Abstract
Prematurely born infants are highly susceptible to various environmental factors, such as inflammation, drug exposure, and also high environmental oxygen concentrations. Hyperoxia induces perinatal brain injury affecting white and gray matter development. It is well known that mitogen-activated protein kinase signaling is involved in cell survival, proliferation, and differentiation. Therefore, we aim to elucidate cell-specific responses of neuronal overexpression of the small GTPase Ras on hyperoxia-mediated brain injury. Six-day-old (P6) synRas mice (neuronal Ras overexpression under the synapsin promoter) or wild-type littermates were kept under hyperoxia (80% oxygen) or room air (21% oxygen) for 24 h. Apoptosis was analyzed by Western blot of cleaved Caspase-3 and neuronal and oligodendrocyte degeneration via immunohistochemistry. Short-term differentiation capacity of oligodendrocytes was assessed by quantification of myelin basic protein expression at P11. Long-lasting changes of hyperoxia-induced alteration of myelin structures were evaluated via transmission electron microscopy in young adult animals (P42). Western blot analysis of active Caspase-3 demonstrates a significant upregulation in wild-type littermates exposed to hyperoxia whereas synRas mice did not show any marked alteration of cleaved Caspase-3 protein levels. Immunohistochemistry revealed a protective effect of neuronal Ras overexpression on neuron and oligodendrocyte survival. Hyperoxia-induced hypomyelination in wild-type littermates was restored in synRas mice. These short-term protective effects through promotion of neuronal survival translated into long-lasting improvement of ultrastructural alterations of myelin sheaths in mice with neuronal overexpression of Ras compared with hyperoxic wild-type mice. Our data suggest that transgenic increase of neuronal Ras activity in the immature brain results in secondary protection of oligodendrocytes from hyperoxia-induced white matter brain injury.
Highlights
Within the last decade, mortality of very preterm infants and critically ill-term born infants has decreased by 25% due to major advances in obstetrics and neonatal intensive care [1]
Given the important role of mitogen-activated protein kinase (MAPK) signaling in oxygen-induced preterm brain injury and the fact that neuronal activity modulates oligodendrocyte development, we aimed to elucidate the impact of a transgenic overexpression of constitutively activated Ras in neurons on hyperoxia-induced oligodendrocyte degeneration, myelination, and long-lasting ultrastructural alterations of the white matter (WM)
Neonatal Hyperoxia-Induced Apoptosis Is Decreased by Neuronal Ras Activation
Summary
Mortality of very preterm infants and critically ill-term born infants has decreased by 25% due to major advances in obstetrics and neonatal intensive care [1]. Even in the absence of severe intracranial pathology such as intraventricular hemorrhage or periventricular leukomalacia affecting 10% of very preterm born children [5], diffuse white matter (WM) injury and reduction of cortical gray matter volume are observed in most survivors. This is often associated with cognitive impairment and behavioral problems such as attention deficit disorder, autism, and development of psychiatric disease in later life [6,7,8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
