degeneration in vitro, and from the effects of neuroinflammatory disease in vivo. This review describes some of the reasons why sodium ions might be expected to accumulate within axons in MS, and recent observations suggesting that it is possible to protect axons from degeneration in neuroinflammatory disease by partial sodium channel blockade.

Animals↗