Abstract
BackgroundInhaled nitric oxide (iNO) is one of the most promising therapies used in neonates. However, little information is known about its impact on the developing brain submitted to excitotoxic challenge.Methodology/Principal FindingsWe investigated here the effect of iNO in a neonatal model of excitotoxic brain lesions. Rat pups and their dams were placed in a chamber containing 20 ppm NO during the first week of life. At postnatal day (P)5, rat pups were submitted to intracranial injection of glutamate agonists. At P10, rat pups exposed to iNO exhibited a significant decrease of lesion size in both the white matter and cortical plate compared to controls. Microglia activation and astrogliosis were found significantly decreased in NO-exposed animals. This neuroprotective effect was associated with a significant decrease of several glutamate receptor subunits expression at P5. iNO was associated with an early (P1) downregulation of pCREB/pAkt expression and induced an increase in pAkt protein concentration in response to excitotoxic challenge (P7).ConclusionThis study is the first describe and investigate the neuroprotective effect of iNO in neonatal excitotoxic-induced brain damage. This effect may be mediated through CREB pathway and subsequent modulation of glutamate receptor subunits expression.
Highlights
Brain injury in the premature infant is a problem of major importance
This study is the first describe and investigate the neuroprotective effect of Inhaled nitric oxide (iNO) in neonatal excitotoxic-induced brain damage. This effect may be mediated through cAMP Response Element Binding Protein (CREB) pathway and subsequent modulation of glutamate receptor subunits expression
Effect of iNO on brain lesion induced by intracranial injection of various glutamate agonists
Summary
10 percent of the survivors from very preterm birth later exhibit cerebral palsy (CP) and an additional 25 to 50 percent exhibit cognitive, attentional, and/or behavioral deficits These neurologic disabilities observed relate in considerable part to cerebral white matter injury [1]. Factors that seem involved in the pathophysiology of CP in these models include hypoxia and ischemia, infection and inflammation, excitotoxicity, accumulation of reactive oxygen species, and deficiencies in growth factors [2,3]. These factors seem to act in combination to cause damage to the developing white matter. Little information is known about its impact on the developing brain submitted to excitotoxic challenge
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