Valproic acid induces microglial dysfunction, not apoptosis, in human glial cultures

Gibbons, Hannah M.; Smith, Amy M.; Teoh, H. Heng; Bergin, Peter M.; Mee, Edward; Faull, Richard L.M.; Dragunow, Mike

doi:10.1016/j.nbd.2010.08.024

Cited by 48 publications

(42 citation statements)

References 46 publications

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“…We hypothesize that the pericyte cells originate from the microvasculature and meninges and, in fact, we see a consistency in cell specific markers and response to inflammatory cues in our dissociated and leptomeningeal explant cultures. Using a number of markers in this and previous studies (CD45, PU.1, GFAP), we are confident with the identification of microglia and astrocytes in our cultures [17,26,41]. …”

Section: Discussionsupporting

confidence: 76%

“…These mixed populations of cells stain positively for microglia, astrocyte, fibroblast and pericyte markers. Since microglia and astrocytes do not normally proliferate in culture, after passaging only pericyte and fibroblast cells remain [17,23,41]. We hypothesize that the pericyte cells originate from the microvasculature and meninges and, in fact, we see a consistency in cell specific markers and response to inflammatory cues in our dissociated and leptomeningeal explant cultures.…”

Section: Discussionmentioning

confidence: 85%

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A role for human brain pericytes in neuroinflammation

Jansson

Rustenhoven

Feng

et al. 2014

J Neuroinflammation

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137

144

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BackgroundBrain inflammation plays a key role in neurological disease. Although much research has been conducted investigating inflammatory events in animal models, potential differences in human brain versus rodent models makes it imperative that we also study these phenomena in human cells and tissue.MethodsPrimary human brain cell cultures were generated from biopsy tissue of patients undergoing surgery for drug-resistant epilepsy. Cells were treated with pro-inflammatory compounds IFNγ, TNFα, IL-1β, and LPS, and chemokines IP-10 and MCP-1 were measured by immunocytochemistry, western blot, and qRT-PCR. Microarray analysis was also performed on late passage cultures treated with vehicle or IFNγ and IL-1β.ResultsEarly passage human brain cell cultures were a mixture of microglia, astrocytes, fibroblasts and pericytes. Later passage cultures contained proliferating fibroblasts and pericytes only. Under basal culture conditions all cell types showed cytoplasmic NFκB indicating that they were in a non-activated state. Expression of IP-10 and MCP-1 were significantly increased in response to pro-inflammatory stimuli. The two chemokines were expressed in mixed cultures as well as cultures of fibroblasts and pericytes only. The expression of IP-10 and MCP-1 were regulated at the mRNA and protein level, and both were secreted into cell culture media. NFκB nuclear translocation was also detected in response to pro-inflammatory cues (except IFNγ) in all cell types. Microarray analysis of brain pericytes also revealed widespread changes in gene expression in response to the combination of IFNγ and IL-1β treatment including interleukins, chemokines, cellular adhesion molecules and much more.ConclusionsAdult human brain cells are sensitive to cytokine challenge. As expected ‘classical’ brain immune cells, such as microglia and astrocytes, responded to cytokine challenge but of even more interest, brain pericytes also responded to such challenge with a rich repertoire of gene expression. Immune activation of brain pericytes may play an important role in communicating inflammatory signals to and within the brain interior and may also be involved in blood brain barrier (BBB) disruption . Targeting brain pericytes, as well as microglia and astrocytes, may provide novel opportunities for reducing brain inflammation and maintaining BBB function and brain homeostasis in human brain disease.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 85%

A role for human brain pericytes in neuroinflammation

Jansson

Rustenhoven

Feng

et al. 2014

J Neuroinflammation

Self Cite

137

144

View full text Add to dashboard Cite

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“…VPA is metabolized in the liver via cytosolic x-oxidation which may produce different reactive metabolites, some of which may be biologically active, and some of them may be involved in VPA-induced toxic effects after an acute overdose of VPA (Spiller et al, 2000). Several groups have investigated the mechanisms of VPA toxicity in various cell lines and tissues using different schemes of administration as well as distinct animal species (Tong et al, 2005a;Fu et al, 2010;Gibbons et al, 2011). Despite the broad use of VPA in the therapy of several diseases, it is also associated with toxicity, with the most serious of those being hepatotoxicity (Pourahmad et al, 2012), teratogenicity (Tung and Winn, 2011) and neurotoxicity (Wang et al, 2011) as evidenced in in vitro models.…”

Section: Introductionmentioning

confidence: 99%

An in vitro approach to assess the neurotoxicity of valproic acid-induced oxidative stress in cerebellum and cerebral cortex of young rats

Chaudhary

Parvez

2012

Neuroscience

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“…On the contrary to the rodent studies, a recent study using human microglia has shown that valproate does not induce the increase of cleaved caspase-3 and apoptosis, and reduces phagocytosis of A 1-42 [140].…”

Section: In Vitro Studiesmentioning

confidence: 72%

Neurotransmitters, Psychotropic Drugs and Microglia: Clinical Implications for Psychiatry

Kato¹,

Yamauchi²,

Horikawa³

et al. 2013

Current Medicinal Chemistry

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Psychiatric disorders have long and dominantly been regarded to be induced by disturbances of neuronal networks including synapses and neurotransmitters. Thus, the effects of psychotropic drugs such as antipsychotics and antidepressants have been understood to modulate synaptic regulation via receptors and transporters of neurotransmitters such as dopamine and serotonin. Recently, microglia, immunological/inflammatory cells in the brain, have been indicated to have positive links to psychiatric disorders. Positron emission tomography (PET) imaging and postmortem studies have revealed microglial activation in the brain of neuropsychiatric disorders such as schizophrenia, depression and autism. Animal models of neuropsychiatric disorders have revealed the underlying microglial pathologies. In addition, various psychotropic drugs have been suggested to have direct effects on microglia. Until now, the relationship between microglia, neurotransmitters and psychiatric disorders has not been well understood. Therefore, in this review, at first, we summarize recent findings of interaction between microglia and neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine and glutamate. Next, we introduce up-to-date knowledge of the effects of psychotropic drugs such as antipsychotics, antidepressants and antiepileptics on microglial modulation. Finally, we propose the possibility that modulating microglia may be a key target in the treatment of various psychiatric disorders. Further investigations and clinical trials should be conducted to clarify this perspective, using animal in vivo studies and imaging studies with human subjects.

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Valproic acid induces microglial dysfunction, not apoptosis, in human glial cultures

Cited by 48 publications

References 46 publications

A role for human brain pericytes in neuroinflammation

A role for human brain pericytes in neuroinflammation

An in vitro approach to assess the neurotoxicity of valproic acid-induced oxidative stress in cerebellum and cerebral cortex of young rats

Neurotransmitters, Psychotropic Drugs and Microglia: Clinical Implications for Psychiatry

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