2. Academic Validation
  3. 4-Phenylbutyrate Induces Functional Elongation of the Microglial Process Through Activation of Akt

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

  • Neurochem Res. 2026 Feb 7;51(1):66. doi: 10.1007/s11064-026-04688-9.
Tianyi Dai # 1,  Qijun Dai # 2,  Yueqin Ding # 3,  Jianbin Su # 4,  Chao Huang # 5,  Rongrong Yang # 6,  Jie Peng # 5,  Zhuo Chen 7,  Rongrong Song 8,  Yunli Fang 5,  Hanxiao Wang 5,  Minxiu Ye 9,  Jianwei Wang 10,  Xu Lu 11 12
Affiliations

Affiliations

  • 1 Department of Traumatology & Orthopedics, Wuxi Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, #8 Zhongnan West Road, Wuxi, 214072, Jiangsu, China.
  • 2 Department of Neurology, Haian Hospital of Traditional Chinese Medicine, #55 Ninghai Middle Road, Haian, 226699, Jiangsu, China.
  • 3 Department of Spleen and Stomach, Haian Hospital of Traditional Chinese Medicine, #55 Ninghai Middle Road, Haian, 226699, Jiangsu, China.
  • 4 Department of Endocrinology, First People's Hospital of Nantong City the Second Affiliated Hospital of Nantong University, #666 Shengli Road, Nantong, 226006, Jiangsu, China.
  • 5 Department of Pharmacology, School of Pharmacy, Nantong University, #9 Seyuan Road, Nantong, 226019, Jiangsu, China.
  • 6 Department of Anesthesiology, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong, 226001, Jiangsu, China.
  • 7 Department of Invasive Technology, First People's Hospital of Nantong City, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong, 226006, Jiangsu, China.
  • 8 Department of Emergency and Critical Care Medicine, Tongzhou People's Hospital, #999 Jianshe Road, Nantong, 226300, Jiangsu, China.
  • 9 Department of Pharmacy, Kunshan Hospital of Traditional Chinese Medicine, #388 Zuchongzhi South Road, Kunshan, Suzhou, 215300, Jiangsu, China. [email protected].
  • 10 Department of Traumatology & Orthopedics, Wuxi Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, #8 Zhongnan West Road, Wuxi, 214072, Jiangsu, China. [email protected].
  • 11 Department of Pharmacology, School of Pharmacy, Nantong University, #9 Seyuan Road, Nantong, 226019, Jiangsu, China. [email protected].
  • 12 Department of Pharmacology, School of Pharmacy, Nantong University, #9 Seyuan Road, Nantong, 226001, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 41653373 DOI: 10.1007/s11064-026-04688-9
Abstract

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.

Keywords

4-PBA; Akt; Elongation; Microglial process; Neuroinflammatory response.

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