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Background <p>Microglial activation in the central nervous system plays a central role in neuroinflammation and contributes to the onset and progression of neurodegenerative diseases. This study aimed to evaluate the anti-inflammatory effects of GNE-317, a phosphoinositide 3-kinase/ mammalian target of rapamycin (PI3K/mTOR) inhibitor, in lipopolysaccharide (LPS)-induced neuroinflammatory models.</p> Methods <p>BV2 microglial cells were stimulated with LPS, and the effects of GNE-317 were examined using Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), nitric oxide (NO) assays, and immunofluorescence. For in vivo experiments, C57BL/6 mice received GNE-317 (25&#xa0;mg/kg/day, intraperitoneal, ip) for three days, followed by LPS injection (5&#xa0;mg/kg, ip). Microglial activation was assessed by anti-ionized calcium-binding adapter molecule-1 (IBA1) immunostaining in the brain.</p> Results <p>GNE-317 inhibited PI3K/protein kinase B (Akt)/mTOR signaling and reduced nuclear factor-kappa B (NF-κB) nuclear translocation in LPS-stimulated BV2 cells. It decreased inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) expression and lowered tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production. In LPS-injected mice, GNE-317 reduced microglial activation in brain tissue.</p> Conclusions <p>GNE-317 attenuates neuroinflammation by suppressing microglial activation through inhibition of the PI3K/Akt/mTOR and NF-κB pathways, supporting its potential as a therapeutic agent for microglia-mediated neuroinflammatory diseases.</p>

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GNE-317 ameliorates neuroinflammation stimulated by lipopolysaccharide via PI3K/Akt/mTOR pathway

  • 期刊论文

  • 发表日期：

    2026年2月4日

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  • Yoojin Lee,
  • Namkwon Kim,
  • Haeun Hwang,
  • Subyn Jeon,
  • Seung Ho Jeon,
  • Yeongae Lee,
  • Jeongmin Son,
  • Sumin Ma,
  • Sora Yoon,
  • Min Sung Gee,
  • Kyoung-Lim Kim,
  • Kyung-Soo Inn,
  • Inwha Baek,
  • Jong Kil Lee

摘要

Background

Microglial activation in the central nervous system plays a central role in neuroinflammation and contributes to the onset and progression of neurodegenerative diseases. This study aimed to evaluate the anti-inflammatory effects of GNE-317, a phosphoinositide 3-kinase/ mammalian target of rapamycin (PI3K/mTOR) inhibitor, in lipopolysaccharide (LPS)-induced neuroinflammatory models.

Methods

BV2 microglial cells were stimulated with LPS, and the effects of GNE-317 were examined using Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), nitric oxide (NO) assays, and immunofluorescence. For in vivo experiments, C57BL/6 mice received GNE-317 (25 mg/kg/day, intraperitoneal, ip) for three days, followed by LPS injection (5 mg/kg, ip). Microglial activation was assessed by anti-ionized calcium-binding adapter molecule-1 (IBA1) immunostaining in the brain.

Results

GNE-317 inhibited PI3K/protein kinase B (Akt)/mTOR signaling and reduced nuclear factor-kappa B (NF-κB) nuclear translocation in LPS-stimulated BV2 cells. It decreased inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) expression and lowered tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production. In LPS-injected mice, GNE-317 reduced microglial activation in brain tissue.

Conclusions

GNE-317 attenuates neuroinflammation by suppressing microglial activation through inhibition of the PI3K/Akt/mTOR and NF-κB pathways, supporting its potential as a therapeutic agent for microglia-mediated neuroinflammatory diseases.