Therapeutic efficacy and mechanism of artesunate for mouse model of polycystic ovary syndrome

To investigate the therapeutic efficacy of artesunate (AS) on polycystic ovary syndrome (PCOS) in mice and explore the potential mechanism primarily.

Twenty-five female C57BL/6J mice were randomly divided into Control group, model group (PCOS group), low- and high-dose AS groups (AS15 and AS30 groups) and metformin group (Met group). In addition to the Control group, the mouse model of PCOS was established by subcutaneous injection of dehydroepiandrosterone (DHEA, 60 mg/kg) following by a high-fat diet for 21 d. After modeling, AS of 15 and 30 mg/kg was intraperitoneally injected into the mice of the AS15 and AS30 groups, respectively, and 200 mg/kg Met was given to those of the Met group by gavage, once per day, for 6 weeks. ELISA was used to detect serum testosterone (T), fasting insulin (FINS), luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and the LH/FSH ratio was calculated. The levels of fasting blood glucose (FBG), triglyceride (TG) and total cholesterol (TC) were detected by automatic biochemical analyzer, and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The estrous cycle was observed, and HE staining was performed for pathological changes in the ovary and uterus. Immunofluorescence assay was employed to measure the expression of p-eIF2α, ATF4 and CHOP in the ovarian tissue. After steroidogenic human granulosa-like tumor cell line KGN were exposed to 100 μmol/L DHEA to simulate the hyperandrogen environment of PCOS, and then treated with 5 and 10 μg/mL AS for 24 h, the protein levels of endoplasmic reticulum stress signaling pathway was detected by Western blotting.

Compared with the Control group, the PCOS mice had disturbed estrous cycle, polycystic changes in the ovaries, and significantly increased serum T level and LH/FSH ratio (P<0.05), and obviously elevated HOMA-IR, TC and TG levels in terms of metabolism (P<0.01). The expression levels of p-eIF2α, ATF4 and CHOP were notably up-regulated in the ovarian granulosa cells of PCOS mice and KGN cells after DHEA exposure (P<0.05). Additionally, AS treatment attenuated the pathological changes of ovary and uterine expression, decreased the serum T level and the LH/FSH ratio (P<0.05), and reduced HOMA-IR, TC and TG levels (P<0.05) when compared with the PCOS mice. Moreover, the expression levels of p-eIF2α, ATF4 and CHOP were significantly down-regulated after AS treatment in both ovarian granulosa cells of PCOS mice and KGN cells (P<0.05).

AS significantly improves glycolipid metabolic disorder and reproductive dysfunction in PCOS mice, which may be associated with its suppressing endoplasmic reticulum stress by inhibiting the PERK/eIF2α/ATF4/CHOP pathway.