Neurotensin receptor agonist PD149163 modulates the adrenal dysfunction in mice intraperitoneally treated with lipopolysaccharide from Escherichia coli O26:B6

Background

Elevated plasma level of Escherichia coli lipopolysaccharide (LPS) from gut microbiota imbalance promotes the increase of pro-inflammatory cytokines which crosses through the blood–brain barrier to elicit activation of the hypothalamic–pituitary–adrenal (HPA) with oxidative damage of the adrenal gland. Neurotensin in neuroendocrine cells can reduce oxidative stress and inhibit secretion of stress hormones.

Aim

This study evaluated the efficacy of PD149163, neurotensin receptor 1 agonist (NTSR1), in reduction of LPS-induced impairment of function of the adrenal gland.

Methods

Mice were maintained in four groups (6 mice/group): Group I served as control; Group II and Group III received LPS intraperitoneally (1 mg/kg daily for 5 days). After 5 days, Group III and Group IV received PD149163 intraperitoneally (100 μg/kg daily for 28 days), and Group II was maintained with no further treatment. After the termination of the experiment, the plasma levels of inflammatory cytokines and corticosterone, adrenal level of oxidative stress and histopathological study of adrenal gland were assessed.

Results

In only LPS-exposed mice, the plasma levels of IL-6, and TNF-α were significantly increased, while IL-10 was significantly decreased. A significant increase in the plasma corticosterone (CORT) indicated HPA axis activation. Adrenal oxidative stress was revealed from elevated TBARS and reduced SOD and CAT. The distorted cellular arrangement, cytoplasmic vacuolization, and fragmented nuclei displayed distinct histopathology. PD149163 supplementation decreased plasma levels of TNF-α, IL-6 and increased IL-10, normalized plasma CORT level, reduced oxidative stress, and adrenal histopathology.

Conclusion

The PD149163 has efficacy in amelioration of LPS-induced adrenal dysfunction by suppressing inflammatory response and oxidative stress and preventing adrenal histopathology.

Graphical abstract