Effects of nestorone, a progesterone receptor agonist, on neonatal hypoxic-ischemic brain injury and reproductive functions in male and female rats

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-03-11 DOI:10.1016/j.neuropharm.2025.110411

Motoki Tanaka , Masahiro Sokabe , Keiko Nakanishi , Masato Asai

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Abstract

Perinatal hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of neonatal death and neurological disorders. We recently demonstrated the neuroprotective effects of nestorone, a progesterone receptor agonist, in adult male rats subjected to focal cerebral ischemia; however, its effects on neonatal ischemic brain injury and on sexual differentiation and reproductive functions remain unclear. Therefore, the present study investigated the effects of nestorone on neonatal hypoxic-ischemic brain injury and reproductive functions in rats of both sexes. Seven-day-old male and female rat pups were subjected to occlusion of the right carotid artery and then exposed to 8 % oxygen (hypoxic-ischemia, HI). Brain lesion sizes and the numbers of activated astrocytes and microglia in male and female rats were significantly lower after administrating 10 μg/kg nestorone than vehicle 48 h after HI. Furthermore, the post-HI administration of nestorone for 7 days (10 μg/kg, once a day) significantly improved motor coordination and tactile responses 28 days after HI and cognitive performance 4 months after HI in male and female rats. The administration of nestorone did not affect the delivery rates or number of weaned pups in HI and sham-operated female rats or in intact female rats mated with HI or sham-operated males. These results suggest that nestorone exerts persistent neuroprotective effects against neonatal HI brain injury without serious adverse effects on reproductive functions in male and female rats. Therefore, nestorone is a promising potent and safe therapeutic agent in newborn infants with HIE of both sexes.

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孕酮受体激动剂依诺酮对雌雄大鼠新生儿缺氧缺血性脑损伤和生殖功能的影响

围产期缺氧缺血性脑病（HIE）是新生儿死亡和神经系统疾病的主要原因之一。我们最近证明了奈斯托酮（一种黄体酮受体激动剂）对局灶性脑缺血的成年雄性大鼠的神经保护作用；然而，其对新生儿缺血性脑损伤、性别分化和生殖功能的影响尚不清楚。因此，本研究探讨了奈斯托酮对新生儿缺氧缺血性脑损伤及雌雄大鼠生殖功能的影响。7天大的雄性和雌性大鼠幼仔进行右颈动脉闭塞，然后暴露于8%的氧气（缺氧缺血，HI）。注射10 μg/kg奈storone后48 h，雄性和雌性大鼠的脑损伤大小、激活的星形胶质细胞和小胶质细胞数量均显著低于对照。此外，HI后给予nestorone 7天（10 μg/kg，每天1次）可显著改善HI后28天的运动协调和触觉反应以及HI后4个月的认知表现。施奈斯托酮不影响HI和假手术雌性大鼠的分娩率或断奶幼崽数量，也不影响与HI或假手术雄性交配的完整雌性大鼠。这些结果表明，奈storone对新生儿HI脑损伤具有持久的神经保护作用，对雌雄大鼠的生殖功能没有严重的不良影响。因此，奈斯托酮是一种有前景的有效和安全的治疗新生儿HIE的药物。

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来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).