Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: attenuation by N-acetyl cysteine
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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.
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N-acetylcysteine prevents this deficit by attenuating the dysfunction of peroxisomes, organelles important for reactive oxygen species detoxification and myelin-lipid metabolism.
“Likewise, NAC prevents this deficit by attenuating the dysfunction of peroxisomes, organelles important for ROS detoxification and myelin-lipid metabolism (Paintlia et al., 2008).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Paintlia et al., 2008
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- 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)
- PMC
- PMC2673813
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
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