The potential effect of scoparone in autophagic disruption associated with PCOS in Letrozole rat model: role of Nrf2 and Sirt1/LKB1/AMPK signaling

Abstract

Background

Polycystic ovarian syndrome (PCOS) is an inflammatory autophagy-deficient disorder with downregulated Nrf2. Scoparone (SCPN), a natural compound from Chinese medicine, directly activates Nrf2 and clinically showed promises in treating inflammatory disorders. Studies reported SCPN’s ability to induce autophagy; yet no study tested SCPN’s ability in correcting disturbed autophagy in PCOS. The present research aim was to examine SCPN’s influence on PCOS-associated autophagic disturbances.

Methods

PCO was induced by Letrozole (1 mg/kg, p.o.) for 21 days and SCPN (12.5 mg/kg, i.p.) either alone or in parallel with an autophagy inhibitor, 3-methyl adenine, for 7 days.

Results

Hematoxylin and eosin (H&E) staining revealed reduced ovarian cysts with mature follicles recovery with SCPN. The immunolabeled ovarian tissues demonstrated that SCPN increased nuclear factor erythroid 2-related factor 2 (Nrf2) expression together with autophagic markers Beclin1, microtubule-associated protein light chain 3 (LC3), and autophagy enzyme 7 while decreasing P62. This signaling activation may be interpreted by autophagic signals upregulation; Sirtuin 1/liver kinase B1/AMP-activated protein kinase (Sirt1/LKB1/AMPK). A downregulation of inflammatory mediators, viz. tumor necrosis factor-alpha (TNF-α) and p65-nuclear factor kappa B (NF-κB) in PCOS ovaries, is associated by restoration of estradiol and FSH/LH balance. Concomitantly, SCPN abrogated testosterone and anti-Müllerian hormone levels besides insulin resistance and leptin levels.

Conclusions

The current study showed mutual link between Nrf2 and autophagic pathway. SCPN showed anti-inflammatory character with autophagic improvement in PCOS may be through Nrf2 activation.