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<p>Conversion of microglia to a branching state is considered a potential strategy to ameliorate neuroinflammation. Inhibition of histone deacetylases (HDACs) may convert microglia to a branching state and thus prevent neuroinflammation. Drugs that inhibit HDACs could be used to alleviate neuroinflammation. Here, we hypothesize that 4-phenylbutyric acid (4-PBA), an HDAC inhibitor, could shift microglia to an anti-inflammatory phenotype by promoting microglial process elongation. As expected, our results showed that 4-PBA induced reversible elongation of branching processes in primary cultured mouse microglia and in microglia in the prefrontal cortex of mice. Pretreatment with 4-PBA also prevented lipopolysaccharide (LPS)-induced shortening of branching processes in microglia under both in vitro and ex vivo conditions, LPS-induced pro-inflammatory responses in cultured microglia and prefrontal cortex, and LPS-induced sickness behavior in mice. Short-term incubation with 4-PBA led to a significant increase in phosphorylation levels of protein kinase B (Akt) in cultured microglia. 4-PBA did not induce microglial process elongation in vitro or ex vivo when cultured microglia or mice were treated with the Akt signaling inhibitor LY294002, suggesting that the pro-elongation effect of 4-PBA on microglial processes require activation of Akt signaling. Moreover, 4-PBA did not prevent LPS-induced inflammatory responses in cultured microglia and prefrontal cortex or LPS-induced sickness behaviors when cultured microglia or mice were treated with LY294002. Altogether, these results indicate that 4-PBA induces microglial process elongation in an Akt-dependent manner, which may underlie the anti-neuroinflammatory properties of 4-PBA.</p>

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4-Phenylbutyrate Induces Functional Elongation of the Microglial Process Through Activation of Akt

  • 期刊论文

  • 发表日期：

    2026年2月7日

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  • Tianyi Dai,
  • Qijun Dai,
  • Yueqin Ding,
  • Jianbin Su,
  • Chao Huang,
  • Rongrong Yang,
  • Jie Peng,
  • Zhuo Chen,
  • Rongrong Song,
  • Yunli Fang,
  • Hanxiao Wang,
  • Minxiu Ye,
  • Jianwei Wang,
  • Xu Lu

摘要

Conversion of microglia to a branching state is considered a potential strategy to ameliorate neuroinflammation. Inhibition of histone deacetylases (HDACs) may convert microglia to a branching state and thus prevent neuroinflammation. Drugs that inhibit HDACs could be used to alleviate neuroinflammation. Here, we hypothesize that 4-phenylbutyric acid (4-PBA), an HDAC inhibitor, could shift microglia to an anti-inflammatory phenotype by promoting microglial process elongation. As expected, our results showed that 4-PBA induced reversible elongation of branching processes in primary cultured mouse microglia and in microglia in the prefrontal cortex of mice. Pretreatment with 4-PBA also prevented lipopolysaccharide (LPS)-induced shortening of branching processes in microglia under both in vitro and ex vivo conditions, LPS-induced pro-inflammatory responses in cultured microglia and prefrontal cortex, and LPS-induced sickness behavior in mice. Short-term incubation with 4-PBA led to a significant increase in phosphorylation levels of protein kinase B (Akt) in cultured microglia. 4-PBA did not induce microglial process elongation in vitro or ex vivo when cultured microglia or mice were treated with the Akt signaling inhibitor LY294002, suggesting that the pro-elongation effect of 4-PBA on microglial processes require activation of Akt signaling. Moreover, 4-PBA did not prevent LPS-induced inflammatory responses in cultured microglia and prefrontal cortex or LPS-induced sickness behaviors when cultured microglia or mice were treated with LY294002. Altogether, these results indicate that 4-PBA induces microglial process elongation in an Akt-dependent manner, which may underlie the anti-neuroinflammatory properties of 4-PBA.