Mechanism of glial activation by S100B: involvement of the transcription factor NFκB

Lam, Amy G.M; Koppal, Tanuja; Akama, Keith T.; Guo, Ling; Craft, Jeffrey M.; Samy, Barat; Schavocky, James P.; Watterson, D. Martin; Eldik, Linda J. Van

doi:10.1016/s0197-4580(01)00233-0

Cited by 116 publications

(78 citation statements)

References 52 publications

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“…It is noteworthy that recent reports documented the presence of RAGE in microglia (Yan et al, 1996), in reactive astrocytes (Sasaki et al, 2001), and at the BBB (Deane et al, 2003). In rat primary cortical astrocytes, S100B was shown to activate nuclear factor kB, iNOS promoter, and nitric oxide production (Lam et al, 2001). Thus, it is tempting to speculate that S100B-induced activation of signal transduction pathways is at least in part mediated by the binding of S100B with RAGE.…”

Section: Subacute Effects Of Arundic Acid After Permanent Middle Cerementioning

confidence: 99%

Modulation of Astrocytic Activation by Arundic Acid (ONO-2506) Mitigates Detrimental Effects of the Apolipoprotein E4 Isoform after Permanent Focal Ischemia in Apolipoprotein E Knock-in Mice

Mori

Town

Tan

et al. 2005

J Cereb Blood Flow Metab

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Using homozygous human apolipoprotein E2 (apoE2) (2/2)-, apoE3 (3/3)-, or apoE4 (4/4)-knock-in (KI) mice, we have shown that delayed infarct expansion and reactive astrocytosis after permanent middle cerebral artery occlusion (pMCAO) were markedly exacerbated in 4/4-KI mice as compared with 2/2- or 3/3-KI mice. Here, we probed the putative causal relationship between enhanced astrocytic activation and exacerbation of brain damage in 4/4-KI mice using arundic acid (ONO-2506, Ono Pharmaceutical Co. Ltd), which is known to oppose astrocytic activation through its inhibitory action on S100B synthesis. In all of the KI mice, administration of arundic acid (10 mg/kg day, intraperitoneal, started immediately after pMCAO) induced significant amelioration of brain damage at 5 days after pMCAO in terms of infarct volumes (results expressed as the mean infarct volume (mm3) ±1s.d. in 2/2-, 3/3-, or 4/4-KI mice in the vehicle groups: 16±2, 15±2, or 22±2; in the arundic acid groups: 11±2 ( P<0.001), 11±2 ( P<0.001), or 12±2 ( P<0.001), as compared with the vehicle groups), neurologic deficits, and S100/glial fibrillary acidic protein burden in the peri-infarct area. The beneficial effects of arundic acid were most pronounced in 4/4-KI mice, wherein delayed infarct expansion together with deterioration of neurologic deficits was almost completely mitigated. The above results support the notion that the apoE4 isoform exacerbates brain damage during the subacute phase of pMCAO through augmentation of astrocytic activation. Thus, pharmacological modulation of astrocytic activation may confer a novel therapeutic strategy for ischemic brain damage, particularly in APOE ɛ4 carriers.

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Section: Subacute Effects Of Arundic Acid After Permanent Middle Cerementioning

confidence: 99%

Modulation of Astrocytic Activation by Arundic Acid (ONO-2506) Mitigates Detrimental Effects of the Apolipoprotein E4 Isoform after Permanent Focal Ischemia in Apolipoprotein E Knock-in Mice

Mori

Town

Tan

et al. 2005

J Cereb Blood Flow Metab

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“…The activated phenotype of astrocytes is characterized by hypertrophy of the soma and processes and by an upregulation of intermediate filaments [glial fibrillary acidic protein (GFAP), vimentin (Vim)], inflammatory/immune/oxidative stress markers, extracellular matrix (ECM) molecules, and growth factors and cytokines (Eddleston and Mucke, 1993;Ridet et al, 1997;Labourdette and Eclancher, 2002). The latter include the important neurotrophic cytokine S100 calcium-binding protein, ␤ subunit (S100B), which can induce oxidative stress pathways (Lam et al, 2001) and ␤-amyloid production by dystrophic neurites (Mrak and Griffin, 2001).…”

Section: Introductionmentioning

confidence: 99%

Calcineurin Triggers Reactive/Inflammatory Processes in Astrocytes and Is Upregulated in Aging and Alzheimer's Models

Norris

Kadish²,

Blalock³

et al. 2005

J. Neurosci.

202

210

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Astrocyte reactivity (i.e., activation) and associated neuroinflammation are increasingly thought to contribute to neurodegenerative disease. However, the mechanisms that trigger astrocyte activation are poorly understood. Here, we studied the Ca 2ϩ -dependent phosphatase calcineurin, which regulates inflammatory signaling pathways in immune cells, for a role in astrogliosis and brain neuroinflammation. Adenoviral transfer of activated calcineurin to primary rat hippocampal cultures resulted in pronounced thickening of astrocyte somata and processes compared with uninfected or virus control cultures, closely mimicking the activated hypertrophic phenotype. This effect was blocked by the calcineurin inhibitor cyclosporin A. Parallel microarray studies, validated by extensive statistical analyses, showed that calcineurin overexpression also induced genes and cellular pathways representing most major markers associated with astrocyte activation and recapitulated numerous changes in gene expression found previously in the hippocampus of normally aging rats or in Alzheimer's disease (AD). No genomic or morphologic evidence of apoptosis or damage to neurons was seen, indicating that the calcineurin effect was mediated by direct actions on astrocytes. Moreover, immunocytochemical studies of the hippocampus/neocortex in normal aging and AD model mice revealed intense calcineurin immunostaining that was highly selective for activated astrocytes. Together, these studies show that calcineurin overexpression is sufficient to trigger essentially the full genomic and phenotypic profiles associated with astrocyte activation and that hypertrophic astrocytes in aging and AD models exhibit dramatic upregulation of calcineurin. Thus, the data identify calcineurin upregulation in astrocytes as a novel candidate for an intracellular trigger of astrogliosis, particularly in aging and AD brain.

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Section: источники и биологические эффекты основных лигандов Rage в нunclassified

“…Оказывая трофическое воздействие на ней-роны в наномолярных концентрациях, белок становится нейротоксичным при аккумуляции его в экстрацеллюляр-ном пространстве и достижении микромолярных концен-траций, индуцируя как апоптоз, так и некроз клеток [49]. В основе последнего эффекта лежит способность S100B как самостоятельно индуцировать секрецию провоспа-лительных цитокинов, активность синтазы оксида азота iNOS [49], так и усиливать другие сигналы, направленные на нейроны и глиальные клетки. Так, S100B способен усиливать экспрессию интерлейкинов (Interleukin, IL) 1 и 6 [50] в микроглии и нейронах, что может приводить к патологическим изменениям свойств нейронов, в част-ности к гиперфосфорилированию τ-протеина, снижению уровня некоторых синаптических белков и увеличению синтеза и активности ацетилхолинэстеразы.…”

Section: источники и биологические эффекты основных лигандов Rage в нunclassified

Ligands of RAGE-Proteins: Role in Intercellular Communication and Pathogenesis of Inflammation

et al. 2015

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Mechanism of glial activation by S100B: involvement of the transcription factor NFκB

Cited by 116 publications

References 52 publications

Modulation of Astrocytic Activation by Arundic Acid (ONO-2506) Mitigates Detrimental Effects of the Apolipoprotein E4 Isoform after Permanent Focal Ischemia in Apolipoprotein E Knock-in Mice

Modulation of Astrocytic Activation by Arundic Acid (ONO-2506) Mitigates Detrimental Effects of the Apolipoprotein E4 Isoform after Permanent Focal Ischemia in Apolipoprotein E Knock-in Mice

Calcineurin Triggers Reactive/Inflammatory Processes in Astrocytes and Is Upregulated in Aging and Alzheimer's Models

Ligands of RAGE-Proteins: Role in Intercellular Communication and Pathogenesis of Inflammation

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