Tumor Necrosis Factor-α Mediates the Blood–Brain Barrier Dysfunction Induced by Activated Microglia in Mouse Brain Microvascular Endothelial Cells

Nishioku, Tsuyoshi; Matsumoto, Junichi; Dohgu, Shinya; Sumi, Noriko; Miyao, K; Takata, Fuyuko; Shuto, Hideki; Yamauchi, Atsushi; Kataoka, Yasufumi

doi:10.1254/jphs.09292sc

Cited by 138 publications

(96 citation statements)

References 15 publications

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“…Namely, it is known that activation of astrocytes may facilitate their synthesis and release of proinflammatory cytokines (3,34,35). In line with these findings, ribavirin-induced reduction of mRNA TNF-α expression after EAE induction, may contribute to down regulation of astrocytes activation and prevent myelin destruction, as we showed previously by cytokine immunohistochemistry (23).…”

Section: Discussionsupporting

confidence: 80%

The Effect of Ribavirin on Reactive Astrogliosis in Experimental Autoimmune Encephalomyelitis

et al. 2012

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Section: Discussionsupporting

confidence: 80%

The Effect of Ribavirin on Reactive Astrogliosis in Experimental Autoimmune Encephalomyelitis

et al. 2012

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“…Pro-inflammatory cytokines trigger the expression and activation of other inflammatory factors including other cytokines, chemokines and reactive oxygen species, that leads to necrotic and apoptotic neural injury [49,50]. Of these cytokines, TNF-α in particular is shown to be upregulated in CNS inflammatory conditions that involve BBB disruption [51].…”

Section: Translational Neurosciencementioning

confidence: 99%

“…Of the pro-inflammatory cytokines released by microglia, TNF-α is thought to be the main factor behind BBB dysfunction resulting in a feedback loop of continual inflammation between the periphery and the CNS [51].…”

Section: Translational Neurosciencementioning

confidence: 99%

Tumour necrosis factor - alpha mediated mechanisms of cognitive dysfunction

Baune

Camara²,

Eyre³

et al. 2012

Translational Neuroscience

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Background: Tumour necrosis factor -alpha (TNF-α) is a pro-inflammatory cytokine that combines a plethora of activities in the early stages of an immune response. TNF-α has gained increasing importance given TNF-α upregulation in multiple brain pathologies like neuropsychiatric conditions such as depression, schizophrenia, as well as neuroinflammatory disorder like multiple sclerosis (MS). Aim: The aim of this review is to critically analyse neurobiological, immunological and molecular mechanisms through which TNF-α influences the development of cognitive dysfunction. Principal findings/results: The review presents several lines of original research showing that the immunological properties of TNF-α exacerbate inflammatory responses in the central nervous system such as microglial and endothelial activation, lymphocytic and monocytic infiltration and the expression of downstream pro-inflammatory cytokines and apoptotic factors. Depression, schizophrenia, and MS all manifest symptoms of activated immune response along with cognitive dysfunction, with TNF-α overexpression as a central clinical feature common to these disorders. Furthermore, TNF-α acts negatively on neuroplasticity and the molecular mechanisms of memory and learning (i.e., long-term potentiation and long-term depression). TNF-α also exerts influence over the production of neurotrophins (i.e., nerve growth factor and brain-derived neurotrophic factor), neurogenesis, and dendritic branching. Conclusions/significance: This review outlines that TNF-α and its receptors have a substantial yet underappreciated influence on the development and progression of neuropsychiatric symptoms across several disease entities. An improved understanding of these underlying mechanisms may help develop novel therapeutic targets in the form of drugs specifically targeting downstream products of TNF-α activation within the central nervous system.

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“…17) Moreover, TNF-α is known to weaken the BBB. 18,19) Taken together, these data suggest that QUIN is produced in peripheral organs by exercise, causing increased blood QUIN levels; QUIN may then enter the brain through the weakened BBB. To confirm this hypothesis, the QUIN levels in cerebrospinal fluid (CSF) must be measured after exercise, although it is difficult to collect CSF samples from mice.…”

Section: Discussionmentioning

confidence: 86%

Increased Blood Quinolinic Acid after Exercise in Mice: Implications for Sensation of Fatigue after Exercise

Morimoto¹,

Zhang²,

Adachi³

2011

JOURNAL OF HEALTH SCIENCE

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We have previously hypothesized that mental fatigue is caused by neuronal brain damage through the activation of N-methyl-D-aspartate receptors by quinolinic acid (QUIN). QUIN is a metabolite of tryptophan in the kynurenine pathway; this pathway is stimulated by several cytokines, including tumor necrosis factor (TNF)-α. Recently, we proved this mental-fatigue hypothesis by studying stress-loaded and lipopolysaccharide-treated mice. In the present study, we measured blood QUIN levels after exercise in mice to investigate whether QUIN also participates in causing the sensation of fatigue after exercise. In a weight-loaded swimming test, steel wires weighing about 5% of body weight were attached to the tails of mice that were then forced to swim until exhaustion. The serum QUIN levels of swimming mice were significantly higher than those of non-swimming mice. The serum TNF-α levels were also increased in swimming mice compared with nonswimming mice, although this effect was not significant. In a treadmill-running test, mice were forced to run for 150 min on a 10-degree uphill incline. The serum levels of both QUIN and TNF-α were significantly higher in treadmill-running mice than in nonrunning mice. Wheel-running counts, which reflect mental activity, were also measured in a running wheel-equipped home cage. Wheel-running counts of treadmill-running mice were significantly reduced compared with those of non-running mice. These results suggest that blood QUIN levels are increased after exercise and that this effect occurs through * To whom correspondence should be addressed: Kampo Research Laboratories, Kracie Pharma, Ltd., 3-1 Kanebo-machi, Takaoka, Toyama 933-0856, Japan. Tel.: +81-766-28-7953; Fax: +81-766-28-7960; E-mail: morimoto@phm.kracie.co.jp enhanced tryptophan metabolism in the kynurenine pathway due to TNF-α production. It is implied that QUIN participates in the sensation of fatigue after exercise.

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Tumor Necrosis Factor-α Mediates the Blood–Brain Barrier Dysfunction Induced by Activated Microglia in Mouse Brain Microvascular Endothelial Cells

Cited by 138 publications

References 15 publications

The Effect of Ribavirin on Reactive Astrogliosis in Experimental Autoimmune Encephalomyelitis

The Effect of Ribavirin on Reactive Astrogliosis in Experimental Autoimmune Encephalomyelitis

Tumour necrosis factor - alpha mediated mechanisms of cognitive dysfunction

Increased Blood Quinolinic Acid after Exercise in Mice: Implications for Sensation of Fatigue after Exercise

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