Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Department of Obstetrics and Gynecology, School of Medicine, International University of Health and Welfare, Narita, Japan.
Endocrinology. 2018 Jun 1;159(6):2264-2274. doi: 10.1210/en.2018-00148.
Brain damage caused by hypoxic ischemic insult during the perinatal period causes hypoxic ischemic encephalopathies (HIEs). Therapeutic hypothermia is indicated for HIE, but because the therapeutic burden is large for its limited therapeutic effectiveness, another strategy is needed. Progesterone (P4) plays a neuroprotective role through the actions of its metabolite, allopregnanolone (Allo), on P4 receptor, γ-aminobutyric acid type A receptors or both. We examined the therapeutic potential of P4 using a newborn rat model of HIE. Fetal rats were exposed to transient ischemic hypoxia by 30-minute bilateral uterine artery clamping on gestational day 18. After spontaneous birth, newborn pups were subcutaneously injected with P4 (0.10 or 0.01 mg), medroxyprogesterone acetate (MPA; 0.12 mg), or Allo (0.10 mg) through postnatal days (PDs) 1 to 9. Brain damage in the rats was assessed using the rotarod test at PD50. The HIE insult reduced the rats' ability in the rotarod task, which was completely reversed by P4 and Allo, but not by MPA. Histological examination revealed that the HIE insult decreased neuronal (the cortex and the hippocampal CA1 region) and oligodendroglial cell density (the corpus callosum) through PD0 to PD50. The axon fiber density and myelin sheath thickness in the corpus callosum were also reduced at PD50. The time-course study revealed that P4 restored oligodendroglial cells by PD5, which was followed by neuroprotective action of P4 that lasted long over the injection period. These results suggest that P4 protects the neonatal brain from HIE insult via restoration of oligodendroglial cells.
围产期缺氧缺血性损伤导致的脑损伤引起缺氧缺血性脑病（HIE）。对于 HIE，治疗性低温是适用的，但由于其治疗效果有限，治疗负担较大，因此需要另一种策略。孕酮（P4）通过其代谢物，别孕烯醇酮（Allo）对 P4 受体、γ-氨基丁酸 A 型受体或两者的作用发挥神经保护作用。我们使用新生大鼠 HIE 模型检查了 P4 的治疗潜力。在妊娠第 18 天，通过 30 分钟双侧子宫动脉夹闭使胎鼠暴露于短暂性缺氧缺血。自发性分娩后，新生幼仔通过皮下注射 P4（0.10 或 0.01 mg）、醋酸甲羟孕酮（MPA；0.12 mg）或 Allo（0.10 mg），从出生后第 1 天到第 9 天。通过旋转棒试验在出生后第 50 天评估大鼠的脑损伤。HIE 损伤降低了大鼠在旋转棒任务中的能力，而 P4 和 Allo 完全逆转了这一损伤，但 MPA 则没有。组织学检查显示，HIE 损伤通过 PD0 至 PD50 降低了神经元（皮质和海马 CA1 区）和少突胶质细胞密度（胼胝体）。胼胝体中的轴突纤维密度和髓鞘厚度也在 PD50 时降低。时间进程研究表明，P4 通过 PD5 恢复少突胶质细胞，随后是 P4 的神经保护作用，该作用在注射期间持续很长时间。这些结果表明，P4 通过恢复少突胶质细胞来保护新生儿大脑免受 HIE 损伤。
