Asiatic Acid Attenuates Salmonella typhimurium-Induced Neuroinflammation and Neuronal Damage by Inhibiting the TLR2/Notch and NF-κB Pathway in Microglia

TL;DR

Asiatic acid reduces brain inflammation and nerve damage caused by Salmonella infection by blocking key immune pathways in microglial cells.

Contribution

The study reveals a novel mechanism by which Asiatic acid inhibits TLR2/Notch and NF-κB pathways to counteract neuroinflammation.

Findings

Asiatic acid pre-treatment reduced iNOS expression and NO production in Salmonella-infected mice and BV-2 cells.

Asiatic acid inhibits the nuclear translocation and complex formation of Notch and p65 proteins under Salmonella stimulation.

Blocking Notch-p65 interactions provides a new theoretical basis for Asiatic acid's clinical use in neuroinflammation.

Abstract

Salmonella typhimurium (S.T) infection of the central nervous system (CNS) induces severe inflammation, leading to elevated expression of inducible nitric oxide synthase (iNOS) in microglia. This process catalyzes excessive production of nitric oxide (NO), resulting in irreversible damage to neuronal mitochondria. Asiatic acid (AA) is a small molecule with neuroprotective potential; however, its ability to counteract nerve injury induced by S.T and the underlying mechanisms remain unclear. In this study, we established an S.T-infected mouse model (in vivo) and an S.T-stimulated microglial model using BV-2 cells (in vitro) and employed techniques including immunofluorescence (IF), Western blot, co-immunoprecipitation (Co-IP), and RNA extraction and quantitative reverse transcription PCR (RT-qPCR) to systematically evaluate the protective effects and mechanisms of AA. The results showed that pre-treatment with AA significantly reduced the expression of iNOS and the production of NO caused by S.T infection in mouse hippocampal tissue and BV-2 cells. Mechanistically, AA exerts its effects by inhibiting the upstream Toll-like receptor 2 (TLR2)/Notch and nuclear factor-κB (NF-κB) signaling axis. It interferes with the nuclear translocation of Notch and p65 proteins and their complex formation under S.T stimulation, thereby blocking downstream expression of iNOS and production of NO. This study reveals a novel mechanism by which AA alleviates infection-related neuroinflammation through targeting Notch-p65 interactions, providing a new theoretical basis for its clinical application.

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