To determine whether BMS-202 can disrupt the pituitary gland and reproductive system. BMS-202 (2.5 mg/kg) was injected intraperitoneally into adult female mice every 96 h for four times. Real-time polymerase chain reaction, western blotting, double immunofluorescence staining and radioimmunoassays (RIA) were used to study the expressions of programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), and detect changes after BMS-202 treatment in the mouse pituitary gland. PD-1 and PD-L1 were expressed in the mouse pituitary gland. Further functional studies demonstrated that BMS-202 inhibited the synthesis and secretion of gonadotropins and prolonged the estrous cycle in mice. Moreover, the increases of cleaved caspase3 (c-caspase3) protein level both in vivo and in vitro indicated that BMS-202 induced apoptosis. Additionally, the effects of BMS-202 on follicle-stimulating hormone and luteinizing hormone mRNA levels were blocked by a p38 MAPK inhibitor. Of note, the inhibition of p38 MAPK pathway decreased the apoptosis induced by BMS-202. BMS-202, as a drug which inhibits the formation of the PD-1/PD-L1 complex, disrupts the normal function of the pituitary gland. Importantly, the results confirmed the potential insecurity of BMS-202 in the pituitary gland and provided data to support the evaluation of its clinical application.
Keywords: BMS-202; apoptosis; estrous cycle; gonadotropin; p38 MAPK.
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