Chen Xiaodi, Zhang Jiyong, Wu Yuqi, Tucker Richard, Baird Grayson L, Domonoske Rose, Barrios-Anderson Adriel, Lim Yow-Pin, Bath Kevin, Walsh Edward G, Stonestreet Barbara S
Department of Pediatrics, Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Women &101 Dudley Street, Providence, RI, 02905-2499, USA.
Department of Diagnostic Imaging, Biostatistics Core Lifespan Hospital System, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA.
Neurotherapeutics. 2022 Mar;19(2):528-549. doi: 10.1007/s13311-022-01217-8. Epub 2022 Mar 15.
Hypoxic-ischemic (HI) brain injury is a major contributor to neurodevelopmental morbidities. Inter-alpha inhibitor proteins (IAIPs) have neuroprotective effects on HI-related brain injury in neonatal rats. However, the effects of treatment with IAIPs on sequential behavioral, MRI, and histopathological abnormalities in the young adult brain after treatment with IAIPs in neonates remain to be determined. The objective of this study was to examine the neuroprotective effects of IAIPs at different neurodevelopmental stages from newborn to young adults after exposure of neonates to HI injury. IAIPs were given as 11-sequential 30-mg/kg doses to postnatal (P) day 7-21 rats after right common carotid artery ligation and exposure to 90 min of 8% oxygen. The resulting brain edema and injury were examined by T-weighted magnetic resonance imaging (MRI) and cresyl violet staining, respectively. The mean T values of the ipsilateral hemisphere from MRI slices 6 to 10 were reduced in IAIP-treated HI males + females on P8, P9, and P10 and females on P8, P9, P10, and P14. IAIP treatment reduced hemispheric volume atrophy by 44.5 ± 29.7% in adult male + female P42 rats and improved general locomotor abilities measured by the righting reflex over time at P7.5, P8, and P9 in males + females and males and muscle strength/endurance measured by wire hang on P16 in males + females and females. IAIPs provided beneficial effects during the learning phase of the Morris water maze with females exhibiting beneficial effects. IAIPs confer neuroprotection from HI-related brain injury in neonates and even in adult rats and beneficial MRI and behavioral benefits in a sex-dependent manner.
缺氧缺血性（HI）脑损伤是导致神经发育疾病的主要因素。α-间抑制蛋白（IAIPs）对新生大鼠HI相关脑损伤具有神经保护作用。然而，新生期用IAIPs治疗后，其对成年幼鼠后续行为、MRI及组织病理学异常的影响仍有待确定。本研究的目的是在新生鼠暴露于HI损伤后，检查IAIPs在从新生到成年不同神经发育阶段的神经保护作用。在右侧颈总动脉结扎并暴露于8%氧气90分钟后，对出生后（P）7至21天的大鼠按11次连续30mg/kg剂量给予IAIPs。分别通过T加权磁共振成像（MRI）和甲酚紫染色检查由此产生的脑水肿和损伤。在P8、P9和P10以及P8、P9、P10和P14的雌性大鼠中，IAIP治疗的HI雄性和雌性大鼠MRI切片6至10同侧半球的平均T值降低。IAIP治疗使成年P42雄性和雌性大鼠的半球体积萎缩减少了44.5±29.7%，并改善了雄性和雌性以及雄性在P7.5、P8和P9时通过翻正反射测量的一般运动能力，以及雄性和雌性在P16时通过悬线试验测量的肌肉力量/耐力。在莫里斯水迷宫学习阶段，IAIPs产生了有益作用，雌性表现出有益效果。IAIPs对新生鼠甚至成年大鼠的HI相关脑损伤具有神经保护作用，并以性别依赖的方式产生有益的MRI和行为效果。
