Department of Pediatrics, University of Michigan Medical School, The University of Michigan, Ann Arbor, MI, USA.
Department of Neurology, University of Michigan Medical School, The University of Michigan, Ann Arbor, MI, USA.
Pediatr Res. 2022 Aug;92(2):415-423. doi: 10.1038/s41390-021-01747-5. Epub 2021 Oct 8.
Systemic inflammation amplifies neonatal hypoxic-ischemic (HI) brain injury. Azithromycin (AZ), an antibiotic with anti-inflammatory properties, improves sensorimotor function and reduces tissue damage after neonatal rat HI brain injury. The objective of this study was to determine if AZ is neuroprotective in two neonatal rat models of inflammation-amplified HI brain injury.
DESIGN/METHODS: Seven-day-old (P7) rats received injections of toll-like receptor agonists lipopolysaccharide (LPS) or PamCys-Ser-(Lys) (PAM) prior to right carotid ligation followed by 50 min (LPS + HI) or 60 min (PAM + HI) in 8% oxygen. Outcomes included contralateral forelimb function (forepaw placing; grip strength), survival, %Intact right hemisphere (brain damage), and a composite score incorporating these measures. We compared postnatal day 35 outcomes in controls and groups treated with three or five AZ doses. Then, we compared P21 outcomes when the first (of five) AZ doses were administered 1, 2, or 4 h after HI.
In both LPS + HI and PAM + HI models, AZ improved sensorimotor function, survival, brain tissue preservation, and composite scores. Benefits increased with five- vs. three-dose AZ and declined with longer initiation delay.
Perinatal systemic infection is a common comorbidity of neonatal asphyxia brain injury and contributes to adverse outcomes. These data support further evaluation of AZ as a candidate treatment for neonatal neuroprotection.
AZ treatment decreases sensorimotor impairment and severity of brain injury, and improves survival, after inflammation-amplified HI brain injury, and this can be achieved even with a 2 h delay in initiation. This neuroprotective benefit is seen in models of inflammation priming by both Gram-negative and Gram-positive infections. This extends our previous findings that AZ treatment is neuroprotective after HI brain injury in neonatal rats.
全身性炎症会放大新生儿缺氧缺血性（HI）脑损伤。阿奇霉素（AZ）是一种具有抗炎特性的抗生素，可改善新生大鼠 HI 脑损伤后的感觉运动功能并减少组织损伤。本研究的目的是确定 AZ 在两种炎症放大的新生大鼠 HI 脑损伤模型中是否具有神经保护作用。
设计/方法：7 日龄（P7）大鼠在右侧颈总动脉结扎后接受 Toll 样受体激动剂脂多糖（LPS）或 PamCys-Ser-（Lys）（PAM）注射，然后在 8%氧气中进行 50 分钟（LPS+HI）或 60 分钟（PAM+HI）。结果包括对侧前肢功能（前爪放置；握力）、存活率、右侧半球完整率（脑损伤）和综合评分。我们比较了对照组和接受三种或五种 AZ 剂量治疗组的生后第 35 天的结果。然后，我们比较了 HI 后 1、2 或 4 小时首次（五次中的一次）给予 AZ 剂量时，P21 期的结果。
在 LPS+HI 和 PAM+HI 模型中，AZ 改善了感觉运动功能、存活率、脑组织保存和综合评分。五剂量 AZ 比三剂量 AZ 的获益更大，而起始时间延迟更长则获益减少。
围产期全身感染是新生儿窒息性脑损伤的常见合并症，并导致不良结局。这些数据支持进一步评估 AZ 作为新生儿神经保护的候选治疗药物。
AZ 治疗可减少炎症放大的 HI 脑损伤后的感觉运动障碍和脑损伤严重程度，并提高存活率，即使起始时间延迟 2 小时也能达到此效果。这种神经保护作用在革兰氏阴性和革兰氏阳性感染引起的炎症启动模型中均可见。这扩展了我们之前的研究结果，即 AZ 治疗对新生大鼠 HI 脑损伤具有神经保护作用。
