Neuropeptide analog PD149163 ameliorates metabolic endotoxemia-driven thyroid inflammation by targeting LPS-LBP signalling in murine model: Insights from in vivo, in silico and network pharmacology analyses.

The present study elucidates the efficacy of the neuropeptide neurotensin/NTS analog PD149163 in ameliorating chronic thyroid inflammation and metabolic endotoxemia induced by E. coli endotoxin lipopolysaccharide/LPS. NTS, a gastrointestinal-tract tri-decapeptide, has anti-inflammatory and anti-oxidative effects. Swiss-albino mice (female/7-8 weeks/25 ± 2.5 g) were divided into six groups: GI/control; GII and GIII were treated with 50 and 100 μg/kg bw of PD149163, respectively, for 4 weeks. GIV-VI was injected with LPS (1 mg/kg bw; 5 days), followed by PD149163 exposure to GV/END+PD50 (50 μg/kg bw) and GVI/END+PD100 (100 μg/kg bw) for 4 weeks. Both the LPS and PD149163 were given intraperitoneally. PD100 treatment has shown efficacy in counteracting chronic thyroid inflammation, metabolic endotoxemia and hormonal impairments. The LPS-induced histopathological alterations in thyroid and visceral adipose tissue are characteristics of inflammation, ameliorated following PD100 supplementation. LPS-exposure elevates cytokines (IL-6/TNF-α), apoptotic protein/CAS3, adipokine/leptin and decreases IL-10, Bcl-2 and NTS, indicating inflammation and cellular apoptosis, normalised by PD100. Supplementation with PD100 reduces LPS-mediated increase in acute-phase protein/CRP and anti-thyroid peroxidase/TPO antibodies in plasma and tissue. The LPS-induced hormonal impairment of the HPT axis (TSH/T4/T3) and metabolic endotoxemia, reflected in altered triglycerides (TAG)/total cholesterol (TC)/high and low-density lipoproteins (HDL-c/LDL-c), were also counteracted by PD100. Molecular docking predicted that LPS/LBP may compete with T3 for its receptors (TRα/TRβ) and can disrupt the thyroid receptor's functioning. Also, docking of PD149163-LBP suggests that PD149163 directly binds to LBP, thereby inhibiting LPS-LBP interaction and attenuating LPS-induced effects. Thus, PD149163 emerges as a potential modulator of endotoxemia-induced thyroid inflammation, hormonal imbalance, and metabolic dysfunction by inhibiting LPS-LBP interaction and downstream signalling.