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

, 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.