Impact of chronic hypoxia on white matter and brain development in neonatal rat model_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

LIU Gang ¹ , SHI Bowen ¹ , HE Xiaomin ¹ , HUANG Junrong ² , CHEN Huiwen ¹ ,  ZHU Zhongqun ¹

1. Department of Cardiothoracic Surgery, Heart Center, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, P.R.China;
2. Department of Cardiothoracic Surgery, Shenzhen Children's Hospital, Shenzhen, 518038, P.R.China;

Corresponding author：

ZHU Zhongqun, Email: zzqheart@aliyun.com

Keywords：

Chronic hypoxia; congenital heart disease; brain development; white matter injury; model

DOI：

10.7507/1007-4848.201801064

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Objective To study the impact of chronic hypoxia on white matter (WM) injury and brain development delay using a neonatal rat model, and to explore its value in simulating chronic hypoxic brain damage in cyanotic congenital heart disease (CHD). Methods Three-day-old Sprague-Dawley (SD) rats were randomly distributed to an experiment group (n=36, FiO₂ 10.5%±1.0%) and a control group (n=36, FiO₂ 21.0%±0.0%) and were raised for 12 days. (1) Body weight of SD rats was recorded every day and fresh brain weight was measured on P14. (2) H&E staining was performed on sections of brain tissue to observe pathological changes and ventricular size. (3) Immunohistochemistry (IHC) was applied to reveal alterations of oligodendroglial progenitor cells (OPC), preoligodendrocytes (PreOL) and myelin basic protein (MBP) in brain WM area. (4) Protein was extracted from 50 mg of brain tissue in WM area and expression of MBP was determined using Western blotting. (5) Motor function and coordination of rats (P30) were assessed via rotation experiment. Results (1) Body weight and brain weight were significantly less in the experiment group compared with the control group on P14 (body weight 14.92±1.26 gvs. 30.26±1.81 g, t=7.51, P<0.01; brain weight 0.68± 0.05 gvs.0.97±0.04 g, t=13.26, P<0.01); (2) HE staining: Sections of brain tissue from the experiment group showed ventricular size enlargement with a statistical difference (P<0.01), disordered cell organization, local neuronal death and leukomalacia. (3) The number of OPC and PreOL in the experiment group were significantly less than those in the control group (64.8±6.3vs. 126.2±8.4, t=11.19, P<0.01; 19.1±7.6vs. 46.7±9.5, t=7.28, P<0.01, respectively). MBP distribution was sparse and disorganized in the experiment group. (4) Western blotting: Expression of MBP was less in the experiment group (P<0.01). (5) Behavioral test: Time on rotarod was less in the experiment group with a statistical difference (P<0.01). Conclusion Chronic hypoxia can result in WM injury and brain development delay in neonatal rats, with features comparable to those seen in infants with cyanotic CHD.

Citation： LIU Gang, SHI Bowen, HE Xiaomin, HUANG Junrong, CHEN Huiwen, ZHU Zhongqun. Impact of chronic hypoxia on white matter and brain development in neonatal rat model. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2018, 25(11): 986-992. doi: 10.7507/1007-4848.201801064 Copy

1.	Mahle WT, Tavani F, Zimmerman RA, et al. An MRI study of neurological injury before and after congenital heart surgery. Circulation, 2002, 106(12 Suppl 1): I109-I114.
2.	International Cardiac Collaborative on Neurodevelopment (ICCON) Investigators. Impact of operative and postoperative factors on neurodevelopmental outcomes after cardiac operations. Ann Thorac Surg, 2016, 102(3): 843-849.
3.	Morton PD, Ishibashi N, Jonas RA, et al. Congenital cardiac anomalies and white matter injury. Trends Neurosci, 2015, 38(6): 353-363.
4.	冷军, 刘慧娟, 王磊, 等. 缺血缺氧性脑损伤动物模型. 国际脑血管病杂志, 2010, 18(4): 315-320.
5.	Semple BD, Blomgren K, Gimlin K, et al. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol, 2013, 106-107: 1-16.
6.	Licht DJ. Brain hypoxia before surgery; a tale of two cells: Astrocytes and oligodendrocytes. J Thorac Cardiovasc Surg, 2016, 151(1): 273-274.
7.	Back SA, Craig A, Luo NL, et al. Protective effects of caffeine on chronic hypoxia-induced perinatal white matter injury. Ann Neurol, 2006, 60(6): 696-705.
8.	Lin S, Fan LW, Pang Y, et al. IGF-1 protects oligodendrocyte progenitor cells and improves neurological functions following cerebral hypoxia-ischemia in the neonatal rat. Brain Res, 2005, 1063(1): 15-26.
9.	Wang Y, Li B, Li Z, et al. Improvement of hypoxia-ischemia-induced white matter injury in immature rat brain by ethyl pyruvate. Neurochem Res, 2013, 38(4): 742-752.
10.	Bellinger DC, Wypij D, Rivkin MJ, et al. Adolescents with d-transposition of the great arteries corrected with the arterial switch procedure: neuropsychological assessment and structural brain imaging. Circulation, 2011, 124(12): 1361-1369.
11.	Licht DJ, Shera DM, Clancy RR, et al. Brain maturation is delayed in infants with complex congenital heart defects. J Thorac Cardiovasc Surg, 2009, 137(3): 529-536.
12.	Filley CM. White matter dementia. Ther Adv Neurol Disord, 2012, 5(5): 267-277.
13.	Jablonska B, Scafidi J, Aguirre A, et al. Oligodendrocyte regeneration after neonatal hypoxia requires FoxO1-mediated p27Kip1 expression. J Neurosci, 2012, 32(42): 14775-14793.
14.	Scafidi J, Hammond TR, Scafidi S, et al. Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature, 2014, 506(7487): 230-234.
15.	Volpe JJ, Kinney HC, Jensen FE, et al. The developing oligodendrocyte: key cellular target in brain injury in the premature infant. Int J Dev Neurosci, 2011, 29(4): 423-440.
16.	Zaghloul N, Patel H, Ahmed MN. A model of periventricular leukomalacia (PVL) in neonate mice with histopathological and neurodevelopmental outcomes mimicking human PVL in neonates. PLoS One, 2017, 12(4): e0175438.
17.	Rice JE 3rd, Vannucci RC, Brierley JB. The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol, 1981, 9(2): 131-141.
18.	Benjelloun N, Renolleau S, Represa A, et al. Inflammatory responses in the cerebral cortex after ischemia in the P7 neonatal Rat. Stroke, 1999, 30(9): 1916-1923.

1. Mahle WT, Tavani F, Zimmerman RA, et al. An MRI study of neurological injury before and after congenital heart surgery. Circulation, 2002, 106(12 Suppl 1): I109-I114.
2. International Cardiac Collaborative on Neurodevelopment (ICCON) Investigators. Impact of operative and postoperative factors on neurodevelopmental outcomes after cardiac operations. Ann Thorac Surg, 2016, 102(3): 843-849.
3. Morton PD, Ishibashi N, Jonas RA, et al. Congenital cardiac anomalies and white matter injury. Trends Neurosci, 2015, 38(6): 353-363.
4. 冷军, 刘慧娟, 王磊, 等. 缺血缺氧性脑损伤动物模型. 国际脑血管病杂志, 2010, 18(4): 315-320.
5. Semple BD, Blomgren K, Gimlin K, et al. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol, 2013, 106-107: 1-16.
6. Licht DJ. Brain hypoxia before surgery; a tale of two cells: Astrocytes and oligodendrocytes. J Thorac Cardiovasc Surg, 2016, 151(1): 273-274.
7. Back SA, Craig A, Luo NL, et al. Protective effects of caffeine on chronic hypoxia-induced perinatal white matter injury. Ann Neurol, 2006, 60(6): 696-705.
8. Lin S, Fan LW, Pang Y, et al. IGF-1 protects oligodendrocyte progenitor cells and improves neurological functions following cerebral hypoxia-ischemia in the neonatal rat. Brain Res, 2005, 1063(1): 15-26.
9. Wang Y, Li B, Li Z, et al. Improvement of hypoxia-ischemia-induced white matter injury in immature rat brain by ethyl pyruvate. Neurochem Res, 2013, 38(4): 742-752.
10. Bellinger DC, Wypij D, Rivkin MJ, et al. Adolescents with d-transposition of the great arteries corrected with the arterial switch procedure: neuropsychological assessment and structural brain imaging. Circulation, 2011, 124(12): 1361-1369.
11. Licht DJ, Shera DM, Clancy RR, et al. Brain maturation is delayed in infants with complex congenital heart defects. J Thorac Cardiovasc Surg, 2009, 137(3): 529-536.
12. Filley CM. White matter dementia. Ther Adv Neurol Disord, 2012, 5(5): 267-277.
13. Jablonska B, Scafidi J, Aguirre A, et al. Oligodendrocyte regeneration after neonatal hypoxia requires FoxO1-mediated p27Kip1 expression. J Neurosci, 2012, 32(42): 14775-14793.
14. Scafidi J, Hammond TR, Scafidi S, et al. Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature, 2014, 506(7487): 230-234.
15. Volpe JJ, Kinney HC, Jensen FE, et al. The developing oligodendrocyte: key cellular target in brain injury in the premature infant. Int J Dev Neurosci, 2011, 29(4): 423-440.
16. Zaghloul N, Patel H, Ahmed MN. A model of periventricular leukomalacia (PVL) in neonate mice with histopathological and neurodevelopmental outcomes mimicking human PVL in neonates. PLoS One, 2017, 12(4): e0175438.
17. Rice JE 3rd, Vannucci RC, Brierley JB. The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol, 1981, 9(2): 131-141.
18. Benjelloun N, Renolleau S, Represa A, et al. Inflammatory responses in the cerebral cortex after ischemia in the P7 neonatal Rat. Stroke, 1999, 30(9): 1916-1923.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Impact of chronic hypoxia on white matter and brain development in neonatal rat model

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