Abstract

The interaction between neuroendocrine and immune components of the gut maintains the organism's physical and psychological health. Its disruption may reflect in disease conditions such as inflammatory bowel disease (IBD) and mental illness. The lipopolysaccharide (LPS) disrupts the endocrine-immune homeostasis resulting in gut toxicity. The Neurotensin receptor-1 (NTR-1) agonist PD 149163 (PD) acts as an atypical antipsychotic drug in psychiatric illness, but its role in modulating gut pathophysiology remains unknown. Therefore, the aim of the present study was to evaluate the protective effect of PD against LPS-induced gut toxicity. Swiss albino female mice (12 weeks) were divided into six groups (n = 6/group): (I) Control, (II) LPS (1 mg/kg, for 5 days), (III) LPS (1 mg/kg, for 5 days)+PD low (100 µg/kg, for 21 days), (IV) LPS (1 mg/kg, for 5 days)+PD high (300 µg/kg, for 21 days), (V) PD low (100 µg/kg, for 21 days), and (VI) PD high (300 µg/kg, for 21 days). Drugs were given intraperitoneal in the morning. PD administration prevented the LPS-induced gut inflammation observed in damage of epithelial barrier, disruption of goblet cells, and condensation of lamina propria (LP). The LPS-induced oxidative stress characterized by decreased superoxide dismutase (SOD) activity and increased lipid hydroperoxide (LOOH) (p < 0.001 for both), and enhanced interleukine-6 (IL-6) & tumor necrosis factor-α (TNF-α) (p < 0.001 for both) as well as immunointensity of NT (p < 0.01) and NTR-1 (p < 0.05) were reversed and normalized to control after PD treatment. Thus, the anti-inflammatory, anti-oxidative, and cell proliferation properties of PD modulate the gut toxicity in LPS-challenged mice.

摘要

神经内分泌和肠道免疫成分之间的相互作用维持机体的身心健康。它的破坏可能反映在炎症性肠病（IBD）和精神疾病等疾病中。脂多糖 (LPS) 破坏内分泌-免疫稳态，导致肠道毒性。神经降压素受体 1 (NTR-1) 激动剂 PD 149163 (PD) 在精神疾病中充当非典型抗精神病药物，但其在调节肠道病理生理学中的作用仍不清楚。因此，本研究的目的是评估 PD 对 LPS 诱导的肠道毒性的保护作用。瑞士白化雌性小鼠（12周）分为六组（n = 6/组）：（I）对照，（II）LPS（1 mg/kg，持续 5 天），（III）LPS（1 mg/kg，持续 5 天）+PD 低（100 µg/kg，持续21 天），（IV）LPS（1 mg/kg，持续 5 天）+PD 高（300 µg/kg，持续 21 天），（V）PD 低（100 µg/kg，持续 21 天），和（ VI) PD 高（300 µg/kg，持续 21 天）。早上腹腔内给药。PD 给药可防止在上皮屏障损伤、杯状细胞破坏和固有层 (LP) 凝结中观察到的 LPS 诱导的肠道炎症。LPS 诱导的氧化应激以降低超氧化物歧化酶 (SOD) 活性和增加脂质氢过氧化物 (LOOH) 为特征（两者p  < 0.001），以及增强的白细胞介素 6 (IL-6) 和肿瘤坏死因子-α (TNF-α) ）（两者p  < 0.001）以及 NT 的免疫强度（p < 0.01) 和 NTR-1 ( p  < 0.05) 在 PD 治疗后被逆转并标准化为对照。因此，PD 的抗炎、抗氧化和细胞增殖特性可调节 LPS 攻击小鼠的肠道毒性。