每日大剂量咖啡因暴露对未成熟羊脑白质发育的影响。

Impact of daily high-dose caffeine exposure on developing white matter of the immature ovine brain.

机构信息

Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.

1] Department of Neonatal Services, Royal Women's Hospital, Victorian Infant Brain Studies, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia [2] Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Victoria, Australia.

出版信息

Pediatr Res. 2014 Jul;76(1):54-63. doi: 10.1038/pr.2014.55. Epub 2014 Apr 16.

DOI:10.1038/pr.2014.55

PMID:24739937

Abstract

BACKGROUND

Caffeine is widely used to treat apnea of prematurity, but the standard dosing regimen is not always sufficient to prevent apnea. Before higher doses of caffeine can be used, their effects on the immature brain need to be carefully evaluated. Our aim was to determine the impact of daily high-dose caffeine administration on the developing white matter of the immature ovine brain.

METHODS

High-dose caffeine (25 mg/kg caffeine base loading dose; 20 mg/kg daily maintenance dose; n = 9) or saline (n = 8) were administered to pregnant sheep from 0.7 to 0.8 of term, equivalent to approximately 27-34 wk in humans. At 0.8 of term, the white and gray matter were assessed histologically and immunohistochemically.

RESULTS

Daily caffeine administration led to peak caffeine concentration of 32 mg/l in fetal plasma at 1 h, followed by a gradual decline, with no effects on mean arterial pressure and heart rate. Initial caffeine exposure led to transient, mild alkalosis in the fetus but did not alter oxygenation. At necropsy, there was no effect of daily high-dose caffeine on brain weight, oligodendrocyte density, myelination, axonal integrity, microgliosis, astrogliosis, apoptosis, or neuronal density.

CONCLUSION

Daily high-dose caffeine administration does not appear to adversely affect the developing white matter at the microstructural level.

摘要

背景

咖啡因被广泛用于治疗早产儿呼吸暂停，但标准的用药剂量并不总是足以预防呼吸暂停。在使用更高剂量的咖啡因之前，需要仔细评估其对未成熟大脑的影响。我们的目的是确定每日高剂量咖啡因给药对未成熟羊脑白质发育的影响。

方法

从妊娠 0.7 到 0.8 期（相当于人类约 27-34 周）给妊娠绵羊给予高剂量咖啡因（25mg/kg 咖啡因碱负荷剂量；20mg/kg 每日维持剂量；n=9）或生理盐水（n=8）。在妊娠 0.8 期，对大脑的白质和灰质进行组织学和免疫组织化学评估。

结果

每日咖啡因给药导致胎儿血浆中的咖啡因浓度在 1 小时内达到 32mg/l 的峰值，随后逐渐下降，对平均动脉压和心率没有影响。初始咖啡因暴露导致胎儿短暂、轻度碱中毒，但不改变氧合作用。尸检时，每日高剂量咖啡因对脑重、少突胶质细胞密度、髓鞘形成、轴突完整性、小胶质细胞增生、星形胶质细胞增生、细胞凋亡或神经元密度均无影响。