Alpha1-antitrypsin protects the immature mouse brain following hypoxic-ischemic injury

Shan Zhang; Wendong Li; Yiran Xu; Tao Li; Joakim Ek; Xiaoli Zhang; Yafeng Wang; Juan Song; Changlian Zhu; Xiaoyang Wang

doi:10.3389/fncel.2023.1137497

Alpha1-antitrypsin protects the immature mouse brain following hypoxic-ischemic injury

Front Cell Neurosci. 2023 Mar 6:17:1137497. doi: 10.3389/fncel.2023.1137497. eCollection 2023.

Authors

Shan Zhang^{1

2}, Wendong Li¹, Yiran Xu¹, Tao Li^{2

3}, Joakim Ek⁴, Xiaoli Zhang¹, Yafeng Wang^{2

3}, Juan Song¹, Changlian Zhu^{1

2

5}, Xiaoyang Wang^{1

4

6}

Affiliations

¹ 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.
² Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
³ Henan Children's Neurodevelopment Engineering Research Center, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
⁴ Centre of Perinatal Medicine and Health, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
⁵ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
⁶ Centre of Perinatal Medicine and Health, Institute of Clinical Science, University of Gothenburg, Gothenburg, Sweden.

Abstract

Introduction: 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. Methods: 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. Results: 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. Conclusion: AAT treatment is neuroprotective against preterm brain injury in neonatal mice, and the effect is more pronounced in males.

Keywords: alpha1-antitrypsin; hypoxia-ischemia; immature brain; motor dysfunction; neonatal brain injury; neuroprotection.

Grants and funding

This study was supported by the National Natural Science Foundation of China (U21A20347 and 81901334), the National Key Research and Development Program of China (2022YFC2704800), the Swedish Research Council (2018-02267, 2021-01950, 2022-01019), Swedish Governmental grants to scientists working in health care (ALFGBG-965197, ALFGBG-966034), the Brain Foundation (FO2022-0120), the Adlerbert Research Foundation (2021-496, 2022-582), and Stiftelsen Edit Jacobsons Donationsfond (2021-102).