Abstract
Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention that could be administered as an alternative to cooling in cases of perinatal hypoxia-ischemia (HI). In the current study we hypothesized that RIPostC in the piglet model of birth asphyxia confers protection by reducing nitrosative stress and subsequent nitrotyrosine formation, as well as having an effect on glial immunoreactivity. Postnatal day 1 (P1) piglets underwent HI brain injury and were randomised to HI (control) or HI + RIPostC. Immunohistochemistry assessment 48 hours after HI revealed a significant decrease in brain nitrotyrosine deposits in the RIPostC-treated group (p = 0.02). This was accompanied by a significant increase in eNOS expression (p < 0.0001) and decrease in iNOS (p = 0.010), with no alteration in nNOS activity. Interestingly, RIPostC treatment was associated with a significant increase in GFAP (p = 0.002) and IBA1 (p = 0.006), markers of astroglial and microglial activity, respectively. The current study demonstrates a beneficial effect of RIPostC therapy in the preclinical piglet model of neonatal asphyxia, which appears to be mediated by modulation of nitrosative stress, despite glial activation.
Highlights
Hypoxic-ischemic encephalopathy (HIE) occurs after intrapartum asphyxia [1] and is responsible for 23% of neonatal deaths worldwide [2]
Nitrotyrosine deposits are present after perinatal asphyxia [23] and positive staining of the neuronal cytoplasm is a marker of cell damage, oxidative stress, and inflammation that correlates with severity of brain damage and poor outcomes [38]
Little to no nitrotyrosine deposits are found in healthy organs [39] or in an infant human case control of spinal muscular atrophy without HIE [23]
Summary
Hypoxic-ischemic encephalopathy (HIE) occurs after intrapartum asphyxia [1] and is responsible for 23% of neonatal deaths worldwide [2]. Hypothermia therapy has been established as standard clinical care for infants diagnosed with moderate to severe neonatal encephalopathy (NE) in the developed world. Cooling started within six hours of birth ameliorates secondary energy failure and cell death, significantly lowering the risk of death and severe disability in treated infants [3, 4]. In the UK, 45% of infants have adverse outcome after HIE despite cooling, with 25% dying and 20% developing cognitive cerebral palsy and other life-long debilitating conditions [5]. Adjunct therapies for hypothermia are needed to enhance overall protection and improve outcome. In low and mid resource settings where cooling is not routine, alternative therapies may be important
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