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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 attenuated LPS-induced HDAC2 and HDAC5 expression in the hippocampus and cortex of mice. 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) (n = 6 in each group). (a) HDAC2 and HDAC5 mRNA were detected using RT-PCR. The right panel shows the quantification of mRNA expression from six independent experiments. ∗P < 0.05 compared with the Control group; #P < 0.05 compared with the LPS-only group. (b) Immunohistochemical staining showed that HDAC2 and HDAC5 expression were increased in the cortex of mice after being LPS challenged, which were reduced in LPS + TSA mice.
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fig3: TSA attenuated LPS-induced HDAC2 and HDAC5 expression in the hippocampus and cortex of mice. 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) (n = 6 in each group). (a) HDAC2 and HDAC5 mRNA were detected using RT-PCR. The right panel shows the quantification of mRNA expression from six independent experiments. ∗P < 0.05 compared with the Control group; #P < 0.05 compared with the LPS-only group. (b) Immunohistochemical staining showed that HDAC2 and HDAC5 expression were increased in the cortex of mice after being LPS challenged, which were reduced in LPS + TSA mice.

Mentions: Mice pretreated with saline (Control) or TSA (0.3 mg/kg) were challenged with saline or LPS (1 mg/kg). Twenty-four hours later, the mice were killed and their cortex and hippocampus were collected. RT-PCR showed that their HDAC2 and HDAC5 mRNA expression levels were higher in the LPS-only-challenged mice. In the mice pretreated with TSA, HDAC2 and HDAC5 mRNA levels were significantly lower in both brain regions (Figure 3(a)). A histological examination showed that HDAC2 and HDAC5 levels were significantly higher in the cortex of LPS-only-challenged mice than in Control mice and in mice that had been pretreated with TSA (Figure 3(b)). HDAC inhibitors modulate cytokine synthesis and release [22–24]; we thus determined the effects of TSA on LPS-induced cytokines expression. After 24 h of LPS challenge, the expressions of TNF-α, IL-1β, MCP-1, and IDO mRNA in cortex and hippocampus were significantly higher than in Control mice. These increases were reduced in the mice pretreated with TSA (Figure 4).


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 attenuated LPS-induced HDAC2 and HDAC5 expression in the hippocampus and cortex of mice. 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) (n = 6 in each group). (a) HDAC2 and HDAC5 mRNA were detected using RT-PCR. The right panel shows the quantification of mRNA expression from six independent experiments. ∗P < 0.05 compared with the Control group; #P < 0.05 compared with the LPS-only group. (b) Immunohistochemical staining showed that HDAC2 and HDAC5 expression were increased in the cortex of mice after being LPS challenged, which were reduced in LPS + TSA mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: TSA attenuated LPS-induced HDAC2 and HDAC5 expression in the hippocampus and cortex of mice. 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) (n = 6 in each group). (a) HDAC2 and HDAC5 mRNA were detected using RT-PCR. The right panel shows the quantification of mRNA expression from six independent experiments. ∗P < 0.05 compared with the Control group; #P < 0.05 compared with the LPS-only group. (b) Immunohistochemical staining showed that HDAC2 and HDAC5 expression were increased in the cortex of mice after being LPS challenged, which were reduced in LPS + TSA mice.
Mentions: Mice pretreated with saline (Control) or TSA (0.3 mg/kg) were challenged with saline or LPS (1 mg/kg). Twenty-four hours later, the mice were killed and their cortex and hippocampus were collected. RT-PCR showed that their HDAC2 and HDAC5 mRNA expression levels were higher in the LPS-only-challenged mice. In the mice pretreated with TSA, HDAC2 and HDAC5 mRNA levels were significantly lower in both brain regions (Figure 3(a)). A histological examination showed that HDAC2 and HDAC5 levels were significantly higher in the cortex of LPS-only-challenged mice than in Control mice and in mice that had been pretreated with TSA (Figure 3(b)). HDAC inhibitors modulate cytokine synthesis and release [22–24]; we thus determined the effects of TSA on LPS-induced cytokines expression. After 24 h of LPS challenge, the expressions of TNF-α, IL-1β, MCP-1, and IDO mRNA in cortex and hippocampus were significantly higher than in Control mice. These increases were reduced in the mice pretreated with TSA (Figure 4).

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