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Histone Deacetylase Inhibitor Trichostatin A Ameliorated Endotoxin-Induced Neuroinflammation and Cognitive Dysfunction.

Hsing CH, Hung SK, Chen YC, Wei TS, Sun DP, Wang JJ, Yeh CH - Mediators Inflamm. (2015)

Bottom Line: Trichostatin A (TSA), an HDAC inhibitor, is documented to be anti-inflammatory and neuroprotective.One hour later, they were injected (i.p.) with saline or Escherichia coli LPS (1 mg/kg).TSA diminished LPS-induced inflammatory responses in the mouse brain and modulated the cytokine-associated changes in cognitive function, which might be specifically related to reducing HDAC2 and HDAC5 expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan ; Department of Anesthesiology, Chi Mei Medical Center, Tainan 710, Taiwan ; Department of Anesthesiology, Taipei Medical University, Taipei 110, Taiwan.

ABSTRACT
Excessive production of cytokines by microglia may cause cognitive dysfunction and long-lasting behavioral changes. Activating the peripheral innate immune system stimulates cytokine secretion in the central nervous system, which modulates cognitive function. Histone deacetylases (HDACs) modulate cytokine synthesis and release. Trichostatin A (TSA), an HDAC inhibitor, is documented to be anti-inflammatory and neuroprotective. We investigated whether TSA reduces lipopolysaccharide- (LPS-) induced neuroinflammation and cognitive dysfunction. ICR mice were first intraperitoneally (i.p.) injected with vehicle or TSA (0.3 mg/kg). One hour later, they were injected (i.p.) with saline or Escherichia coli LPS (1 mg/kg). We analyzed the food and water intake, body weight loss, and sucrose preference of the injected mice and then determined the microglia activation and inflammatory cytokine expression in the brains of LPS-treated mice and LPS-treated BV-2 microglial cells. In the TSA-pretreated mice, microglial activation was lower, anhedonia did not occur, and LPS-induced cognitive dysfunction (anorexia, weight loss, and social withdrawal) was attenuated. Moreover, mRNA expression of HDAC2, HDAC5, indoleamine 2,3-dioxygenase (IDO), TNF-α, MCP-1, and IL-1β in the brain of LPS-challenged mice and in the LPS-treated BV-2 microglial cells was lower. TSA diminished LPS-induced inflammatory responses in the mouse brain and modulated the cytokine-associated changes in cognitive function, which might be specifically related to reducing HDAC2 and HDAC5 expression.

No MeSH data available.


Related in: MedlinePlus

TSA reduced the LPS-induced activation of microglial cells in mice and BV-12 cells. (a) Mice were pretreated with saline (Controls) or TSA (0.3 mg/kg) for 1 h and then intraperitoneally challenged with saline or E. coli LPS (1 mg/kg). Immunohistochemistry staining shows that Iba1 expression in the hippocampus and the cortex of mice was higher after 24 h of LPS challenge than in Control and LPS + TSA mice. (b) One hour after BV-2 cells had been pretreated with TSA (10 ng/mL), they were treated with LPS. Four hours later, the protein was collected. Western blotting shows Iba1 and acetyl histone H3 expression in BV-2 cells. The right panel shows the quantification of protein expression from three independent experiments. ∗P < 0.05 compared with the Control group; #P < 0.05 compared with the LPS-only group.
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fig5: TSA reduced the LPS-induced activation of microglial cells in mice and BV-12 cells. (a) Mice were pretreated with saline (Controls) or TSA (0.3 mg/kg) for 1 h and then intraperitoneally challenged with saline or E. coli LPS (1 mg/kg). Immunohistochemistry staining shows that Iba1 expression in the hippocampus and the cortex of mice was higher after 24 h of LPS challenge than in Control and LPS + TSA mice. (b) One hour after BV-2 cells had been pretreated with TSA (10 ng/mL), they were treated with LPS. Four hours later, the protein was collected. Western blotting shows Iba1 and acetyl histone H3 expression in BV-2 cells. The right panel shows the quantification of protein expression from three independent experiments. ∗P < 0.05 compared with the Control group; #P < 0.05 compared with the LPS-only group.

Mentions: Microglia mediate cytokines expression in CNS and limiting microglial activity is considered beneficial for neuroinflammation [17–19]. We next determined the effects of TSA on LPS-induced microglia activation. A histological examination showed that Iba1 levels were significantly higher in the hippocampus and cortex of LPS-only-challenged mice, which were reduced in mice pretreated with TSA (Figure 5(a)). In the in vitro experiment, Iba1 protein expression was significantly higher in LPS-only-treated BV-2 microglial cells than in PBS Control and in LPS + TSA-treated cells (Figure 5(b)).


Histone Deacetylase Inhibitor Trichostatin A Ameliorated Endotoxin-Induced Neuroinflammation and Cognitive Dysfunction.

Hsing CH, Hung SK, Chen YC, Wei TS, Sun DP, Wang JJ, Yeh CH - Mediators Inflamm. (2015)

TSA reduced the LPS-induced activation of microglial cells in mice and BV-12 cells. (a) Mice were pretreated with saline (Controls) or TSA (0.3 mg/kg) for 1 h and then intraperitoneally challenged with saline or E. coli LPS (1 mg/kg). Immunohistochemistry staining shows that Iba1 expression in the hippocampus and the cortex of mice was higher after 24 h of LPS challenge than in Control and LPS + TSA mice. (b) One hour after BV-2 cells had been pretreated with TSA (10 ng/mL), they were treated with LPS. Four hours later, the protein was collected. Western blotting shows Iba1 and acetyl histone H3 expression in BV-2 cells. The right panel shows the quantification of protein expression from three independent experiments. ∗P < 0.05 compared with the Control group; #P < 0.05 compared with the LPS-only group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig5: TSA reduced the LPS-induced activation of microglial cells in mice and BV-12 cells. (a) Mice were pretreated with saline (Controls) or TSA (0.3 mg/kg) for 1 h and then intraperitoneally challenged with saline or E. coli LPS (1 mg/kg). Immunohistochemistry staining shows that Iba1 expression in the hippocampus and the cortex of mice was higher after 24 h of LPS challenge than in Control and LPS + TSA mice. (b) One hour after BV-2 cells had been pretreated with TSA (10 ng/mL), they were treated with LPS. Four hours later, the protein was collected. Western blotting shows Iba1 and acetyl histone H3 expression in BV-2 cells. The right panel shows the quantification of protein expression from three independent experiments. ∗P < 0.05 compared with the Control group; #P < 0.05 compared with the LPS-only group.
Mentions: Microglia mediate cytokines expression in CNS and limiting microglial activity is considered beneficial for neuroinflammation [17–19]. We next determined the effects of TSA on LPS-induced microglia activation. A histological examination showed that Iba1 levels were significantly higher in the hippocampus and cortex of LPS-only-challenged mice, which were reduced in mice pretreated with TSA (Figure 5(a)). In the in vitro experiment, Iba1 protein expression was significantly higher in LPS-only-treated BV-2 microglial cells than in PBS Control and in LPS + TSA-treated cells (Figure 5(b)).

Bottom Line: Trichostatin A (TSA), an HDAC inhibitor, is documented to be anti-inflammatory and neuroprotective.One hour later, they were injected (i.p.) with saline or Escherichia coli LPS (1 mg/kg).TSA diminished LPS-induced inflammatory responses in the mouse brain and modulated the cytokine-associated changes in cognitive function, which might be specifically related to reducing HDAC2 and HDAC5 expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan ; Department of Anesthesiology, Chi Mei Medical Center, Tainan 710, Taiwan ; Department of Anesthesiology, Taipei Medical University, Taipei 110, Taiwan.

ABSTRACT
Excessive production of cytokines by microglia may cause cognitive dysfunction and long-lasting behavioral changes. Activating the peripheral innate immune system stimulates cytokine secretion in the central nervous system, which modulates cognitive function. Histone deacetylases (HDACs) modulate cytokine synthesis and release. Trichostatin A (TSA), an HDAC inhibitor, is documented to be anti-inflammatory and neuroprotective. We investigated whether TSA reduces lipopolysaccharide- (LPS-) induced neuroinflammation and cognitive dysfunction. ICR mice were first intraperitoneally (i.p.) injected with vehicle or TSA (0.3 mg/kg). One hour later, they were injected (i.p.) with saline or Escherichia coli LPS (1 mg/kg). We analyzed the food and water intake, body weight loss, and sucrose preference of the injected mice and then determined the microglia activation and inflammatory cytokine expression in the brains of LPS-treated mice and LPS-treated BV-2 microglial cells. In the TSA-pretreated mice, microglial activation was lower, anhedonia did not occur, and LPS-induced cognitive dysfunction (anorexia, weight loss, and social withdrawal) was attenuated. Moreover, mRNA expression of HDAC2, HDAC5, indoleamine 2,3-dioxygenase (IDO), TNF-α, MCP-1, and IL-1β in the brain of LPS-challenged mice and in the LPS-treated BV-2 microglial cells was lower. TSA diminished LPS-induced inflammatory responses in the mouse brain and modulated the cytokine-associated changes in cognitive function, which might be specifically related to reducing HDAC2 and HDAC5 expression.

No MeSH data available.


Related in: MedlinePlus