Endoplasmic Reticulum Stress, Inflammation, and Perinatal Brain Damage

Bueter, Wolfgang; Dammann, Olaf; Leviton, Alan

doi:10.1203/pdr.0b013e3181baa083

Cited by 24 publications

(15 citation statements)

References 123 publications

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“…Misfolded proteins can be prematurely degraded, aggregate within the cell, or trigger an unfolded protein response [46–48]. It is estimated that just 10% of normal galactosylceramidase (GALC) function is necessary to avoid the neurological symptoms associated with Krabbe disease [49].…”

Section: Krabbe Diseasementioning

confidence: 99%

Disease specific therapies in leukodystrophies and leukoencephalopathies

Helman

Haren

Bonkowsky

et al. 2015

Molecular Genetics and Metabolism

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The leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or phase I/II clinical trials. This shifts the care of leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, leukodystrophy patients are in need of advanced therapies and if possible, a cure.

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Section: Krabbe Diseasementioning

confidence: 99%

Disease specific therapies in leukodystrophies and leukoencephalopathies

Helman

Haren

Bonkowsky

et al. 2015

Molecular Genetics and Metabolism

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“…(1-3) These processes, which are likely inflammatory, involve the fetus,(4) are complex,(5-10) probably persist for days if not weeks,(11) and need not be initiated by microorganisms. (12) Originally our focus was on inflammatory exposures associated with preterm labor and pre-labor premature rupture of membranes, but has since been expanded to the processes that impair fetal growth as well.…”

Section: Introductionmentioning

confidence: 99%

The ELGAN study of the brain and related disorders in extremely low gestational age newborns

O’Shea

Allred

Dammann

et al. 2009

Early Human Development

297

270

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IntroductionIn the late 1990's, we designed and laid the foundations for a study intended to advance our understanding of what contributes to brain damage in extremely low gestational age newborns (ELGANs). Our planning considered the following: A model of brain damage in the preterm newbornWe postulate that the preterm newborn is at very high risk of brain damage, for at least three reasons.First, the very processes that lead to preterm delivery can contribute to brain damage.(1-3) These processes, which are likely inflammatory, involve the fetus,(4) are complex,(5-10) probably persist for days if not weeks,(11) and need not be initiated by microorganisms. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interests:The authors declare that they have no conflicts of interests. NIH Public Access Author ManuscriptEarly Hum Dev. Author manuscript; available in PMC 2010 November 1. Published in final edited form as:Early Hum Dev. 2009 November ; 85(11): 719-725. doi:10.1016/j.earlhumdev.2009.060. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOriginally our focus was on inflammatory exposures associated with preterm labor and prelabor premature rupture of membranes, but has since been expanded to the processes that impair fetal growth as well.Second, the developmental processes during the 23 rd through 27 th weeks of gestation might be among the most vulnerable. The transformation of oligodendrocyte precursor to oligodendrocyte is one maturational process that appears particularly vulnerable. (13) Another is the migration of neuron precursors from the germinal plate to their final destination. (14,15) In addition, excitatory neurotransmitter pathways are up-regulated in the immature brain, apparently to faciliate neuronal migration, division, and organization, and the development of synapses and synaptic networks.(16) This heightened excitatory state enhances the vulnerability of the brain to excitotoxic injury from inflammatory or metabolic disorders.Third, ELGANs are born before they can synthesize adequate amounts of proteins normally provided by the placenta/mother. These proteins, many of which satisfy criteria for being called neurotrophins because they promote the differentiation/maturation of neurons and oligodendroglia, have the capacity to protect these cells against perturbation/adversity. (17,17,18) The combination of a potentially damaging exposure, easily disturbed developmental processes, and the lack of protection against the disturbances provoked by the damaging exposure are what we think make the developing brain so vulner...

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“…[6] These include persistence of an inflammatory stimulus,[48] hampered resolution of inflammation,[49, 50] a pro-inflammatory profile characteristic of extremely preterm newborns,[51, 52] limited ability to degrade inflammation-related proteins,[53-55] positive feedback loops between innate and adaptive immune systems,[56] epigenetic phenomena,[57] endoplasmic reticulum stress resulting in an unfolded protein response,[58] impairments of ubiquitylation,[59] and impairments of autophagy. [60]…”

Section: Discussionmentioning

confidence: 99%

Systemic inflammation on postnatal days 21 and 28 and indicators of brain dysfunction 2years later among children born before the 28th week of gestation

Leviton

Allred

Fichorova

et al. 2016

Early Human Development

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Background Systemic inflammation during the first two postnatal weeks in extremely preterm newborns (< 28 weeks gestation) has been associated with an increased risk of neurodevelopmental dysfunctions. Little is known, however, about the relationship between systemic inflammation during the third and fourth postnatal weeks and subsequent development. Methods We measured the concentrations of 16 inflammation-related proteins in blood spots collected on postnatal days 21 (N = 749) and 28 (N = 697) from infants born before the 28th week of gestation and assessed at age 2 years. We then sought the developmental correlates of top quartile concentrations for gestational age and day the specimen was collected. Odds ratios and 95% confidence intervals were calculated from regular or multinomial logistic regression models (as appropriate). Results Top quartile concentrations of CRP, IL-1β, IL-6, IL-6R, TNF-R2, IL-8, ICAM-1, and TSH on both days 21 and 28 were associated with ventriculomegaly (when in the NICU) and microcephaly at age 2 years. Top quartile concentrations of CRP, SAA, IL-6, TNF-R2, IL-8, and ICAM-1 were associated with Mental Development Index (MDI) of the Bayley-II < 55, while top quartile concentrations of CRP, TNF-α (inversely), IL-8, and ICAM-1 were associated with Psychomotor Development Index (PDI) < 55 Conclusion Extremely preterm newborns who had systemic inflammation during the third and fourth postnatal weeks were at increased risk of ventriculomegaly during the months after birth, and of microcephaly, and low Bayley Scale scores at 2 years of age.

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Endoplasmic Reticulum Stress, Inflammation, and Perinatal Brain Damage

Cited by 24 publications

References 123 publications

Disease specific therapies in leukodystrophies and leukoencephalopathies

Disease specific therapies in leukodystrophies and leukoencephalopathies

The ELGAN study of the brain and related disorders in extremely low gestational age newborns

Systemic inflammation on postnatal days 21 and 28 and indicators of brain dysfunction 2years later among children born before the 28th week of gestation

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