White matter injury after cardiopulmonary bypass in a brain slice model of neonatal rats with perfusion_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

HUANG Junrong ¹ ,  ZHU Zhongqun ¹ , LIU Gang ¹ , CHEN Huiwen ¹ , FENG Linyin ²

1. Department of Cardiothoracic Surgery, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, P.R.China;
2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, P.R.China;

Corresponding author：

ZHU Zhongqun, Email: zzqheart@aliyun.com

Keywords：

Congenital heart disease; cardiopulmonary bypass; deep hypothermic cardiac arrest; white matter; preoligodendrocytes

DOI：

10.7507/1007-4848.201605007

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Objective Through establishment of brain slice model in rats with perfusion and oxygen glucose deprivation (OGD), we investigated whether this model can replicate the pathophysiology of brain injury in cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) or not and whether perfusion and OGD can induce preoligodendrocytes (preOL) injury or not, to provide cytological evidence for white matter injury after cardiopulmonary bypass. Methods Three to five living brain slices were randomly obtained from each of forty seven-day-old (P7) Sprague-Dawley (SD) rats with a mean weight of 14.7±1.5 g. Brain slices were randomly divided into five groups with 24 slices in each group: control group with normothermic artificial cerebralspinal fluid (aCSF) perfusion (36℃) and DHCA groups: OGD at 15℃, 25℃, 32℃ and 36℃. The perfusion system was established, and the whole process of CPB and DHCA in cardiac surgery was simulated. The degree of oligodendrocyte injury was evaluated by MBP and O4 antibody via application of immunohistochemistry. Results In the OGD group, the mature oligodendrocytes (MBP-positive) cells were significantly damaged, their morphology was greatly changed and fluorescence expression was significantly reduced. The higher the OGD temperature was, the more serious the damage was; preOL (O4-positive) cells showed different levels of fluorescence expression reduce in 36℃, 32℃ and 25℃ groups, and the higher the OGD temperature was, the more obvious decrease in fluorescence expression was. There was no statistically significant difference in the O4-positive cells between the control group and the 15℃ OGD group. Conclusion The perfused brain slice model is effective to replicate the pathophysiology of brain injury in CPB/DHCA which can induce preOL damage that is in critical development stages of oligodendrocyte cell line, and reduce differentiation of oligodendrocyte cells and eventually leads to hypomyelination as well as cerebral white matter injury.

Citation： HUANG Junrong, ZHU Zhongqun, LIU Gang, CHEN Huiwen, FENG Linyin. White matter injury after cardiopulmonary bypass in a brain slice model of neonatal rats with perfusion. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2017, 24(4): 295-300. doi: 10.7507/1007-4848.201605007 Copy

1.	Gaynor JW. Periventricular leukomalacia following neonatal and infant cardiac surgery. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu, 2004, 7: 133-140.
2.	Kussman BD, Wypij D, Laussen PC, et al. Relationship of intraoperative cerebral oxygen saturation to neurodevelopmental outcome and brain magnetic resonance imaging at 1 year of age in infants undergoing biventricular repair. Circulation, 2010, 122(3): 245-254.
3.	Jerrell JM, Shuler CO, Tripathi A. Long-term neurodevelopmental outcomes in children and adolescents with congenital heart disease. Prim Care Companion CNS Disord, 2015, 17(5). doi: 10.4088/PCC.15m01842. .
4.	Korotcova L, Kumar S, Agematsu K, et al. Prolonged white matter inflammation after cardiopulmonary bypass and circulatory arrest in a juvenile porcine model. Ann Thorac Surg, 2015, 100(3): 1030-1037.
5.	Pastuszko P, Schears GJ, Greeley WJ, et al. Granulocyte colony stimulating factor reduces brain injury in a cardiopulmonary bypass-circulatory arrest model of ischemia in a newborn piglet. Neurochem Res, 2014, 39(11): 2085-2092.
6.	Ishibashi N, Scafidi J, Murata A, et al. White matter protection in congenital heart surgery. Circulation, 2012, 125(7): 859-871.
7.	Agematsu K, Korotcova L, Morton PD, et al. Hypoxia diminishes the protective function of white-matter astrocytes in the developing brain. J Thorac Cardiovasc Surg, 2016, 151(1): 265-272.
8.	Agematsu K, Korotcova L, Scafidi J, et al. Effects of preoperative hypoxia on white matter injury associated with cardiopulmonary bypass in a rodent hypoxic and brain slice model. Pediatr Res, 2014, 75(5): 618-625.
9.	Murata A, Agematsu K, Korotcova L, et al., Rodent brain slice model for the study of white matter injury. J Thorac Cardiovasc Surg, 2013, 146(6): 1526-1533.e1.
10.	Allard J, Paci P, Vander Elst L, et al. Regional and time-dependent neuroprotective effect of hypothermia following oxygen-glucose deprivation. Hippocampus, 2015, 25(2): 197-207.
11.	Ziemka-Nałęcz M, Stanaszek L, Zalewska T. Oxygen-glucose deprivation promotes gliogenesis and microglia activation in organotypic hippocampal slice culture: involvement of metalloproteinases. Acta Neurobiol Exp (Wars), 2013, 73(1): 130-142.
12.	Huang Y, Williams JC, Johnson SM. Brain slice on a chip: opportunities and challenges of applying microfluidic technology to intact tissues. Lab Chip, 2012, 12(12): 2103-2117.
13.	Queval A, Ghattamaneni NR, Perrault CM, et al. Chamber and microfluidic probe for microperfusion of organotypic brain slices. Lab Chip, 2010, 10(3): 326-334.
14.	Hájos N, Mody I. Establishing a physiological environment for visualized in vitro brain slice recordings by increasing oxygen supply and modifying aCSF content. J Neurosci Methods, 2009, 183(2): 107-113.
15.	Ishibashi N, Iwata Y, Okamura T, et al., Differential neuronal vulnerability varies according to specific cardiopulmonary bypass insult in a porcine survival model. J Thorac Cardiovasc Surg, 2010, 140(6): 1408-1415.
16.	Anttila V, Hagino I, Zurakowski D, et al. Higher bypass temperature correlates with increased white cell activation in the cerebral microcirculation. J Thorac Cardiovasc Surg, 2004, 127(6): 1781-1788.
17.	Back SA, Luo NL, Borenstein NS, et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci, 2001, 21(4): 1302-1312.
18.	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.
19.	Billiards SS, Haynes RL, Folkerth RD, et al. Myelin abnormalities without oligodendrocyte loss in periventricular leukomalacia. Brain Pathol, 2008, 18(2): 153-163.
20.	Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol, 2009, 8(1): 110-124.

1. Gaynor JW. Periventricular leukomalacia following neonatal and infant cardiac surgery. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu, 2004, 7: 133-140.
2. Kussman BD, Wypij D, Laussen PC, et al. Relationship of intraoperative cerebral oxygen saturation to neurodevelopmental outcome and brain magnetic resonance imaging at 1 year of age in infants undergoing biventricular repair. Circulation, 2010, 122(3): 245-254.
3. Jerrell JM, Shuler CO, Tripathi A. Long-term neurodevelopmental outcomes in children and adolescents with congenital heart disease. Prim Care Companion CNS Disord, 2015, 17(5). doi: 10.4088/PCC.15m01842. .
4. Korotcova L, Kumar S, Agematsu K, et al. Prolonged white matter inflammation after cardiopulmonary bypass and circulatory arrest in a juvenile porcine model. Ann Thorac Surg, 2015, 100(3): 1030-1037.
5. Pastuszko P, Schears GJ, Greeley WJ, et al. Granulocyte colony stimulating factor reduces brain injury in a cardiopulmonary bypass-circulatory arrest model of ischemia in a newborn piglet. Neurochem Res, 2014, 39(11): 2085-2092.
6. Ishibashi N, Scafidi J, Murata A, et al. White matter protection in congenital heart surgery. Circulation, 2012, 125(7): 859-871.
7. Agematsu K, Korotcova L, Morton PD, et al. Hypoxia diminishes the protective function of white-matter astrocytes in the developing brain. J Thorac Cardiovasc Surg, 2016, 151(1): 265-272.
8. Agematsu K, Korotcova L, Scafidi J, et al. Effects of preoperative hypoxia on white matter injury associated with cardiopulmonary bypass in a rodent hypoxic and brain slice model. Pediatr Res, 2014, 75(5): 618-625.
9. Murata A, Agematsu K, Korotcova L, et al., Rodent brain slice model for the study of white matter injury. J Thorac Cardiovasc Surg, 2013, 146(6): 1526-1533.e1.
10. Allard J, Paci P, Vander Elst L, et al. Regional and time-dependent neuroprotective effect of hypothermia following oxygen-glucose deprivation. Hippocampus, 2015, 25(2): 197-207.
11. Ziemka-Nałęcz M, Stanaszek L, Zalewska T. Oxygen-glucose deprivation promotes gliogenesis and microglia activation in organotypic hippocampal slice culture: involvement of metalloproteinases. Acta Neurobiol Exp (Wars), 2013, 73(1): 130-142.
12. Huang Y, Williams JC, Johnson SM. Brain slice on a chip: opportunities and challenges of applying microfluidic technology to intact tissues. Lab Chip, 2012, 12(12): 2103-2117.
13. Queval A, Ghattamaneni NR, Perrault CM, et al. Chamber and microfluidic probe for microperfusion of organotypic brain slices. Lab Chip, 2010, 10(3): 326-334.
14. Hájos N, Mody I. Establishing a physiological environment for visualized in vitro brain slice recordings by increasing oxygen supply and modifying aCSF content. J Neurosci Methods, 2009, 183(2): 107-113.
15. Ishibashi N, Iwata Y, Okamura T, et al., Differential neuronal vulnerability varies according to specific cardiopulmonary bypass insult in a porcine survival model. J Thorac Cardiovasc Surg, 2010, 140(6): 1408-1415.
16. Anttila V, Hagino I, Zurakowski D, et al. Higher bypass temperature correlates with increased white cell activation in the cerebral microcirculation. J Thorac Cardiovasc Surg, 2004, 127(6): 1781-1788.
17. Back SA, Luo NL, Borenstein NS, et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci, 2001, 21(4): 1302-1312.
18. 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.
19. Billiards SS, Haynes RL, Folkerth RD, et al. Myelin abnormalities without oligodendrocyte loss in periventricular leukomalacia. Brain Pathol, 2008, 18(2): 153-163.
20. Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol, 2009, 8(1): 110-124.

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