The sodium glucose transporter 2 inhibitor Dapagliflozin Regulates kisspeptin and GABA receptors mRNA expression in hypothalamic arcuate nucleus in polycystic ovary rat model , Can it be a therapeutic target ?

Abstract

Background: Polycystic ovary syndrome (PCOS) is a reproductive disease that causes metabolic, endocrine and cardiovascular effects.  Dapagliflozin (DAPA) is a sodium glucose transporter 2 (SGLT-2) inhibitors that control glucose level, and improve insulin sensitivity, DAPA  improved sex hormones profile and ovulation rate in obese mouse model.

Objective: The study aimed to detect if there is a role of  DAPA on ovarian function in estradiol-induced PCOS rats.

Material and methods: Thirty rats were divided into 2 groups. Group Ι  (control) were given 0.5 ml saline intramuscular (IM) once, after 60 days, they were given. 0.9% saline by gastric gavage. Group II (PCOS- induced group) where rats were administered 4 mg/kg of estradiol valerate by single IM injection, 60 days later. PCO group was  subdivided into subgroup IIa where rats were given 0.9% saline. Subgroup IIb included rats that were given DAPA 5 mg/kg/day. Both  subgroups were administered by gastric gavage for 4 weeks. At end of experiment, serum sex hormones profile, insulin, glucose, ovarian  oxidative stress and inflammatory markers, ovarian histopathology, transforming growth factor B1 (TGF-Β1) immunohistochemistry,  hypothalamic kisspeptin and GABA B receptor gene expression were estimated.

Results: In PCO group IIa, value of kisspeptin expression  was increased significantly (p <0.01), value of GABA B receptor expression was decreased significantly (P < 0.01), compared to  Dapagliflozin-treated PCO group IIb. The same opposing results when both compared to normal control group I (P< 0.001). Moreover,  there was a significant increase in kisspeptin expression (P<0.05) and significant decrease in GABA B receptor expression (P< 0.01) in Dapagliflozin-treated PCO group IIa compared to normal control group I.

Conclusion: DAPA improved inflammatory status, oxidative  stress markers, hormonal profile, ovarian histological structure and decreased TGF-Β1 immunoreactivity and kisspeptin and increased  GABA B receptor gene expression. DAPA can be used as a therapeutic target for PCOS.