Funda Tuzun

Erythropoietin in neonatal brain protection: The past, the present and the future

Over the last decade, neuroprotective effects of erythropoietin (Epo) and its underlying mechanisms in terms of signal transduction pathways have been defined and there is a growing interest in the potential therapeutic use of Epo for neuroprotection. Several mechanisms by which Epo provides neuroprotection are recognized. In this review, we focused on the neuroprotective mechanisms of Epo and provide a short overview on both experimental and clinical studies, testing Epo as a neuroprotective agent in the neonatal brain injury, and the safety concerns with the clinical use of Epo treatment in neonates.

Maternal omega-3 fatty acid supplementation protects against lipopolysaccharide-induced white matter injury in the neonatal rat brain

Objectives: Periventricular leukomalacia (PVL) is the predominant form of brain injury in premature infants, and no specific treatment currently exists for this condition. We have evaluated whether maternal omega-3 fatty acid (ω3 FA) treatment reduces endotoxin-induced PVL in the developing rat brain. Methods: Wistar rats with dated pregnancies were fed a standard diet or a diet enriched in ω3 FA (70% docosahexaenoic acid + 30% eicosapentaenoic acid mixture) during gestation. Intraperitoneal injection of lipopolysaccharide (LPS) was administered consecutively on the 18th and 19th embryonic days to establish the endotoxin-induced PVL rat model. The animals were divided into four groups: (i) control, (ii) PVL, (iii) PVL+low-dose ω3 FA and (iv) PVL+high-dose ω3 FA. At day P7, apoptosis and hypomyelination in periventricular white matter were evaluated by immunohistochemical assessments. Results: High-dose maternal ω3 FA treatment reduced brain weight loss. Maternal ω3 FA treatment given either in low or high doses greatly decreased caspase-3 immunoreactivity and increased myelin basic protein immunoreactivity, indicating a decrease in apoptosis and hypomyelination. Conclusion: Considering that no specific treatment is available for PVL, maternal ω3 FA supplementation may provide a nutritional strategy to limit periventricular white matter damage caused by infections during pregnancy.

Genetic basis of apnoea of prematurity and caffeine treatment response: role of adenosine receptor polymorphisms: genetic basis of apnoea of prematurity.

Aim:  Caffeine treatment reduces the frequency of apnoea of prematurity (AOP) and eliminates the need for mechanical ventilation by acting as a nonspecific inhibitor of adenosine A1 and adenosine 2A receptors. Patients with AOP have demonstrated variant responses to caffeine therapy. We proposed to investigate the role of A1 and 2A polymorphisms in the development of AOP and individual differences in caffeine response. Secondly, we aimed to determine whether these polymorphisms have any effect on bronchopulmonary dysplasia (BPD) development.

Impact of volume guarantee on synchronized ventilation in preterm infants: a randomized controlled trial

PurposeThe aim of this randomized controlled trial was to assess whether the addition of volume guarantee (VG) to triggered ventilation decreases the duration of ventilation in very low birth weight (VLBW) infants with respiratory distress syndrome (RDS).MethodsInfants were randomized into two groups to initially receive either assist/control (A/C) or A/C plus VG ventilation and then weaned with synchronized intermittent mandatory ventilation (SIMV) or SIMV plus VG.ResultsForty-five infants were included in the study. The demographic and clinical characteristics, values of tidal volume (VT), peak inspiratory pressure (PIP), fraction of inspired oxygen, carbon dioxide tension, and pH were similar for all participating infants initially. During the follow-up, the VT levels were more stable, and the PIP levels were significantly decreasing in the VG group. Although the duration of ventilation was shorter in the VG group, this trend was not statistically significant. The incidences of death and bronchopulmonary dysplasia (BPD) were not significantly different, but the combined outcome of death or BPD was lower in the VG group. Although the VG group experienced less frequent BPD, periventricular leukomalacia, and intraventricular hemorrhage, these differences were not statistically different.ConclusionThe VG option, when combined with A/C (in the acute phase of RDS) and SIMV (in the weaning), reduced VT variability, and may have shortened the duration of ventilation in VLBW infants. Overall mortality and BPD rates did not change, but their combined outcome was significantly improved in infants treated with VG modes as compared to those treated with synchronized pressure-limited modes alone.

Maternal prenatal omega-3 fatty acid supplementation attenuates hyperoxia-induced apoptosis in the developing rat brain.

Supraphysiologic amounts of oxygen negatively influences brain maturation and development. The aim of the present study was to evaluate whether maternal ω‐3 long‐chain polyunsaturated fatty acid (ω‐3 FA) supplementation during pregnancy protects the developing brain against hyperoxic injury. Thirty‐six rat pups from six different dams were divided into six groups according to the diet modifications and hyperoxia exposure. The groups were: a control group (standard diet + room air), a hyperoxia group (standard diet + 80% O2 exposure), a hyperoxia + high‐dose ω‐3 FA‐supplemented group, a hyperoxia + low‐dose ω‐3 FA‐supplemented group, a room air + low‐dose ω‐3 FA‐supplemented + group, and a room air + high dose ω‐3 FA‐supplemented group. The ω‐3 FAs were supplemented as a mixture of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from the second day of pregnancy until birth. Rat pups in the hyperoxic groups were exposed to 80% oxygen from birth until postnatal day 5 (P5). At P5, all animals were sacrificed. Neuronal cell death and apoptosis were evaluated by cell count, TUNEL, and active Caspase‐3 immunohistochemistry. Histopathological examination showed that maternally ω‐3 FA deficient diet and postnatal hyperoxia exposure were associated with significantly lower neuronal counts and significantly higher apoptotic cell death in the selected brain regions. Ω‐3 FA treatment significantly diminished apoptosis, in the selected brain regions, in a dose dependent manner. Our results suggest that the maternal ω‐3 FA supply may protect the developing brain against hyperoxic injury.

Lipopolysaccharide-preconditioning protects against endotoxin-induced white matter injury in the neonatal rat brain.

BACKGROUND Exposing the brain to a sub-damaging stimulus can protect against a subsequent lethal insult, a phenomenon termed preconditioning. The aim of this study was to investigate the neuroprotective effect of low dose LPS (lipopolysaccharide) pretreatment in endotoxin induced periventricular leukomalacia (PVL) in a rat model. METHODS Wistar rats with dated pregnancies were allocated to 5 groups: (i) no LPS administered, intraperitoneally (i.p.) pyrogen-free saline injected (Control group), (ii) 500μg/kg LPS administrated i.p. on days 18 and 19 (PVL group), (iii) 50μg/kg LPS administrated i.p. on day 17 followed by 500μg/kg LPS i.p. on days 18 and 19 (PC-PVL group), (iv) 50μg/kg LPS administrated on day 17 (PC only), and (v) i.p. pyrogen-free saline injected control group on day 17. RESULTS LPS-preconditioning given 24h before potent LPS exposure significantly reduced the number of apoptotic cell deaths and prevented hypomyelination. Antioxidant enzyme gene expression levels (Superoxide Dismutase-SOD1, SOD2, and SOD3) were increased and Tumor Necrosis Factor (TNF)α expression levels were decreased in the PC+PVL group when compared with the PVL group. CONCLUSION Low-dose LPS given one day before potent doses of LPS reduces antepartum LPS-induced brain damage. The mechanisms of protection might involve oxidation and inflammation.

Neuroprotective effect of neotrofin in a neonatal rat model of periventricular leukomalacia.

Periventricular leukomalacia (PVL) is the dominant form of brain injury in premature infants and no specific treatment is currently available. Neotrofin, a neurotrophin agonist, has been shown to provide neuroprotection in several in vivo and in vitro studies. The aim of this study was to investigate the neuroprotective effect of neotrofin treatment after endotoxin induced PVL in a rat model. Wistar rat pups were divided into four groups as: (1) control, (2) lipopolysaccharide (LPS)-administered group, (3) LPS-administered and prenatal maternal neotrofin-treated group and (4) LPS-administered and postnatal neotrofin-treated group. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) was administered consecutively at the 18th and 19th embryonic days to establish endotoxin-induced PVL model. In the prenatal treatment group dams received an i.p. injection of neotrofin (60 mg/kg) following after the second LPS dose; and in the postnatal treatment group rat pups received i.p. injection of neotrofin (60 mg/kg) at birth. At P7, apoptosis and hypomyelination in periventricular white matter were evaluated by immunohistochemical assessments. The prenatal maternal neotrofin treatment significantly reduced the number of apoptotic cell death and greatly prevented LPS-stimulated loss of hypomyelinization. However, neotrofin treatment in the postnatal period was not as effective as intrauterine treatment. Given our results, neotrofin may be useful in reducing brain injury and possessing clinical relevance for the treatment of white matter injury in newborns.

Breast milk jaundice: effect of bacteria present in breast milk and infant feces.

Objective: Breast milk is an important source of bacteria in establishing the infantile intestinal microbiota that appear to influence the enterohepatic circulation of bilirubin. The aim of the present study was to evaluate the effect of breast milks microbiological content on the development of breast milk jaundice (BMJ). Methods: A total number of 60 mother-infant pairs enrolled to the study. Two groups were defined: BMJ group (n = 30), full-term otherwise healthy newborns who were considered BMJ; control group (n = 30), full-term healthy newborns without jaundice. All newborns in the study were exclusively breast-fed. The breast milk samples and the feces of infants were evaluated for content of selected bacterial populations (Bifidobacterium, Lactobacillus, Clostridium, Staphylococcus, and Streptococcus species) with real-time polymerase chain reaction. Results: Bifidobacterium bifidum content in the breast milk and B adolescentis, B bifidum, and B longum content in the fecal samples were higher in the control group than in the BMJ group. The milk and fecal concentrations of B bifidum were significantly correlated. The concentrations of breast milk B bifidum and fecal B bifidum, B adolescentis, and B longum were found to be negatively correlated with bilirubin levels. Conclusions: Our results suggest that Bifidobacterium species in breast milk may protect against BMJ.

Effects of neotrofin on neonatal hypoxic ischemic brain injury.

Hypoxia-ischemia is a major cause of perinatal brain injury in the newborn. Neotrofin, a neurotrophin agonist, has been shown to provide neuroprotection in several in vivo and in vitro studies. The aim of this study is to investigate the neuroprotective and ameliorating effects of neotrofin treatment after hypoxic-ischemic-injury-induced neuronal cell death, apoptosis in a neonatal hypoxic-ischemic brain injury rat model. Twenty-one seven-day-old Wistar rat pups were used in this study. The groups were: (1) a neotrofin-treated hypoxic-ischemic-group, (2) a saline-treated hypoxic-ischemic-group, and (3) a sham-operated group. Rat pups were subjected to left carotid artery occlusion followed by 2.5h of hypoxic exposure. After the hypoxic exposure, group one received an intra-peritoneal injection of neotrofin at a dose of 60mg/kg. Forty-eight hours after hypoxia, the animals were killed for histopathological evaluation to detect apoptosis and density of neurons. We found that neotrofin attenuates hypoxia-ischemia induced with neuronal density of the hippocampus, the prefrontal and the parietal cortex, and decreased apoptotic cell index in the same regions. Given our results, neotrofin may be useful in reducing brain injury; it possesses clinical relevance for the treatment of hypoxic-ischemic encephalopathy in the newborn.

Milk kinship hypothesis in light of epigenetic knowledge

BackgroundA wet nurse can be used if a baby’s natural mother is unable or chooses not to breastfeed her infant. The practice of using wet nurses is ancient and common to many cultures.Presentation of the hypothesisWe hypothesize that infants breastfeeding from the same woman may develop consanguinity even in cases in which they are not blood relatives, and that children of two individuals breastfed by the same woman may thus be at risk of several genetic diseases because of such consanguinity.Testing the hypothesisPossible evidence for the milk kinship hypothesis is to be found in the composition of breast milk, which is composed of living substances such as stem cells or substances that can affect epigenetic regulation such as microRNAs.Implications of the hypothesisIf these epigenetic modifications are heritable, marriages between individuals breastfed by the same woman may result in the same consequences as consanguineous marriages. In this paper, we attempt to assess this possibility.