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

Abstract

Cerebral white matter injury during prenatal maternal infection characterized as periventricular leukomalacia (PVL) 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 in OLs after maternal LPS exposure. Conversely, NAC abolished these LPS-induced effects in the developing brain. CP brains imitated these changes in peroxisomal/myelin proteins in the postnatal brain after maternal LPS exposure. In vitro studies revealed that proinflammatory cytokines cause OL-injury via peroxisomal dysfunction and ROS generation. NAC or WY14643 (peroxisome proliferators activated receptor (PPAR)-α agonist) reverses these effects of proinflammatory cytokines in the wild-type OLs, but not in PPAR-α (−/−) OLs. Similarly treated B12 oligodenroglial cells co-transfected with PPAR-α siRNAs/pTK-PPREx3-Luc, and LPS exposed PPAR-α (−/−) pregnant mice treated with NAC or WY14643 further suggested that PPAR-α activity mediates NAC-induced protective effects. Collectively, these data provide unprecedented evidence that LPS-induced peroxisomal dysfunction exacerbates cerebral white matter injury and NACinduced protection is via a PPAR-α dependent mechanism expands therapeutic avenues for PVL and related demyelinating diseases.

Toll-like receptor 4-mediated immune stress in pregnant rats activates STAT3 in the fetal brain: role of interleukin-6

“…Prenatal LPS has been associated with neural cell death by apoptosis (12,13). One of the hallmark of neural cells committed to apoptosis is their expression of activated caspase 3 (14).…”

Relation between prognosis and changes of MBP and S100B in premature infants with periventricular leukomalacia

“…All infants were followed once a month until they were 1 year old, and Gesell developmental scales were used to test the intelligence quotient and physical development index of the premature infants once every 3 months (Paintlia et al, 2008;Haynes and van Leyen, 2013).…”

Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy

“…Recently, our laboratory observed decreased peroxisomal proteins and increased VLCFA in the CNS of animals with experimental autoimmune encephalomyelitis, which is an animal model of multiple sclerosis (20). Inflammatory mediators are also reported to downregulate peroxisome function, leading to VLCFA accumulation (21)(22)(23). In fact, VLCFA accumulation in the inflammatory region was eight to ten times greater than in the histologically normal X-ALD brain, suggesting that induction of inflammatory mediators further downregulates peroxisome function, propagating a cycle (22,23).…”