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Introduction: High oxygen concentrations have been identified as one factor contributing to the pathogenesis of the retinopathia of prematurity, chronic lung disease of the preterm infant and preterm brain injury. Preterm infants also show short- and long-term alterations of the endocrine system. If hyperoxia is one pathogenetic factor has not been investigated yet. With regard to the high prevalence of neurodevelopmental impairments in preterm infants, the hypothalamus-pituitary-thyroid (HPT) axis, the hypothalamus-pituitary-adrenal (HPA) axis and the hypothalamus-pituitary-somatotropic (HPS) axis are of special interest due to their important role in neurodevelopment. Objective: The aim of this study was to investigate the effect of hyperoxia on the endocrine system in the neonatal rat by analyzing the activities of the HPT, HPA and HPS axes, respectively. Methods: Three-days old Wistar rats were exposed to hyperoxia (oxygen 80%, 48 h). On postnatal day 5 (P5) and P11, transcript levels of thyroid-stimulating hormone (TSH), proopiomelanocortin and growth hormone (GH) were analyzed in pituitary sections by in situ hybridization. Serologic quantification of TSH and thyroxine (T4), adrenocorticotropic hormone and GH were performed by Multiplex analysis and Enzyme-linked Immunosorbent Assay. Results: At P5, significantly lower GH levels were observed in pituitaries (mRNA) and in sera of rats exposed to hyperoxia. Serum TSH was significantly elevated without changes in T4. Conclusion: This is the first study demonstrating transient endocrine alterations following hyperoxia in the neonatal rat making oxygen a possible contributor to the pathogenesis of endocrine alterations seen in preterm infants. Considering the detrimental multi-organ effects of hyperoxia on the immature organism, a rational use of therapeutic oxygen in the treatrnent of preterm infants is of utmost importance.

Additional file 1. Additional figures and tables.

Background: Microglia are key mediators of inflammation during perinatal brain injury. As shown experimentally after inflammation-sensitized hypoxic ischemic (HI) brain injury, microglia are activated into a pro-inflammatory status 24 h after HI involving the NLRP3 inflammasome pathway. The chemokine (C-X-C motif) ligand 1 (CXCL1), and its cognate receptor, CXCR2, have been shown to be involved in NLRP3 activation, although their specific role during perinatal brain injury remains unclear. In this study we investigated the involvement of CXCL1/CXCR2 in brain tissue and microglia and brain tissue after inflammation-sensitized HI brain injury of newborn rats. Methods: Seven-day old Wistar rat pups were either injected with vehicle (NaCl 0.9%) or E. coli lipopolysaccharide (LPS), followed by left carotid ligation combined with global hypoxia (8% O₂ for 50 min). Pups were randomized into four different treatment groups: (1) Sham group (n = 21), (2) LPS only group (n = 20), (3) Veh/HI group (n = 39), and (4) LPS/HI group (n = 42). Twenty-four hours post hypoxia transcriptome and gene expression analysis were performed on ex vivo isolated microglia cells in our model. Additionally protein expression was analyzed in different brain regions at the same time point. Results: Transcriptome analyses showed a significant microglial upregulation of the chemokine CXCL1 and its receptor CXCR2 in the LPS/HI group compared with the other groups. Gene expression analysis showed a significant upregulation of CXCL1 and NLRP3 in microglia cells after inflammation-sensitized hypoxic-ischemic brain injury. Additionally, protein expression of CXCL1 was significantly upregulated in cortex of male pups from the LPS/HI group. Conclusion: These results indicate that the CXCL1/CXCR2 pathway may be involved during pro-inflammatory microglia activation following inflammation-sensitized hypoxic-ischemic brain injury in neonatal rats. This may lead to new treatment options altering CXCR2 activation early after HI brain injury. OA Förderung 2020

Introduction: Preterm infants born before 28 weeks of gestation are at high risk of neurodevelopmental impairment in later life. Cerebral white and gray matter injury is associated with adverse outcomes. High oxygen levels, often unavoidable in neonatal intensive care, have been identified as one of the main contributing factors to preterm brain injury. Thus, preventive and therapeutic strategies against hyperoxia-induced brain injury are needed. Erythropoietin (Epo) is a promising and also neuroprotective candidate due to its clinical use in infants as erythropoiesis-stimulating agent. Objective: The objective of this study was to investigate the effects of repetitive Epo treatment on the cerebral white matter and long-term motor-cognitive outcome in a neonatal rodent model of hyperoxia-induced brain injury. Methods: Three-day old Wistar rats were exposed to hyperoxia (48 h, 80% oxygen). Four doses of Epo (5,000 IU/kg body weight per day) were applied intraperitoneally from P3-P6 with the first dose at the onset of hyperoxia. Oligodendrocyte maturation and myelination were evaluated via immunohistochemistry and Western blot on P11. Motor-cognitive deficits were assessed in a battery of complex behavior tests (Open Field, Novel Object Recognition, Barnes maze) in adolescent and fully adult animals. Following behavior tests animals underwent post-mortem diffusion tensor imaging to investigate long-lasting microstructural alterations of the white matter. Results: Repetitive treatment with Epo significantly improved myelination deficits following neonatal hyperoxia at P11. Behavioral testing revealed attenuated hyperoxia-induced cognitive deficits in Epo-treated adolescent and adult rats. Conclusion: A multiple Epo dosage regimen protects the developing brain against hyperoxia-induced brain injury by improving myelination and long-term cognitive outcome. Though current clinical studies on short-term outcome of Epo-treated prematurely born children contradict our findings, long-term effects up to adulthood are still lacking. Our data support the essential need for long-term follow-up of preterm infants in current clinical trials. OA Förderung 2020

In industralisierten Ländern werden 5.5-11.4% der Kinder zu früh geboren (Geburten zwischen der 23-37 Schwangerschaftswoche). Trotz der großen Vorteile in der Geburtshilfe und der Neonatalversorgung, zeigen Frühgeborene ein erhöhtes Risiko langfristig neurologische Defizite zu entwickeln. Das unreife Gehirn ist sehr vulnerabel gegenüber verschiedenen Noxen wie der Hypoxie oder Hyperoxie. In Experimentellen Studien wurde bereits gezeigt, dass eine neonatale Hyperoxie eine Schädigung der weißen Substanz verursacht, die mit einer Degeneration der Oligodendrozyten und Hypomyelinisierung assoziiert ist. Diese korrelieren mit ultrastrukturellen Veränderungen der weißen Substanz. Obwohl das Wissen über die Pathophysiologie der perinatalen Hirnschädigung zunimmt, gibt es bis zum heutigen Zeitpunkt keine effektive Therapie. Daher untersuchten wir das therapeutische Potential des Sphingosin-1-Phosphat-Rezeptor Agonisten Fingolimod, welches sich für die Behandlung der demyeliniserenden Erkrankung multiple Sklerose bereits bewährt, in dem Modell der Hyperoxie-induzierten Hirnschädigung in vivo und in vitro. In dieser Arbeit konnte gezeigt werden, dass eine einmalige Behandlung mit FTY720 die Hyperoxie-induzierte Hypomyeliniserung sowie langfristige Veränderungen der Mikrostruktur der weißen Substanz verbessert. Außerdem wurden kognitive Dysfunktionen im Erwachsenenalter, die aus einer neonatale Hyperoxie resultieren, durch eine FTY720 Gabe reduziert. Analysen der zugrunde liegenden Mechanismen ergaben, dass eine neonatale Hyperoxie zu einer erhöhten Freisetzung von pro-inflammatorischen Zytokinen wie TNF-α und IL-1β, sowie zu einer Aktivierung von Iba1 markierten Mikroglia führt, welche durch eine einmalige Injektion von FTY720 auf Normalniveau minimiert wurden. Zudem wurde die Hyperoxie-induzierte erhöhte Expression der oxidativen Stressparameter durch die FTY720 Behandlung verbessert. Diese Ergebnisse suggerieren, dass die protektive Wirkung von FTY720 in Richtung Myelinisierung und langfristigem Verhalten auf seine anti-inflammatorische und anti-oxidative Wirkung zurückgeführt werden kann. Weitere in vitro Analysen mit einem selektiven S1P1-Rezeptor Antagonisten zeigten, dass die protektive Wirkung von FTY720 durch eine direkte Interaktion mit Oligodendrozyten reguliert wird. Auf Grund dieser Ergebnisse, scheint FTY720 ein vielversprechender Kandidat für die Behandlung von Frühgeboren zu sein, die ein erhöhtes Risiko für die Entwicklung einer Schädigung der weißen Substanz zeigen., 5.5-11.4% of all live births in industrialised countries are preterm born infants (born between gestational ages of 23-37 week). Despite major advances in obstetrics and neonatal intensive care, preterm born infants are at high risk to develop neurological deficits in later life. The immature brain is very susceptible to injury caused by different environmental factors such as hypoxia or hyperoxia. Experimental studies demonstrated that neonatal hyperoxia induces white matter injury, which is associated with oligodendroglial cell death, hypomyelination and with ultrastructural changes of the developing white matter. Despite increasing knowledge about the pathophysiology of perinatal brain injury, up to now there is no effective therapy. Therefore, we investigated the therapeutic potential of the sphingosine-1-phosphate (S1P) receptor agonist FTY720, which is already approved for the treatment of the demyelinating disease multiple sclerosis, in a model of hyperoxia-induced brain injury in vivo and in vitro. Herein we demonstrated that a single dose of FTY720 improved hyperoxia-induced hypomyelination and long-term microstructural alterations in the white matter. Furthermore, neonatal hyperoxia resulted in long-lasting impairment of cognitive function in adulthood, which was reduced by FTY720 treatment. Analysis of underlying mechanisms revealed that neonatal hyperoxia caused an increased release of pro-inflammatory cytokines, such as TNF-α and IL-1β, and induced an increased activation of Iba1-labeled microglia, which were normalized by FTY720 administration. Moreover, hyperoxia-induced upregulation of oxidative stress parameters was ameliorated by FTY720 treatment. These results suggest that FTY720´s protective effects in terms of myelination and long-term functional improvement may be attributed to its anti-inflammatory and anti-oxidative effects. Further in vitro analysis with a selective S1P1-receptor antagonist demonstrated that FTY720 also mediates its protective effect through a direct interaction with the S1P1 receptor on oligodendrocytes. With these findings, FTY720 has been identified as a promising candidate for treating preterm babies with an increased risk for the development of white matter injury.

Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix. OA Förderung 2014