Histone Deacetylase Inhibitor Trichostatin A Ameliorated Endotoxin-Induced Neuroinflammation and Cognitive Dysfunction.
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.
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.
Chung-Hsi
CH
Hsing
Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital, Chiayi 622, Taiwan ; School of Medicine, Tzu Chi University, Hualien 970, Taiwan.
Shih-Kai
SK
Hung
Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan ; Department of Anesthesiology, Chi Mei Medical Center, Tainan 710, Taiwan.
Yeong-Chang
YC
Chen
Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan.
Tsui-Shan
TS
Wei
Department of Surgery, Chi Mei Medical Center, Tainan 710, Taiwan.
Ding-Ping
DP
Sun
Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan ; Department of Anesthesiology, Chi Mei Medical Center, Tainan 710, Taiwan.
Jhi-Joung
JJ
Wang
Department of Medicinal Botanicals and Health Applications, Da-Yeh University, Changhua 515, Taiwan.
Ching-Hua
CH
Yeh
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects; D002460:Cell Line; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D004731:Endotoxins; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004731:Endotoxins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C012589:trichostatin A; C404500:HDAC5 protein, human; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases