Tran Nhi T, Ellery Stacey J, Kelly Sharmony B, Sévigny Juliane, Chatton Madeleine, Lu Hui, Polglase Graeme R, Snow Rod J, Walker David W, Galinsky Robert
The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia.
Department of Obstetrics and Gynecology, Monash University, Melbourne, Victoria, Australia.
Ann Neurol. 2025 Apr;97(4):673-687. doi: 10.1002/ana.27150. Epub 2024 Dec 7.
Hypoxic-ischemic encephalopathy (HIE) is a major cause of perinatal brain injury. Creatine is a dietary supplement that can increase intracellular phosphocreatine to improve the provision of intracellular adenosine triphosphate (ATP) to meet the increase in metabolic demand of oxygen deprivation. Here, we assessed prophylactic fetal creatine supplementation in reducing acute asphyxia-induced seizures, disordered electroencephalography (EEG) activity and cerebral inflammation and cell death histopathology.
Fetal sheep (118 ± 1 days' gestational age [dGA]; 0.8 gestation) were implanted with electrodes to continuously record EEG and nuchal electromyogram activity. At 121 dGA, fetuses were randomly assigned to sham control (i.v. saline infusion without umbilical cord occlusion [UCO]; SalCon), continuous i.v. creatine infusion (6 mg/kg/h; CrUCO) or isovolumetric saline (SalUCO) followed by UCO at 128 ± 2 dGA that lasted until the mean arterial blood pressure reached 19 mmHg. Brain tissue was collected for histopathology after 72 hours of recovery.
Creatine supplementation had no effects on basal systemic or neurological physiology. UCO duration did not differ between CrUCO and SalUCO. After reperfusion, CrUCO fetuses had improved EEG power and frequency recovery and reduced electrographic seizure incidence (SalUCO, 86% vs CrUCO, 29%) and burden. At 72 hours after UCO, cell death in the cerebral cortex and astrogliosis in the periventricular white matter were reduced in CrUCO fetuses compared with SalUCO.
Creatine supplementation reduced post-asphyxial seizures and improved EEG recovery. Improvements in functional recovery with creatine were associated with regional reductions in cell death and astrogliosis. Prophylactic creatine treatment has the potential to mitigate functional indices of HIE in the late gestation fetal brain. ANN NEUROL 2025;97:673-687.
缺氧缺血性脑病（HIE）是围产期脑损伤的主要原因。肌酸是一种膳食补充剂，可增加细胞内磷酸肌酸，以改善细胞内三磷酸腺苷（ATP）的供应，从而满足缺氧时代谢需求的增加。在此，我们评估了预防性补充胎儿肌酸对减少急性窒息引起的癫痫发作、脑电图（EEG）活动紊乱以及脑炎症和细胞死亡组织病理学的影响。
将胎羊（妊娠龄118±1天[dGA]；妊娠0.8期）植入电极，以连续记录EEG和颈部肌电图活动。在121 dGA时，将胎儿随机分为假手术对照组（静脉输注生理盐水，不进行脐带闭塞[UCO]；SalCon）、连续静脉输注肌酸（6 mg/kg/h；CrUCO）或等容生理盐水（SalUCO），然后在128±2 dGA时进行UCO，持续至平均动脉血压达到19 mmHg。恢复72小时后收集脑组织进行组织病理学检查。
补充肌酸对基础全身或神经生理学无影响。CrUCO组和SalUCO组的UCO持续时间无差异。再灌注后，CrUCO组胎儿的EEG功率和频率恢复改善，脑电图癫痫发作发生率（SalUCO组为86%，CrUCO组为29%）和负担降低。UCO后72小时，与SalUCO组相比，CrUCO组胎儿大脑皮质的细胞死亡和脑室周围白质的星形胶质细胞增生减少。
补充肌酸可减少窒息后癫痫发作并改善EEG恢复。肌酸改善功能恢复与细胞死亡和星形胶质细胞增生的局部减少有关。预防性肌酸治疗有可能减轻晚期妊娠胎儿脑HIE的功能指标。《神经病学年鉴》2025年；97：673 - 687。
