Tran Nhi T, Muccini Anna M, Hale Nadia, Tolcos Mary, Snow Rod J, Walker David W, Ellery Stacey J
The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.
Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia.
Front Cell Neurosci. 2023 Mar 30;17:1154772. doi: 10.3389/fncel.2023.1154772. eCollection 2023.
Creatine supplementation during pregnancy is a promising prophylactic treatment for perinatal hypoxic brain injury. Previously, in near-term sheep we have shown that fetal creatine supplementation reduces cerebral metabolic and oxidative stress induced by acute global hypoxia. This study investigated the effects of acute hypoxia with or without fetal creatine supplementation on neuropathology in multiple brain regions.
Near-term fetal sheep were administered continuous intravenous infusion of either creatine (6 mg kg h) or isovolumetric saline from 122 to 134 days gestational age (dGA; term is approx. 145 dGA). At 131 dGA, global hypoxia was induced by a 10 min umbilical cord occlusion (UCO). Fetuses were then recovered for 72 h at which time (134 dGA) cerebral tissue was collected for either RT-qPCR or immunohistochemistry analyses.
UCO resulted in mild injury to the cortical gray matter, thalamus and hippocampus, with increased cell death and astrogliosis and downregulation of genes involved in regulating injury responses, vasculature development and mitochondrial integrity. Creatine supplementation reduced astrogliosis within the corpus callosum but did not ameliorate any other gene expression or histopathological changes induced by hypoxia. Of importance, effects of creatine supplementation on gene expression irrespective of hypoxia, including increased expression of anti-apoptotic () and pro-inflammatory (e.g., β) genes, particularly in the gray matter, hippocampus, and striatum were identified. Creatine treatment also effected oligodendrocyte maturation and myelination in white matter regions.
While supplementation did not rescue mild neuropathology caused by UCO, creatine did result in gene expression changes that may influence cerebral development.
孕期补充肌酸是一种很有前景的围产期缺氧性脑损伤预防性治疗方法。此前，我们在近足月绵羊中发现，补充胎儿肌酸可降低急性全脑缺氧诱导的脑代谢和氧化应激。本研究调查了急性缺氧伴或不伴胎儿肌酸补充对多个脑区神经病理学的影响。
在妊娠122至134天（dGA；足月约为145 dGA）期间，对近足月胎儿绵羊持续静脉输注肌酸（6 mg·kg-1·h-1）或等体积生理盐水。在131 dGA时，通过10分钟的脐带阻断（UCO）诱导全脑缺氧。然后让胎儿恢复72小时，此时（134 dGA）收集脑组织进行RT-qPCR或免疫组织化学分析。
UCO导致皮质灰质、丘脑和海马轻度损伤，细胞死亡增加、星形胶质细胞增生，以及参与调节损伤反应、血管发育和线粒体完整性的基因下调。补充肌酸可减少胼胝体内的星形胶质细胞增生，但不能改善缺氧诱导的任何其他基因表达或组织病理学变化。重要的是，确定了无论是否缺氧，补充肌酸对基因表达的影响，包括抗凋亡（如）和促炎（如β）基因的表达增加，特别是在灰质、海马和纹状体中。肌酸治疗还影响了白质区域少突胶质细胞的成熟和髓鞘形成。
虽然补充肌酸未能挽救UCO引起的轻度神经病理学改变，但肌酸确实导致了可能影响脑发育的基因表达变化。
