Zhang Shan, Li Wendong, Xu Yiran, Li Tao, Ek Joakim, Zhang Xiaoli, Wang Yafeng, Song Juan, Zhu Changlian, Wang Xiaoyang
Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Front Cell Neurosci. 2023 Mar 6;17:1137497. doi: 10.3389/fncel.2023.1137497. eCollection 2023.
Preterm brain injury often leads to lifelong disabilities affecting both cognitive and motor functions, and effective therapies are limited. Alpha1-antitrypsin (AAT), an endogenous inhibitor of serine proteinases with anti-inflammatory, anti-apoptotic, and cytoprotective properties, might be beneficial in treating preterm brain injury. The aim of this study was to investigate whether AAT has neuroprotective effects in a mouse preterm brain injury model. Preterm brain injury was induced on postnatal day 5, and mouse pups' right common carotid arteries were cut between two ligations followed by hypoxia induction. Brain injury was evaluated through immunohistochemistry staining and magnetic resonance imaging. Fluoro-Jade B and immunohistochemistry staining were performed to investigate the neuronal cell death and blood-brain barrier (BBB) permeability. The motor function and anxiety-like behaviors were revealed by CatWalk gait analysis and the open field test. After hypoxia-ischemia (HI) insult, brain injury was alleviated by AAT treatment, and this was accompanied by reduced BBB permeability, reduced neuronal cell death and caspase-3 activation, and inhibition of microglia activation. In addition, AAT administration significantly improved HI-induced motor function deficiencies in mice. The neuroprotective effect of AAT was more pronounced in male mice. AAT treatment is neuroprotective against preterm brain injury in neonatal mice, and the effect is more pronounced in males.
早产脑损伤常导致影响认知和运动功能的终身残疾，且有效的治疗方法有限。α1-抗胰蛋白酶（AAT）是一种具有抗炎、抗凋亡和细胞保护特性的丝氨酸蛋白酶内源性抑制剂，可能对治疗早产脑损伤有益。本研究的目的是调查AAT在小鼠早产脑损伤模型中是否具有神经保护作用。在出生后第5天诱导早产脑损伤，在两个结扎之间切断幼鼠的右颈总动脉，随后进行缺氧诱导。通过免疫组织化学染色和磁共振成像评估脑损伤。进行荧光金B和免疫组织化学染色以研究神经元细胞死亡和血脑屏障（BBB）通透性。通过CatWalk步态分析和旷场试验揭示运动功能和焦虑样行为。在缺氧缺血（HI）损伤后，AAT治疗减轻了脑损伤，同时伴有BBB通透性降低、神经元细胞死亡减少和半胱天冬酶-3激活减少，以及小胶质细胞激活受到抑制。此外，给予AAT显著改善了HI诱导的小鼠运动功能缺陷。AAT的神经保护作用在雄性小鼠中更为明显。AAT治疗对新生小鼠的早产脑损伤具有神经保护作用，且该作用在雄性小鼠中更为明显。
