Peroxisomal Proliferation Prevents Loss of Oligodendrocyte Progenitors and Hypomyelination in Periventricular Leukomalacia‐like Brain

Hypomyelination is the hallmark of fetal brain white matter injury responsible for the development of periventricular leukomalacia (PVL) lesions, present in most cases of cerebral palsy (CP). Previously, we showed that a systemic maternal injection of LPS at Embryonic day E18 causes the depletion of oligodendrocytes (OL) and subsequent hypomyelination later in the life of offspring, similar to what is observed in PVL which could be blocked by antioxidant, N‐acetyl cysteine (NAC). Here we explored the protective role of peroxisomes against the depletion of OLs in PVL. Interestingly, the LPS exposure caused the selective depletion of developing OLs in the fetal brain with subsequent hypomyelination in the later life of offspring, accompanied by progressive loss of peroxisomal proliferation/functions. CP brain also showed similar observations to PVL‐like brain, suggesting a possible link between peroxisomes and PVL. NAC pretreatment halted this LPS‐induced progression of PVL‐like pathobiology via attenuation of oxidative‐stress and replenishment of glutathione. Furthermore, in vitro studies with NAC and peroxisome proliferators activated receptor (PPAR)‐ α agonist including co‐transfection studies with PPAR‐α small‐interfering RNA revealed that peroxisomal proliferation can attenuate the progression of PVL. This study for the first time suggest a direct link between peroxisomal proliferation and OLs survival in PVL, expanding therapeutic avenues for CP/PVL and other related demyelinating diseases. Supported by: NIH grants NS‐22576, NS‐34741, NS‐37766 and NS‐40810