Nitric Oxide Production in the Striatum and Cerebellum of a Rat Model of Preterm Global Perinatal Asphyxia

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12640-017-9700-6) contains supplementary material, which is available to authorized users.

Deep hypothermia prevents striatal alterations produced by perinatal asphyxia: Implications for the prevention of dyskinesia and psychosis

“…This could reduce even further the inhibitory capacity of the striatum and increase the effect of dopamine in the structure worsening the symptoms of dyskinesia and psychosis. This point of view, is supported by previous works where PA produced an increase in the number of cells labeled using antibodies against neuronal nitric oxide synthase and cyclic guanosine monophosphate in the striatum (Barkhuizen, Van De Berg, et al, 2017). This is consistent with previous related research in the same model of asphyxia, where an increased striatal cGMP production was found at P10 (Loidl et al, 1998).…”

A Preterm Rat Model for Immunonutritional Studies

“…In this context, studies using preterm animal models could be useful to increase our knowledge of the state of prematurity, and to explore new insights in the field of nutritional interventions in preterm neonates in order to counteract immunodeficiencies. To date, there are few preterm models in rodents, and most of these are only focused on the impact of prematurity on brain [16] or lung development [17] or NEC [18,19], but none study immune system maturation, which is especially affected in prematurity. To our knowledge, the only premature animal model studying immunity was performed in pigs [20].…”

Free Radicals and Neonatal Brain Injury: From Underlying Pathophysiology to Antioxidant Treatment Perspectives

“…Following an acute ischemic insult in term infants, the deep grey nuclei are commonly involved [ 11 ]. This is ascribable to the presence of NOS-expressing striatal neurons, that are relatively resistant to hypoxia-ischemia injury and glutamate excitotoxicity [ 18 ] and, in response to the ischemic event, produce excessive amounts of RNS [ 19 ], exerting extensive nitrosative effects on the adjacent neural structures and thus further contributing to their damage.…”