Abstract
Oxygen free radicals have been implicated in the pathogenesis of hypoxic-ischemic encephalopathy. It has previously been shown in traumatic brain injury animal models that treatment with cyclosporine reduces brain injury. However, the potential neuroprotective effect of cyclosporine in asphyxiated neonates has yet to be fully studied. Using an acute newborn swine model of hypoxia-reoxygenation, we evaluated the effects of cyclosporine on the brain, focusing on hydrogen peroxide (H2O2) production and markers of oxidative stress. Piglets (1–4 d, 1.4–2.5 kg) were block-randomized into three hypoxia-reoxygenation experimental groups (2 h hypoxia followed by 4 h reoxygenation)(n = 8/group). At 5 min after reoxygenation, piglets were given either i.v. saline (placebo, controls) or cyclosporine (2.5 or 10 mg/kg i.v. bolus) in a blinded-randomized fashion. An additional sham-operated group (n = 4) underwent no hypoxia-reoxygenation. Systemic hemodynamics, carotid arterial blood flow (transit-time ultrasonic probe), cerebral cortical H2O2 production (electrochemical sensor), cerebral tissue glutathione (ELISA) and cytosolic cytochrome-c (western blot) levels were examined. Hypoxic piglets had cardiogenic shock (cardiac output 40–48% of baseline), hypotension (mean arterial pressure 27–31 mmHg) and acidosis (pH 7.04) at the end of 2 h of hypoxia. Post-resuscitation cyclosporine treatment, particularly the higher dose (10 mg/kg), significantly attenuated the increase in cortical H2O2 concentration during reoxygenation, and was associated with lower cerebral oxidized glutathione levels. Furthermore, cyclosporine treatment significantly attenuated the increase in cortical cytochrome-c and lactate levels. Carotid blood arterial flow was similar among groups during reoxygenation. Conclusively, post-resuscitation administration of cyclosporine significantly attenuates H2O2 production and minimizes oxidative stress in newborn piglets following hypoxia-reoxygenation.
Highlights
Asphyxia contributes to over 1 million neonatal deaths per year worldwide, with hypoxic-ischemic encephalopathy (HIE) being the most common morbidity in survivors [1]
The tissue levels were significantly higher in the piglets treated with 10 than with 2.5 mg/kg (Fig. 5). This is the first study to demonstrate that post-resuscitation cyclosporine treatment attenuates (1) cortical H2O2 concentration and oxidative stress, (2) cortical lactate and cytosol cytochrome-c levels in newborn piglets during reoxygenation after a severe hypoxic insult, with no associated changes in carotid hemodynamics
These findings support the therapeutic potential of cyclosporine as a neuroprotective agent of cyclosporine in neonatal asphyxia with its attenuation of H-R induced cerebral damage
Summary
Asphyxia contributes to over 1 million neonatal deaths per year worldwide, with hypoxic-ischemic encephalopathy (HIE) being the most common morbidity in survivors [1]. HIE may result in disruption of long-term learning and memory in the survivors. These asphyxiated neonates may suffer from seizures, feeding difficulties and neuromotor impairment [3,4]. Excess production of reactive oxygen species (ROS) such as superoxide anion, hydroxyl radical, hydrogen peroxide (H2O2) and nitric oxide has been reported during ischemia-reperfusion or hypoxia-reoxygenation (H–R). These ROS and their metabolites cause cellular damage and cell death by oxidizing proteins, inducing lipid peroxidation and damaging DNA. Swelling may lead to rupture of the outer mitochondrial membrane and release of apoptotic signaling molecules such as cytochrome-c [6,7,8]
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