Neurotensin modulates the female reproductive system via extracellular signal-regulated kinase 1/2 signaling pathway: an in vivo and in silico study in mice

Abstract

Background: The present study elucidated the modulation of the female reproductive system by neurotensin (NTS) receptor 1 (NTSR₁) agonist PD149163.

Method: Female mice were maintained in three groups (12/group): Group I-control, Group II and Group III were intraperitoneally exposed with NTSR₁-agonist PD149163 (100 µg /kg bw) and NTSR₁-antagonist SR48692 (500 µg /kg bw), respectively for 28 days.

Results: Treatment with PD149163 facilitated the ovarian follicular growth, as revealed from the histology; follicular size, granulosa and theca cell layers increased compared to controls. The uterine horn also showed improved endometrium with well-developed endometrial glands. The plasma levels of NTS and LH were significantly increased, while FSH and estradiol showed a non-significant increasing trend. On the contrary, SR48692-treated mice showed a lower level of NTS and all reproductive hormones, but an elevation in the histopathological scores in both the ovary and uterine horn. While there was no alteration in oxidative stress biomarkers in the PD149163-treated mice, the pro-oxidant levels were significantly increased, and the anti-oxidant enzyme activities were reduced on antagonist treatment. Thus, NTS might facilitate ovulation and maintain uterus acting through NTSR₁. Furthermore, in silico docking analysis showed that SR48692 exhibited high binding affinity with ERK-1 and ERK-2, indicating inhibition of ERK1/2 signalling pathways and suppression of ameliorative effect of NTS.

Conclusion: In conclusion, NTS receptor analogs may provide a better understanding of the mechanisms by which neurotensin modulates reproduction and could be further exploited for managing various reproductive disorders.

Keywords: Neurotensin; Ovary; PD149163; Reproduction; SR48692; Uterine horn.