Shati Ali A, Khalil Mohammad A
Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia.
Department of Basic Medical Sciences, Division of Physiology, College of Medicine, King Fahad Medical City, Riyadh, KSA.
J Cancer Res Ther. 2023 Jul-Sep;19(5):1194-1205. doi: 10.4103/jcrt.jcrt_1756_21.
Exogenous administration of acylated ghrelin (AG) afforded reproductive protective effect in several animal models but not in those treated with doxorubicin (DOX). This study evaluated the protective effect of AG against DOX-induced testicular damage and impairment in sperm parameters in rats and examined the potential mechanisms of action.
Adult male rats were divided into five groups (n = 8/each) as control, control + AG (40 nmol/kg/day; subcutaneous), DOX (10 mg/kg/day 1; intraperitoneal [i.p.]), DOX + AG, and DOX + AG + brusatol (an Nrf2 inhibitor) (2 mg/kg/every 3 days; i.p.). The treatment regimen continued for 65 days.
AG prevented testicular damage and apoptosis; increased sperm count, motility, and viability; and reduced the number of abnormal sperms. It also increased their circulatory levels of AG, des-acylated ghrelin (DAG), and AG/DAG ratio and the testicular mRNA levels of ghrelin and growth hormone secretagogue receptor 1a Concomitantly, AG increased serum and testicular testosterone levels, reduced serum levels of the follicle-stimulating hormone and luteinizing hormone, and upregulated the testicular protein levels of the steroidogenic acute regulatory protein and 3β-hydroxysteroid dehydrogenase in DOX-treated rats. In the testes of the control and DOX-treated rats, AG increased the phosphorylation of mammalian target of rapamycin and stimulated the levels of glutathione and superoxide dismutase, as well as the nuclear activation of Nrf2. All these effects were completely prevented by co-treatment with brusatol.
AG replacement therapy could be a novel strategy to prevent reproductive toxicity in cancer patients.
外源性给予酰基化胃饥饿素（AG）在多种动物模型中具有生殖保护作用，但在接受阿霉素（DOX）治疗的动物模型中却没有。本研究评估了AG对DOX诱导的大鼠睾丸损伤及精子参数损害的保护作用，并探讨了其潜在作用机制。
成年雄性大鼠分为五组（每组n = 8），即对照组、对照 + AG组（40 nmol/kg/天；皮下注射）、DOX组（10 mg/kg/天；腹腔注射[i.p.]）、DOX + AG组以及DOX + AG + 布沙替尼（一种Nrf2抑制剂）组（2 mg/kg/每3天；腹腔注射）。治疗方案持续65天。
AG可预防睾丸损伤和细胞凋亡；增加精子数量、活力和存活率；减少异常精子数量。它还提高了循环中AG、去酰基化胃饥饿素（DAG）的水平以及AG/DAG比值，以及睾丸中胃饥饿素和生长激素促分泌素受体1a的mRNA水平。同时，AG可提高DOX处理大鼠的血清和睾丸睾酮水平，降低血清促卵泡生成素和促黄体生成素水平，并上调睾丸中类固醇生成急性调节蛋白和3β-羟基类固醇脱氢酶的蛋白水平。在对照组和DOX处理大鼠的睾丸中，AG增加了雷帕霉素靶蛋白的磷酸化，刺激了谷胱甘肽和超氧化物歧化酶的水平以及Nrf2的核激活。与布沙替尼联合处理可完全阻断所有这些作用。
AG替代疗法可能是预防癌症患者生殖毒性的一种新策略。
