Toll-like receptor 4 mediates lipopolysaccharide-induced emesis

Area of Science:

• Neuroscience
• Immunology
• Gastroenterology

Background:

• Lipopolysaccharide (LPS) triggers inflammation and sepsis via Toll-like receptor 4 (TLR4) activation.
• While some animals vomit after LPS administration, the role of TLR4 in this response and the anti-emetic potential of TLR4 antagonists remain unconfirmed.

Purpose of the Study:

• To investigate if LPS-induced emesis and physiological changes indicative of nausea are mediated by TLR4 in the Suncus murinus model.
• To characterize TLR4 distribution in the brain and periphery of Suncus murinus.
• To assess the efficacy of the TLR4 antagonist resatorvid as an anti-emetic.

Main Methods:

• Radiotelemetry transmitters were implanted in Suncus murinus to monitor physiological changes.
• TLR4 distribution was characterized in the brain and periphery.
• The potency of resatorvid was tested on isolated ileum, and its effects on LPS-induced emesis, behavioral changes, and brainstem activation were evaluated.

Main Results:

• TLR4 mRNA was detected in the brainstem and gastrointestinal tract, showing homology with human TLR4.
• LPS induced dose-dependent emesis, increased defecation, reduced food intake, and caused hyperthermia, alongside increased c-Fos and Iba1 expression in the brainstem.
• Resatorvid significantly reduced LPS-induced emesis, hyperthermia, and behavioral changes, and antagonized LPS effects on food intake and gastric slow waves.

Conclusions:

• TLR4 activation is involved in LPS-induced emesis and associated behavioral changes.
• Glial cell and neuronal activation likely play a role in these mechanisms.
• TLR4 antagonists demonstrate potential clinical utility as anti-emetics.