Neurotensin modulation of immune and oxido-inflammatory homeostasis targeting TGF-β activated kinase 1/Nuclear factor-kappa βeta pathway: an integrated in vivo and in silico study.

Abstract

Background: Neurotensin (NTS) is a brain peptide and is known to regulate several brain pathways. Subsequently NTS involvement in psychosis was administered having its promising therapeutic effects as an antipsychotic drug. Therefore, it has been deduced that targeting the NTS system in the regulation of the immune organs would prove to be a productive strategy for developing the novel immune modulatory drugs.

Objective: The present study elucidated the potential anti-inflammatory properties of NTS receptor 1 (NTSR1) agonist PD149163 (PD) in modulation of immune organs specifically, spleen and thymus investigating the potential immunomodulatory mechanisms targeting NF-κB /TAK1 signaling pathway.

Methods: Swiss albino female mice were randomly grouped: Group I-control, treatment groups- Group II, Group III and Group IV were intraperitoneally exposed with NTSR1-agonist PD low dose/ PD₅₀ (50 µg /kg bw), PD high dose/ PD₁₀₀ (100 µg /kg bw) and NTSR1-antagonist SR48692 (500 µg /kg bw), respectively for 28 days. Biochemical, hematological, histopathological, and bioinformatics analyses were performed. Differences were considered statistically significant at P < 0.05.

Results: The levels of Nuclear factor kappa beta/NF-κB, Tumor necrosis factor- alpha/TNF-α, Interleukine-6/IL-6, Corticosterone/CORT and pro-oxidant, Lipid-peroxidation/LPx were visibly similar to control after the treatment of PD₁₀₀ as well as PD₅₀ dose however the elevation was observed with the SR. PD₁₀₀ dose has a prominent effect on the plasma Interleukine-10/IL-10, CORT, NTS levels and tissue anti-oxidants superoxide dismutase/SOD, catalase/CAT as well as positively regulated the hematological and histological parameters, clearly deciphering NTS's immunomodulatory effects. Furthermore, in silico molecular docking analyses showed that PD exhibited high binding affinity with TGF-β activated kinase 1/TAK1 inflammatory protein, indicating inhibition of TAK1/NF-κB downstream signaling pathways.

Conclusion: NTS receptor 1 analogs might provide a better understanding of the mechanisms by which NTS regulates immune-system and could be further exploited for managing various immune-related disorders.