Neurotensin receptor agonist PD149163 modulates LPS-induced sub-acute gut inflammation by inhibiting TLR4/NF-κB/NLRP3 inflammasome pathway: In vivo, in silico and network pharmacology analyses.

Bacterial lipopolysaccharide (LPS)-induced sub-acute gut inflammation and barrier impairment contribute to several gastrointestinal tract (GIT) disorders, including inflammatory bowel disease, celiac disease, and sepsis. The present study elucidates the efficacy of neurotensin receptor 1 (NTSR1) agonist against LPS-induced sub-acute gut inflammation. PD149163, a nonpeptide analog of GIT tridecapeptide neurotensin (NTS), possesses anti-inflammatory and antioxidative properties. Swiss-albino mice (female/8-weeks/25 ± 2.5 g) were divided into six groups: Group-I/control; Group II (only PD149163Low: 0.05 mg/kg bw); and Group III (only PD149163High: 0.1 mg/kg bw) treated for 28 days. Groups IV to VI were injected with LPS (1000 μg/kg bw; days 1-5), followed by PD149163 exposure to Group-V/LPS + PD149163Low (0.05 mg/kg bw) and Group-VI/LPS + PD149163High (0.1 mg/kg bw) for 28 days. All treatments were given intraperitoneally. PD149163High treatment has shown efficacy in counteracting gut inflammation and barrier impairment. Supplementation with PD149163High restored the LPS-mediated decrease in intestinal alkaline phosphatase, plasma alkaline phosphatase and NTS, alleviating GIT barrier injury and tissue damage. PD149163High reverses LPS-induced elevated C-reactive protein levels in the GIT and plasma, thereby mitigating inflammation. LPS-mediated redox imbalance and histopathological alterations in the GIT were also counteracted by PD149163High. Furthermore, LPS-induced elevated proinflammatory, proapoptotic proteins, along with reduced anti-inflammatory, antiapoptotic proteins, were normalised by PD149163High. Our in silico analysis predicted the binding of PD149163 to NF-kB and NLRP3, suggesting PD149163-mediated potential inhibition of NF-κB/NLRP3 inflammasome activation. Our PPI, KEGG, and GO analyses further highlighted LPS-TLR4/MD2 signalling intermediates as critical therapeutic targets in sepsis-associated disorders. Overall, this study identifies PD149163 as a promising candidate for managing inflammation-induced gut injury and barrier dysfunction.