2. Academic Validation
  3. Indole-3-Propionic Acid Attenuates Neuroinflammation and Cognitive Deficits by Inhibiting the RAGE-JAK2-STAT3 Signaling Pathway

Indole-3-Propionic Acid Attenuates Neuroinflammation and Cognitive Deficits by Inhibiting the RAGE-JAK2-STAT3 Signaling Pathway

  • J Agric Food Chem. 2025 Mar 5;73(9):5208-5222. doi: 10.1021/acs.jafc.4c08548.
Zhizhong Hao 1,  Rong Ji 1,  Yujing Su 1,  Hao Wang 1,  Wenzhi Yang 1,  Shenhong Zhang 1,  Yongli Liu 2,  Shanshan Ma 1,  Fangxia Guan 1,  Yuanbo Cui 3
Affiliations

Affiliations

  • 1 School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
  • 2 Zhengzhou Golden Finger Health Technology Co., Ltd., Zhengzhou, Henan 450001, China.
  • 3 Department of Trauma and Metabolism Institute of Zhengzhou University, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan 450001, China.
PMID: 39992888 DOI: 10.1021/acs.jafc.4c08548
Abstract

Cognitive disorders such as Alzheimer's disease (AD) are highly prevalent and place heavy burdens on society. Neuroinflammation is a driver of cognitive impairment, with no effective drugs. Indole 3-propionic acid (IPA) is a tryptophan metabolite mainly produced byClostridium sporogenes, which exhibits multiple functions, including antioxidant, anti-inflammatory, antiaging, and neuroprotective properties. However, the restorative effects and molecular mechanisms of IPA in cognitive impairment remain to be investigated. In this study, we found that IPA reduced LPS-induced Apoptosis and oxidative damage in HT22 cells and decreased LPS-induced inflammation in BV2 cells. Besides, IPA promoted neurogenesis, inhibited glial cell activation, maintained the integrity of the BBB and intestinal barrier, and remodeled the gut microbiota, thereby alleviating memory impairment in LPS-induced cognitively impaired mice. At the mechanistic level, IPA inhibited the RAGE-JAK2-STAT3 signaling pathway and thus ameliorated neuroinflammation. Interestingly, Colivelin TFA, an activator of JAK2-STAT3 signaling, partially reversed the neurorestorative effects of IPA. In conclusion, IPA ameliorates neuroinflammation and cognitive deficits via the inhibition of the RAGE-JAK2-STAT3 signaling pathway. Thus, IPA may be a potential drug for the treatment of cognitive disorders.

Keywords

RAGE-JAK2-STAT3 signaling pathway; cognitive impairment; indole-3-propionic acid; network pharmacology; neuroinflammation.

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