LY294002, a PI3K pathway inhibitor, prevents leptin-induced adverse effects on spermatozoa in Sprague-Dawley rats

Abstract

This study examined the effects of PI3K and AMPK signalling pathway inhibitors on leptin‐induced adverse effects on rat spermatozoa. Sprague‐Dawley rats, aged 14–16 weeks, were randomised into control, leptin‐, leptin + dorsomorphin (AMPK inhibitor)‐, and leptin+LY294002 (PI3K inhibitor)‐treated groups with six rats per group. Leptin was given once daily for 14 days via the intraperitoneal (i.p.) route at a dose of 60 ug kg−1 body weight. Rats in the leptin and inhibitor‐treated groups received concurrently either dorsomorphin (5 mg kg−1 day−1) or LY294002 (1.2 mg kg−1 day−1) i.p. for 14 days. Controls received 0.1 ml of normal saline. Upon completion, sperm count, sperm morphology, seminiferous tubular epithelial height (STEH), seminiferous tubular diameter (STD), 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG) and phospho‐Akt/total Akt ratio were estimated. Data were analysed using ANOVA. Sperm count, STEH and STD were significantly lower, while the percentage of spermatozoa with abnormal morphology and the level of 8‐OHdG were significantly higher in rats treated with leptin and leptin + dorsomorphin when compared to those in controls and LY294002‐treated rats. Testicular phospho‐Akt/total Akt ratio was significantly higher in leptin and leptin + LY294002‐treated rats. In conclusion, LY294002 prevents leptin‐induced changes in rat sperm parameters, suggesting the potential role of the PI3K signalling pathway in the adverse effects of leptin on sperm parameters.

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

“…LY294002 and wortmannin are well-studied first-generation pan-PI3K inhibitors [72]. LY294002 is a reversible pan-PI3K inhibitor, and wortmannin is an irreversible pan-PI3K inhibitor.…”

Leptin: a pleitropic factor in physiology

“…Blockade of PI3-kinase activity prevents the anorectic action of leptin [122,123]. Recently the PI3K inhibitor, LY294002 was found to prevent the adverse effects of leptin on spermatozoa in the rat, suggesting that the PI3K pathway might be involved in the physiological actions of leptin on the testes [124].…”

Leptin and reproductive dysfunction in obese men

“…Similar findings were reported a few years later by another group of researchers using a similar study design and doses of leptin (Abbasihormozi et al, ). Studies on Sprague‐Dawley rats treated with 60 μg/kg body weight of leptin for either 6 or 2 weeks also came to the same conclusions (Almabhouh et al, ; Md Mokhtar et al, ). Similar response was also noted in mice recently when given exogenous leptin, although the doses ranging from 0.5 to 3.0 mg/Kg body used in this study were much higher than those used in Sprague‐Dawley rats (Wang, Zhang, Hu, & Li, ).…”

“…In general, it appears that oxidative stress following leptin treatment is responsible for the increased apoptosis of spermatozoa and seminiferous tubular cells, which might then be responsible for the decreased sperm concentration (Almabhouh et al, ; Wang et al, ). In fact, this might have also contributed to the leptin‐induced decreases in height and diameter of seminiferous tubules and sperm count reported recently in Sprague‐Dawley (Haron et al, ; Md Mokhtar et al, ).…”