Abstract
Hypoxic ischemic (HI) injury in neonates may have devastating, long-term consequences. Recently completed clinical trials in HI neonates indicate that hypothermia within 6 h of birth results in modest improvement in the combined outcome of death or severe disability. The aim of this study was to investigate the effects of combining hypothermia and N-acetylcysteine (NAC) on brain injury, neonatal reflexes and myelination after neonatal HI. Seven-day-old rats were subjected to right common carotid artery ligation and hypoxia (8% oxygen) for 2 h. Systemic hypothermia (30 + 0.5°C) was induced immediately after the period of HI and was maintained for 2 h. NAC (50 mg/kg) was administered by intraperitoneal injection daily until sacrifice. Brain infarct volumes were significantly reduced at 48 h post-HI in the hypothermia plus NAC group (21.5 ± 3.84 mm3) compared with vehicle (240.85 ± 4.08 mm3). Neonatal reflexes were also significantly improved by combination therapy at days 1 and 7. There was a significant loss of right hemispheric brain volume in the untreated group at 2 and 4 wk after HI insult. Brain volumes were preserved in hypothermia plus NAC group and were not significantly different when compared with the sham group. Similarly, increased myelin expression was seen in brain sections from hypothermia plus NAC group, when stained for Luxol Fast Blue (LFB), Myelin Basic Protein (MBP) and Proteolipid protein (PLP). These results indicate that hypothermia plus NAC combination therapy improves infarct volume, myelin expression and functional outcomes after focal HI injury.
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Abbreviations
- HI:
-
hypoxia-ischemia
- LFB:
-
luxol fast blue
- MBP:
-
myelin basic protein
- NAC:
-
N-acetylcysteine
- PLP:
-
proteolipid protein
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Acknowledgements
The authors thank Ms. Joyce Bryan and Ms. Hope Terry for their help in arrangement of animals and chemicals. We also thank Ms. Carrie Barnes for providing histopathological support. We thank the Children's Research Institute for providing the laboratory space and the animal facility for carrying out the work.
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This work was supported by grants (NS-40144, NS-22576, NS-34741, NS-37766, and NS-40810) from the National Institutes of Health (NIH).
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Jatana, M., Singh, I., Singh, A. et al. Combination of Systemic Hypothermia and N-acetylcysteine Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats. Pediatr Res 59, 684–689 (2006). https://doi.org/10.1203/01.pdr.0000215045.91122.44
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DOI: https://doi.org/10.1203/01.pdr.0000215045.91122.44
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