Cited by 93Neonatal and fetal brain pathologyNeuroinflammation and Neurodegeneration MechanismsMetabolism and Genetic Disorders

Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: attenuation by N-acetyl cysteine

Open access
Paintlia, Manjeet K., Paintlia, Ajaib S., Contreras, Miguel A., Singh, Inderjit, Singh, Avtar K.·2008·Experimental Neurology

Abstract

Cerebral white matter injury during prenatal maternal infection characterized as periventricular leukomalacia is the main substrate for cerebral palsy (CP) in premature infants. Previously, we reported that maternal LPS exposure causes oligodendrocyte (OL)-injury/hypomyelination in the developing brain which can be attenuated by an antioxidant agent, N-acetyl cysteine (NAC). Herein, we elucidated the role of peroxisomes in LPS-induced neuroinflammation and cerebral white matter injury. Peroxisomes are important for detoxification of reactive oxidative species (ROS) and metabolism of myelin-lipids in OLs. Maternal LPS exposure induced selective depletion of developing OLs in the fetal brain which was associated with ROS generation, glutathione depletion and peroxisomal dysfunction. Likewise, hypomyelination in the postnatal brain was associated with decrease in peroxisomes and OLs after maternal LPS exposure. Conversely, NAC abolished these LPS-induced effects in the developing brain. CP brains imitated these observed changes in peroxisomal/myelin proteins in the postnatal brain after maternal LPS exposure. In vitro studies revealed that pro-inflammatory cytokines cause OL-injury via peroxisomal dysfunction and ROS generation. NAC or WY14643 (peroxisome proliferators activated receptor (PPAR)-alpha agonist) reverses these effects of pro-inflammatory cytokines in the wild-type OLs, but not in PPAR-alpha(-/-) OLs. Similarly treated B12 oligodenroglial cells co-transfected with PPAR-alpha siRNAs/pTK-PPREx3-Luc, and LPS exposed PPAR-alpha(-/-) pregnant mice treated with NAC or WY14643 further suggested that PPAR-alpha activity mediates NAC-induced protective effects. Collectively, these data provide unprecedented evidence that LPS-induced peroxisomal dysfunction exacerbates cerebral white matter injury and its attenuation by NAC via a PPAR-alpha dependent mechanism expands therapeutic avenues for CP and related demyelinating diseases.

Integrity signals

Registry

Crossref · 10.1016/j.expneurol.2007.12.011

Cites

79 of 79 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

2 of the 81 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Authors
Paintlia, M. K., Paintlia, A. S., Contreras, M. A., Singh, I., & Singh, A. K.
Affiliations
  • Medical University of South Carolina (US)
  • Ralph H. Johnson VA Medical Center (US)
Corresponding author
Singh, Avtar K.
Venue
Experimental Neurology
Publisher
Elsevier BV
Published
2008-04
Volume
210
Issue
2
Pages
560-576
ISSN
0014-4886 (ISSN-L)
OpenAlex
W1986696152
Cited by
93
References
81
Citations by year
2026: 1 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 5 · 2017: 6 · 2016: 9 · 2015: 10 · 2014: 8 · 2013: 7 · 2012: 7
FWCI
4.12
Type
journal article
Language
en
Open access
Locations
  • Experimental Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (1c06rr015455-01a1, 1c06rr018823-01)
  • National Institute of Neurological Disorders and Stroke (R01NS034741, NS-22576, NS 37766, R01NS040810, R01NS037766, NS-40810, NS-34741, R01NS022576, R37NS022576)
  • National Center for Research Resources (C06 RR-015455, C06 RR-018823)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
lipopolysaccharide, peroxisomal dysfunction, cerebral white matter injury, N-acetylcysteine, periventricular leukomalacia, cerebral palsy, oligodendrocyte damage, hypomyelination, reactive oxygen species, glutathione depletion, PPARα, inflammatory cytokines, maternal infection, demyelinating disease, Wy-14,643
MeSH terms
Acetylcysteine, Acyltransferases, Analysis of Variance, Animals, Brain Injuries, Cells, Cultured, Child, Preschool, Drug Interactions, Female, Fetus, Flow Cytometry, Humans, Infant, Lipopolysaccharides, Neuroglia, Pregnancy, Prenatal Exposure Delayed Effects, Time Factors, Transfection, Case-Control Studies, Free Radical Scavengers, Reactive Oxygen Species, Peroxisomal Disorders, Peroxisomes, RNA, Small Interfering, In Vitro Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review