Neurotensin receptor agonist PD149163 modulates LPS-induced enterocyte apoptosis by downregulating TNFR pathway and executioner caspase 3 in endotoxemic mice: insights from in vivo and in silico study.

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This study was designed to evaluate the dose-dependent efficacy of neurotensin receptor-1 (NTSR1) agonist PD149163 in the amelioration of the lipopolysaccharide (LPS)-induced apoptosis in the gastrointestinal tract (GIT) of mice. PD149163 is an analogue of NTS, a GIT tri-decapeptide with anti-inflammatory and anti-oxidative effects. Swiss-albino mice (female/8 weeks/25±2.5g) were divided into six groups: control; LPS, LPS+PD149163L, and LPS+PD149163H groups were treated with LPS (0.2μmol/L/kgBW; 5 days), followed by exposure of PD149163 to LPS+PD149163L (10.6μmol/L/kgBW), and LPS+PD149163H (21.2μmol/L/kgBW) for 28 days. OnlyPD149163L (10.6μmol/L/kgBW) and onlyPD149163H (21.2μmol/L/kgBW) groups were maintained for 28 days. Both the LPS and PD149163 were given intraperitoneally. PD149163 treatment for 4 weeks alleviated the LPS-induced enterocyte apoptosis in a dose-dependent manner. LPS-induced excessive levels of caspase-3, tumour necrosis factor-α, and leptin (biomarkers of LPS-induced apoptosis) in plasma were decreased by PD149163H treatment. Moreover, LPS-induced gut oxidative stress was ameliorated by PD149163H supplementation, as evidenced by the decreased content of malondialdehyde, lipid-hydroperoxide and increased level of superoxide-dismutase, catalase. Furthermore, PD149163H mediated elevation of the plasma anti-apoptotic protein (B-cell leukaemia/lymphoma-2) along with the NTS level contributed to the modulation of LPS-induced enterocyte apoptosis, reflected in histopathology. In vivo results were substantiated with in silico molecular docking analysis that predicted the binding of PD149163-TLR4 complex, suggesting that PD149163 can act as a TLR4 modulator and inhibit the activation of TLR4. The role of PD149163 in ameliorating GIT apoptosis by its anti-apoptotic and antioxidative effects is suggested. Further research may provide significant insights into the therapeutic intervention of PD149163 in apoptosis-related diseases of GIT.