Related Experiment Video
Updated: Jul 7, 2026
Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: attenuation by N-acetyl
Manjeet K Paintlia1, Ajaib S Paintlia, Miguel A Contreras
1Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
Insights
Prenatal infection causes brain injury and cerebral palsy (CP) in infants. N-acetyl cysteine (NAC) protects against this by improving peroxisomal function and reducing inflammation via PPAR-alpha.
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- Prenatal maternal infection, particularly LPS exposure, is linked to periventricular leukomalacia and cerebral palsy (CP) in premature infants.
- Oligodendrocyte (OL) injury and hypomyelination in the developing brain are key pathological features.
- N-acetyl cysteine (NAC), an antioxidant, has shown potential in mitigating these effects.
Purpose of the Study:
- To investigate the role of peroxisomes in lipopolysaccharide (LPS)-induced neuroinflammation and cerebral white matter injury.
- To elucidate the protective mechanisms of NAC in the context of prenatal infection-induced brain damage.
- To explore the involvement of peroxisome proliferator-activated receptor alpha (PPAR-α) in mediating these protective effects.
Main Methods:
- Maternal LPS exposure in a mouse model to induce white matter injury.
- Assessment of oligodendrocyte markers, peroxisomal function, and reactive oxygen species (ROS) generation in fetal and postnatal brains.
- In vitro studies using oligodendrocyte cultures exposed to pro-inflammatory cytokines.
- Pharmacological interventions with NAC and WY14643 (a PPAR-α agonist) in vitro and in vivo.
- Genetic manipulation using PPAR-α knockout models and siRNA in cell cultures.
Main Results:
- Maternal LPS exposure led to selective oligodendrocyte depletion, increased ROS, glutathione depletion, and peroxisomal dysfunction in the developing brain.
- Hypomyelination correlated with decreased peroxisomes and oligodendrocytes post-LPS exposure.
- NAC treatment reversed LPS-induced oligodendrocyte injury, peroxisomal dysfunction, and hypomyelination.
- Pro-inflammatory cytokines induced oligodendrocyte injury via peroxisomal dysfunction and ROS generation in vitro.
- NAC and WY14643 protected oligodendrocytes in a PPAR-α-dependent manner, as demonstrated in PPAR-α deficient cells and models.
Conclusions:
- LPS-induced peroxisomal dysfunction exacerbates prenatal cerebral white matter injury.
- NAC exerts protective effects against neuroinflammation and white matter injury through a PPAR-α-dependent mechanism.
- Targeting peroxisomal function via PPAR-α activation presents a promising therapeutic strategy for CP and related demyelinating diseases.
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.
