Abstract:
:Laquinimod (LAQ) is a new oral immunomodulatory compound that reduces relapse rate, brain atrophy and disability progression in multiple sclerosis (MS). LAQ has well-documented effects on inflammation in the periphery, but little is known about its direct activity within the central nervous system (CNS). To elucidate the impact of LAQ on CNS-intrinsic inflammation, we investigated the effects of LAQ on cuprizone-induced demyelination in mice in vivo and on primary CNS cells in vitro. Demyelination, inflammation, axonal damage and glial pathology were evaluated in LAQ-treated wild type and Rag-1-deficient mice after cuprizone challenge. Using primary cells we tested for effects of LAQ on oligodendroglial survival as well as on cytokine secretion and NF-κB activation in astrocytes and microglia. LAQ prevented cuprizone-induced demyelination, microglial activation, axonal transections, reactive gliosis and oligodendroglial apoptoses in wild type and Rag-1-deficient mice. LAQ significantly decreased pro-inflammatory factors in stimulated astrocytes, but not in microglia. Oligodendroglial survival was not affected by LAQ in vitro. Astrocytic, but not microglial, NF-κB activation was markedly reduced by LAQ as evidenced by NF-κB reporter assay. LAQ also significantly decreased astrocytic NF-κB activation in cuprizone-treated mice. Our data indicate that LAQ prevents cuprizone-induced demyelination by attenuating astrocytic NF-κB activation. These effects are CNS-intrinsic and not mediated by peripheral immune cells. Therefore, LAQ downregulation of the astrocytic pro-inflammatory response may be an important mechanism underlying its protective effects on myelin, oligodendrocytes and axons. Modulation of astrocyte activation may be an attractive therapeutic target to prevent tissue damage in MS.
journal_name
Acta Neuropatholjournal_title
Acta neuropathologicaauthors
Brück W,Pförtner R,Pham T,Zhang J,Hayardeny L,Piryatinsky V,Hanisch UK,Regen T,van Rossum D,Brakelmann L,Hagemeier K,Kuhlmann T,Stadelmann C,John GR,Kramann N,Wegner Cdoi
10.1007/s00401-012-1009-1subject
Has Abstractpub_date
2012-09-01 00:00:00pages
411-24issue
3eissn
0001-6322issn
1432-0533journal_volume
124pub_type
杂志文章abstract::Axonal degeneration contributes to the transient and permanent neurological deficits seen in multiple sclerosis, an inflammatory disease of the central nervous system. To study the immunological mechanisms causing axonal degeneration, we induced experimental autoimmune encephalomyelitis (EAE) in wildtype Lewis rats an...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-006-0047-y
更新日期:2006-06-01 00:00:00
abstract::Extracellular deposition of amyloid β-protein (Aβ) in amyloid plaques and intracellular accumulation of abnormally phosphorylated τ-protein (p-τ) in neurofibrillary tangles (NFTs) represent pathological hallmark lesions of Alzheimer's disease (AD). Both lesions develop in parallel in the human brain throughout the pre...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-019-02053-5
更新日期:2019-12-01 00:00:00
abstract::Isocitrate dehydrogenase 1 (IDH1) mutations are frequent in astrocytomas, oligoastrocytomas and oligodendrogliomas. We previously reported the generation of a mutation-specific antibody that specifically detects R132H mutated IDH1 protein (clone H09). Here, we investigate the feasibility of H09 immunohistochemistry to...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-010-0770-2
更新日期:2011-02-01 00:00:00
abstract::Accumulation of amyloid-β (Aβ) and neurofibrillary tangles in the brain, inflammation and synaptic and neuronal loss are some of the major neuropathological hallmarks of Alzheimer's disease (AD). While genetic mutations in amyloid precursor protein and presenilin-1 and -2 (PS1 and PS2) genes cause early-onset familial...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-012-1065-6
更新日期:2013-02-01 00:00:00
abstract::When 22 members of the BrainNet Europe (BNE) consortium assessed 31 cases with alpha-synuclein (alphaS) immunoreactive (IR) pathology applying the consensus protocol described by McKeith and colleagues in 2005, the inter-observer agreement was 80%, being lowest in the limbic category (73%). When applying the staging p...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-009-0523-2
更新日期:2009-06-01 00:00:00
abstract::The distribution of the calcium-binding protein calretinin was investigated by immunohistochemistry in the hippocampus, the subicular areas, and the entorhinal cortex in patients with Alzheimer's disease and in control subjects. By double immunolabelling, the calretinin immunoreactivity was compared to the immunoreact...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00294357
更新日期:1994-01-01 00:00:00
abstract::Essential mixed cryoglobulinemia, which can cause hypersensitivity vasculitis, was observed in five patients with peripheral neuropathy. Three cases presented with multifocal neuropathies and two cases with symmetrical polyneuropathy. One had cryoglobulinemia with IgM monoclonal gammopathy IgG polyclonal gammopathy, a...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00686206
更新日期:1988-01-01 00:00:00
abstract::Spinal cord of the rat was investigated immunohistochemically to detect signs of extravasation of fibronectin in animals in which the cord was subjected to different degrees of compression trauma. Immunohistochemistry was performed after survival periods of 4 and 24 h and parallel sections were incubated for albumin i...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00227738
更新日期:1992-01-01 00:00:00
abstract::We described the first two unrelated Polish families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In the morphological examination with light microscopy, two kinds of changes were observed: (1). panarteritis nodosa-like changes with eosinophilic fibrinoid n...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-003-0764-4
更新日期:2003-12-01 00:00:00
abstract::We investigated whether the brainstem is affected by the pathologic process of sporadic Creutzfeldt-Jakob disease (sCJD), with particular attention to brainstem atrophy, neuronal loss, pyramidal tract degeneration, and prion protein (PrP) deposition, in 33 patients with sCJD. Brainstem atrophy, particularly in the pon...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-005-0981-0
更新日期:2005-06-01 00:00:00
abstract::This study tests the effects of chronic electrostimulation on denervated/reinnervated skeletal muscle in producing an optimal restoration of size and mechanical and histochemical properties. We compared tibialis anterior muscles in four groups of rats: in unoperated control (C) and 10 weeks following nerve lesion with...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-006-0035-2
更新日期:2006-06-01 00:00:00
abstract::We examined the immunohistochemical localization of the proinflammatory cytokines tumor necrosis factor-alpha, lymphotoxin and interferon-gamma in 22 autopsy brains of patients with either cerebrovascular disease (CVD) or other neurological diseases as well as 2 non-neurological control brains. These cytokines were co...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050519
更新日期:1996-09-01 00:00:00
abstract::The kidney of a 7-month-old male Cairn terrier with globoid cell leukodystrophy (GLD) was investigated with light and electron microscopes. A few tubular epithelial cells in the inner medulla as well as some exfoliated cells in the lumina revealed PAS-positive cytoplasm in which needle-like structures were to be seen ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00687036
更新日期:1986-01-01 00:00:00
abstract::Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood yet. In t...
journal_title:Acta neuropathologica
pub_type: 杂志文章,评审
doi:10.1007/s00401-008-0411-1
更新日期:2008-09-01 00:00:00
abstract::Peroxiredoxin-ll (Prxll) and glutathione peroxidase-l (GPxl) are regulators of the redox system that is one of the most crucial supporting systems in neurons. This system is an antioxidant enzyme defense system and is synchronously linked to other important cell supporting systems. To clarify the common self-survival ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-005-1019-3
更新日期:2005-08-01 00:00:00
abstract::We report an experimental model of Creutzfeldt-Jakob's disease (CJD) in mice leading to the formation of giant autophagic vacuoles (AV) in neurons of the cerebral cortex. These AV appear at the end of the incubation period (4-6 months postinoculation), together with spongy changes and clinical symptoms. Autophagy, a p...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00688178
更新日期:1989-01-01 00:00:00
abstract::Bundles of paired helical filaments (PHF) accumulate in the pyramidal neurons that degenerate during Alzheimer's disease. This neurofibrillary degeneration is highly correlated with clinical signs of dementia. During the degenerating process, Tau proteins, which are the major antigenic components of PHF, are abnormall...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00308912
更新日期:1990-01-01 00:00:00
abstract::Immunofluorescence and immunogold labelling were used to localise the 43-kDa dystrophin-associated glycoprotein (43DAG) of the dystrophin-glycoprotein complex in control and Duchenne muscular dystrophy (DMD) biopsies. In control muscle 43DAG was localised by immunofluorescence to the periphery of the fibre and, by imm...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00313603
更新日期:1994-01-01 00:00:00
abstract::Basal ganglionic lesions in three young infants were found in a prospective search for early stages of status marmoratus. The lesions had formed and had passed into glial scars well before myelination of the basal ganglia commenced. The myelinating fibers crossing the scarred tissue were disoriented; however, fiber st...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00688558
更新日期:1977-05-16 00:00:00
abstract::The nuclei for the nerves of a dorsal (m. splenius) and a ventral (m. longus capitis) neck muscle of the rat were retrogradely labeled by applying horseradish peroxidase (HRP) to the respective cut muscle nerves. Motoneurons of both muscles were analyzed for their localization, diameter of perikarya, and area of dendr...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00690368
更新日期:1981-01-01 00:00:00
abstract::A histopathological study was carried out on the brains of eight ex-boxers (ages 56 to 83) using conventional histological staining methods and immunocytochemistry with antibodies to amyloid beta-protein and the PHF-related tau protein. All cases showed a large number of tau-immunoreactive neurofibrillary tangles and ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00308813
更新日期:1991-01-01 00:00:00
abstract::The mechanisms underlying neurodegenerative diseases are the outcome of pathological alterations of evolutionary conserved molecular and cellular cascades. For this reason, Drosophila and C. elegans serve as useful model systems to study various aspects of neurodegenerative diseases. Here, we introduce the advantageou...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-010-0689-7
更新日期:2010-08-01 00:00:00
abstract::The pro-inflammatory and blood-brain barrier (BBB) effects of intratumoral (IT) injection of human recombinant tumor necrosis factor-alpha (rTNF-alpha) were studied in the Fischer rat RT-2 glioma model. Animals received a single stereotaxic injection of either 6 x 10(4) U rTNF-alpha or excipient (vehicle) into the cen...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/pl00007398
更新日期:1997-01-01 00:00:00
abstract::This study was designed to compare the degree of reactive astrogliosis occurring around a puncture wound in the brain of normal rats and at different intervals after a similar puncture wound in rats with a portocaval anastomosis. The gliosis was evaluated by the number of astrocytes, the thickness of their processes a...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00310926
更新日期:1991-01-01 00:00:00
abstract::VM mice were inoculated by intracerebral and intraperitoneal routes with brain homogenates containing the 87V strain of scrapie. The distribution and numbers of plaques were found for the parietal cortex, cingulate cortex, corpus callosum and hippocampus/dentate in coronal sections cut at the level of the thalamus and...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00688311
更新日期:1986-01-01 00:00:00
abstract::Underlying the Lambert-Eaton myasthenic syndrome (LEMS) is a decrease in the release of the neurotransmitter acetylcholine. Only few reports on light and transmission electron microscopical observations of motor endplates in LEMS are available and changes reported so far differ from those found in experimental blockin...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00308480
更新日期:1992-01-01 00:00:00
abstract::Rats were given isoniazid either in a single large dose or continuously in drinking water and killed 5--105 days later. The distribution of degenerating fibres in various nerves (sensory and mixed) and in various sites along nerves and spinal roots was studied by light and electron microscopy. It was found that sensor...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00691784
更新日期:1979-10-01 00:00:00
abstract::Interleukin-6 (IL-6) immunoreactivity has previously been shown in plaques in Alzheimer's disease (AD) and elevated IL-6 concentrations have been measured biochemically in brains of AD patients. In this study, we investigated the appearance of IL-6 immunoreactivity in AD plaques according to the stage of plaque format...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00571510
更新日期:1995-01-01 00:00:00
abstract::Amplification of the epidermal growth factor receptor (EGFR) gene is found in about 40% of glioblastomas (GBMs) but is rarely detected in GBM cell lines. We confirmed that the exceptional SKMG-3 GBM cell line retained amplified EGFR genes in vitro, and found that these sequences were concentrated on extra-chromosomal ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010000332
更新日期:2001-06-01 00:00:00
abstract::Oxidative stress has been implicated in the pathogenesis of a number of diseases including Alzheimer's disease (AD). The oxidative stress hypothesis of AD pathogenesis, in part, is based on beta-amyloid peptide (Abeta)-induced oxidative stress in both in vitro and in vivo studies. Oxidative modification of the protein...
journal_title:Acta neuropathologica
pub_type: 杂志文章,评审
doi:10.1007/s00401-009-0517-0
更新日期:2009-07-01 00:00:00