Abstract
Encephalopathy due to perinatal asphyxia (PA) is a major cause of neonatal morbidity and mortality in the period around birth. Preterm infants are especially at risk for cognitive, attention and motor impairments. Therapy for this subgroup is limited to supportive care, and new targets are thus urgently needed. Post-asphyxic excitotoxicity is partially mediated by excessive nitric oxide (NO) release. The aims of this study were to determine the timing and distribution of nitric oxide (NO) production after global PA in brain areas involved in motor regulation and coordination. This study focused on the rat striatum and cerebellum, as these areas also affect cognition or attention, in addition to their central role in motor control. NO/peroxynitrite levels were determined empirically with a fluorescent marker on postnatal days P5, P8 and P12. The distributions of neuronal NO synthase (nNOS), cyclic guanosine monophosphate (cGMP), astroglia and caspase-3 were determined with immunohistochemistry. Apoptosis was additionally assessed by measuring caspase-3-like activity from P2-P15. On P5 and P8, increased intensity of NO-associated fluorescence and cGMP immunoreactivity after PA was apparent in the striatum, but not in the cerebellum. No changes in nNOS immunoreactivity or astrocytes were observed. Modest changes in caspase-3-activity were observed between groups, but the overall time course of apoptosis over the first 11 days of life was similar between PA and controls. Altogether, these data suggest that PA increases NO/peroxynitrite levels during the first week after birth within the striatum, but not within the cerebellum, without marked astrogliosis. Therapeutic benefits of interventions that reduce endogenous NO production would likely be greater during this time frame.
Highlights
Neonatal encephalopathy (NE) due to perinatal asphyxia (PA) is a common cause of morbidity and mortality in the period around birth
We conclude that PA has a greater impact on nitric oxide (NO)/peroxynitrite production in the striatum than that in the cerebellum
NO/peroxynitrite was observed throughout the cerebellum, this can be ascribed to the high neuronal nitric oxide synthase (nNOS) activity of the region
Summary
Neonatal encephalopathy (NE) due to perinatal asphyxia (PA) is a common cause of morbidity and mortality in the period around birth. PA causes both white matter injury of the developing oligodendrocytes (periventricular leukomalacia) in the sub-cortical regions and associated grey matter injury to the striatum and other basal ganglia structures, thalamus, basis pontis, brain stem and cerebellum (Cabaj et al 2012; Logitharajah et al 2009; Shah et al 2006). Injury in these infants is a combination of primary destruction after PA and secondary maturational and trophic disease (Volpe 2009a)
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