Mild intermittent hypoxemia in neonatal mice causes permanent neurofunctional deficit and white matter hypomyelination

Juliano, Courtney; Sosunov, Sergey A.; Niatsetskaya, Zoya; Isler, Joseph; Utkina-Sosunova, Irina; Jang, Isaac; Ratner, Veniamin; Ten, Vadim S.

doi:10.1016/j.expneurol.2014.11.010

Cited by 50 publications

(46 citation statements)

References 38 publications

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“…Our results are consistent with those of Juliano, et al (11) and Cai, et al (12) in mice who found biochemical and electron microscopy evidence for impaired axonal myelination. Another study in rats, using DTI, studied the combination of hyperoxia and mild IH reported transient adverse MRI changes in RD, AD and FA white matter regions that did not persist beyond P14 (13).…”

Section: Discussionsupporting

confidence: 94%

“…On average for each hour, SATS were below 90% for 5 minutes and below 85% for 4.5 minutes. This level of hypoxia exposure compares favorably with the data reported by Juliano, et al (11) for human premature infants born at 24–27 weeks gestation over the first 6 weeks of life. Exposure to RA was accomplished in identical chambers where air flow, noise, and pressure changes mimicked those during IH exposure, except that an intermittent influx of room air was used instead of nitrogen.…”

Section: Methodssupporting

confidence: 89%

“…For the exposure to IH, a computerized system (Biospherix) was used to provide a customized pattern that has been previously described (14) to closely approximate what is experienced by premature infants with apnea and periodic breathing (11). The system was programmed to provide 6 decreases in chamber oxygen concentration (CHO 2 ) per hour alternating with an hour of normoxia (Figure 1a).…”

Section: Methodsmentioning

confidence: 99%

“…However, two studies in mice have indicated that early postnatal exposure to relatively mild IH report biochemical and electron microscopy evidence for a decrease in myelination possibly due to impaired myelinogenesis, impaired axonal maturation, short and long term neuro-functional deficits and electrophysiological changes that may form the basis for more long-term neurobehavioral sequelae (11, 12). An additional study in rats examined the effects of postnatal hyperoxia combined with mild IH on retinopathy of prematurity and reported transient MRI changes in radial (RD) and axial (AD) diffusivity and fractional anisotropy (FA) in certain white matter regions that did not persist beyond P14 (13).…”

Section: Introductionmentioning

confidence: 99%

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Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism

et al. 2017

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BackgroundPreterm infants are frequently exposed to intermittent hypoxia (IH) associated with apnea and periodic breathing that may result in inflammation and brain injury that later manifests as cognitive and executive function deficits. We used a rodent model to determine whether early postnatal exposure to IH would result in inflammation and brain injury.MethodsRat pups were exposed to IH from P2–P12. Control animals were exposed to room air. Cytokines were analyzed in plasma and brain tissue at P13 and P18. At P20–P22, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were performed.ResultsPups exposed to IH had increased plasma Gro/CXCL1 and cerebellar IFN-γ and IL-1β at P13, and brainstem enolase at P18. DTI showed a decrease in FA and AD in the corpus callosum (CC) and cingulate gyrus and an increase in RD in the CC. MRS revealed decreases in NAA/Cho, Cr, Tau/Cr and Gly/Cr and increases in TCho and GPC in the brainstem and decreases in NAA/Cho in the hippocampus.ConclusionsWe conclude that early postnatal exposure to IH, similar in magnitude experienced in human preterm infants, is associated with evidence for pro-inflammatory changes, decreases in white matter integrity, and metabolic changes consistent with hypoxia.

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Section: Discussionsupporting

confidence: 94%

Section: Methodssupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism

et al. 2017

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“…It has been shown that perinatal oxidative stress in the mouse causes a long-term decrease in oligodendrocyte number and impairs myelination . Intermittent hypoxemia episodes reproduced in neonatal mice were shown to replicate the phenotype of non-cystic WM injury [34]. Purines, especially eATP and its metabolite Ado are potent mediators of inflammation [35].…”

Section: Evaluation Of the Hypothesismentioning

confidence: 99%

Why do premature newborn infants display elevated blood adenosine levels?

et al. 2016

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Link to publicationCitation for published version (APA): Panfoli, I., Cassanello, M., Bruschettini, M., Colella, M., Cerone, R., Ravera, S., ... Ramenghi, L. (2016). Why do premature newborn infants display elevated blood adenosine levels ? Medical Hypotheses, 90, 53-56. DOI: 10.1016/j.mehy.2016 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. WHY DO PREMATURE NEWBORN INFANTS DISPLAY ELEVATED BLOOD ADENOSINE LEVELS?Isabella ABSTRACTOur preliminary data show high levels of adenosine in the blood of very low birth weight (VLBW) infants, positively correlating to their prematurity (i.e. body weight class). This prompted us to look for a mechanism promoting such impressive adenosine increase. We hypothesized a correlation with oxygen challenge. In fact, it is recognized that either oxygen lack or its excess contribute to the pathogenesis of the injuries of prematurity, such as retinopathy (ROP) and periventricular white matter lesions (PWMI). The optimal concentration of oxygen for resuscitation of VLBW infants is currently under revision.We propose that the elevated adenosine blood concentrations of VLBW infants recognizes two sources. The first could be its activity-dependent release from unmyelinated brain axons.

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Key roles of glial cells in the encephalopathy of prematurity

Van Steenwinckel,

Bokobza,

Laforge

et al. 2023

Glia

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Across the globe, approximately one in 10 babies are born preterm, that is, before 37 weeks of a typical 40 weeks of gestation. Up to 50% of preterm born infants develop brain injury, encephalopathy of prematurity (EoP), that substantially increases their risk for developing lifelong defects in motor skills and domains of learning, memory, emotional regulation, and cognition. We are still severely limited in our abilities to prevent or predict preterm birth. No longer just the “support cells,” we now clearly understand that during development glia are key for building a healthy brain. Glial dysfunction is a hallmark of EoP, notably, microgliosis, astrogliosis, and oligodendrocyte injury. Our knowledge of glial biology during development is exponentially expanding but hasn't developed sufficiently for development of effective neuroregenerative therapies. This review summarizes the current state of knowledge for the roles of glia in infants with EoP and its animal models, and a description of known glial‐cell interactions in the context of EoP, such as the roles for border‐associated macrophages. The field of perinatal medicine is relatively small but has worked passionately to improve our understanding of the etiology of EoP coupled with detailed mechanistic studies of pre‐clinical and human cohorts. A primary finding from this review is that expanding our collaborations with computational biologists, working together to understand the complexity of glial subtypes, glial maturation, and the impacts of EoP in the short and long term will be key to the design of therapies that improve outcomes.

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Mild intermittent hypoxemia in neonatal mice causes permanent neurofunctional deficit and white matter hypomyelination

Cited by 50 publications

References 38 publications

Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism

Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism

Why do premature newborn infants display elevated blood adenosine levels?

Key roles of glial cells in the encephalopathy of prematurity

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