Nitrotyrosine in brain tissue of neonates after perinatal asphyxia

Floris Groenendaal ^1*, Harry Lammers ², Diane Smit ² and Peter G.J. Nikkels ²

¹ Wilhemina Children's Hospital/University Medical Center Utrecht, Netherlands
² University Medical Center Utrecht, Netherlands

^* To whom correspondence should be addressed. E-mail: f.groenendaal{at}umcutrecht.nl.

Accepted 2 July 2006

Abstract

Objective: the hypothesis was tested that nitrotyrosine, a reaction product of peroxynitrite and proteins, could be demonstrated in post-mortem brain tissue of fullterm neonates who suffered from severe perinatal asphyxia.

Patients and Methods: brain tissue of 22 fullterm neonates who died after severe perinatal asphyxia was examined, including cerebral cortex, basal ganglia, thalamus, hippocampus, brain stem, olives, and cerebellum. Median age at death was 52 hours. Routine histopathological examination was performed, and additional immunohistological staining with anti-CPP antibodies to detect activated caspase-3, anti- nitrotyrosine antibodies to detect nitrotyrosine, and anti-CD-68 antibodies to detect activated microglia and macrophages, which might be involved in producing nitric oxide. Staining was scored as none, weak (1-25% positive cells), moderate (26-75% positive cells) or severe (>75% positive cells).

Results: 14 patients showed global injury, 4 demonstrated mainly injury of the basal ganglia and thalamus, and 4 predominantly parasagittal brain injury. One neonate without perinatal asphyxia served as a control. In asphyxiated neonates nitrotyrosine staining of neurons was demonstrated in all neonates, mostly in thalamus (70 %) and inferior olives (68%). Total nitrotyrosine staining tended to be less in the basis of the pons and inferior olives of neonates with parasagittal brain injury. Activated caspase-3 was demonstrated mostly in thalamus (60%) and hippocampus (53%). Positive CD-68 staining was mainly present in the thalamus (70% positive).

Conclusion: nitrotyrosine was demonstrated in brain tissue of fullterm neonates, suggesting that nitric oxide toxicity might play a role in hypoxic- ischemic brain injury at term. This may be relevant for neuroprotective strategies in fullterm neonates with perinatal asphyxia.

Keywords: brain, encephalopathy, hypoxia-ischemia, nitric oxide, nitrotyrosine

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