Asadi-Azarbaijani Babak, Santos Regiane R, Jahnukainen Kirsi, Braber Saskia, van Duursen Majorie B M, Toppari Jorma, Saugstad Ola D, Nurmio Mirja, Oskam Irma C
Women and Children's Division, Oslo University Hospital, Rikshospitalet, Oslo, Norway; University of Oslo, Oslo, Norway.
Faculty of Veterinary Medicine, IRAS, Utrecht University, Utrecht, The Netherlands; Laboratory of Wild Animal Biology and Medicine, Federal University of Pará, Castanhal, Pará, Brazil.
Reprod Biol. 2017 Mar;17(1):25-33. doi: 10.1016/j.repbio.2016.11.003. Epub 2016 Dec 28.
Imatinib mesylate is an anti-cancer agent that competitively inhibits several receptor tyrosine kinases (RTKs). RTKs play important roles in the regulation of primordial follicle formation, the recruitment of primordial follicles into the pool of growing follicles and maturation of the follicles. In the present study, we investigated the effects of the tyrosine kinase inhibitor imatinib on primordial follicle assembly and early folliculogenesis in postnatal rats. Female Sprague-Dawley rats were treated with either imatinib (150mg/kg) or placebo (water) on postnatal days 2-4. Bilateral ovariectomy was performed on postnatal day 2 and 5. Histology, immunohistochemistry, and mRNA analysis were performed. Imatinib treatment was associated with increased density of the multi-oocyte follicles (P<0.01), oogonia (p<0.01) and germline clusters (P<0.05), decreased activation of primordial follicles, increased expression of c-Kit and AMH, and decreased protein expression of Kit-ligand and GDF9 when compared to age-matched controls. In conclusion, imatinib affects folliculogenesis in postnatal rat ovaries by delaying the cluster breakdown, follicular assembly and early activation of the primordial follicle pool.
甲磺酸伊马替尼是一种抗癌药物，它能竞争性抑制多种受体酪氨酸激酶（RTK）。RTK在原始卵泡形成、原始卵泡募集进入生长卵泡池以及卵泡成熟的调节中发挥着重要作用。在本研究中，我们调查了酪氨酸激酶抑制剂伊马替尼对出生后大鼠原始卵泡组装和早期卵泡发生的影响。在出生后第2至4天，对雌性斯普拉格-道利大鼠分别给予伊马替尼（150mg/kg）或安慰剂（水）处理。在出生后第2天和第5天进行双侧卵巢切除术。进行了组织学、免疫组织化学和mRNA分析。与年龄匹配的对照组相比，伊马替尼治疗导致多卵母细胞卵泡密度增加（P<0.01）、卵原细胞增加（P<0.01）和生殖系细胞团增加（P<0.05），原始卵泡激活减少，c-Kit和AMH表达增加，Kit配体和GDF9蛋白表达减少。总之，伊马替尼通过延迟细胞团分解、卵泡组装和原始卵泡池的早期激活来影响出生后大鼠卵巢的卵泡发生。
