Piao Hongying, Ishikawa Hiroshi, Kobayashi Tatsuya, Kitajo Keiko, Yamaguchi Atsushi, Koga Kaori, Shozu Makio
Department of Obstetrics and Gynecology, Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Department of Obstetrics and Gynecology, Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Pediatr Neonatol. 2025 May;66(3):216-222. doi: 10.1016/j.pedneo.2024.03.012. Epub 2024 Aug 22.
Hypoxic-ischemic (HI) insult in infants induces brain injury and results in motor coordination impairments associated with cerebral palsy; however, preventive measures for HI brain injury in preterm infants remain unclear. We investigated the impact of progesterone (P4) in a rat HI insult model that mimics HI brain injury in preterm infants.
Neonatal male rats with their right common carotid artery coagulated were exposed to a 1-h hypoxia (6% oxygen) on postnatal day (PND) 3. P4 (0.2 mg) was subcutaneously administered daily from PND4-12. Motor coordination function and muscular strength were evaluated on PND50 using rotarod and grip strength tests, respectively. Brain histology was evaluated via immunohistochemistry using anti-NeuN, anti-Olig2, and anti-IbaI antibodies on PND15 and PND50.
In male rats, P4 significantly improved the latency-to-fall off on the rotarod test in the insult rats to the levels of the sham-operation rats. Neither the insult nor P4 administration impacted the grip strength results. No significant differences were observed in the number of neurons, oligodendrocyte progenitor cells (OPCs), and microglia in the motor and somatosensory area of the cortex between the insult and insult followed by P4-administered rats on PND50. The number of OPCs in the corpus callosum was significantly increased in the ipsilateral side compared with the contralateral side of the insult in the P4-administered rats, indicating that P4 facilitates recruitment of OPCs to the corpus callosum. HI insult accelerated neuronal differentiation in rats on PND15, which was abrogated in the P4-administerd group, suggesting that P4 suppresses transient neuronal differentiation caused by the insult.
P4 administration restored motor coordination impairments caused by postnatal HI insult in male rats. The insult timing corresponds to that of human preterm infants, indicating P4's potential for protecting HI brain injury in preterm male infants.
婴儿的缺氧缺血性（HI）损伤会导致脑损伤，并引发与脑瘫相关的运动协调障碍；然而，早产儿HI脑损伤的预防措施仍不明确。我们在一个模拟早产儿HI脑损伤的大鼠HI损伤模型中研究了孕酮（P4）的影响。
出生后第3天（PND 3），将右侧颈总动脉结扎的新生雄性大鼠暴露于1小时的低氧环境（6%氧气）中。从PND 4至12每天皮下注射P4（0.2毫克）。分别在PND 50时使用转棒试验和握力试验评估运动协调功能和肌肉力量。在PND 15和PND 50时，通过使用抗NeuN、抗Olig2和抗IbaI抗体的免疫组织化学方法评估脑组织结构。
在雄性大鼠中，P4显著改善了损伤大鼠在转棒试验中的掉落潜伏期，使其达到假手术大鼠的水平。损伤和P4给药均未影响握力结果。在PND 50时，损伤组大鼠与损伤后给予P4的大鼠之间，皮质运动和体感区域的神经元、少突胶质前体细胞（OPC）和小胶质细胞数量未观察到显著差异。与损伤侧对侧相比，给予P4的大鼠损伤同侧胼胝体中的OPC数量显著增加，表明P4促进OPC向胼胝体募集。HI损伤加速了PND 15大鼠的神经元分化，而在给予P4的组中这种现象被消除，这表明P4抑制了由损伤引起的短暂神经元分化。
给予P4可恢复雄性大鼠出生后HI损伤所致的运动协调障碍。损伤时间与人类早产儿的情况相符，表明P4在保护早产雄性婴儿HI脑损伤方面具有潜力。
