Peroxisome Injury in Multiple Sclerosis: Protective Effects of 4-Phenylbutyrate in CNS-Associated Macrophages

Multiple sclerosis (MS) is a progressive and inflammatory demyelinating disease of the CNS. Peroxisomes perform critical functions that contribute to CNS homeostasis. We investigated peroxisome injury and mitigating effects of peroxisome-restorative therapy on inflammatory demyelination in models of MS. Human autopsied CNS tissues (male and female), human cell cultures, and cuprizone-mediated demyelination mice (female) were examined by RT-PCR, Western blotting, and immunolabeling. The therapeutic peroxi-some proliferator, 4-phenylbutyrate (4-PBA) was investigated in vitro and in vivo. White matter from MS patients showed reduced peroxisomal transcript and protein levels, including PMP70, compared with non-MS controls. Cultured human neural cells revealed that human microglia contained abundant peroxisomal proteins. TNF-a-exposed microglia displayed reduced immunolabeling of per-oxisomal proteins, PMP70 and PEX11b, which was prevented with 4-PBA. In human myeloid cells exposed to TNF-a or nigericin, suppression of PEX11b and catalase protein levels were observed to be dependent on NLRP3 expression. Hindbrains from cuprizone-exposed mice showed reduced Abcd1, Cat, and Pex5l transcript levels, with concurrent increased Nlrp3 and Il1b transcript levels, which was abrogated by 4-PBA. In the central corpus callosum, Iba-1 in CNS-associated macrophages and peroxisomal thiolase immu-nostaining after cuprizone exposure was increased by 4-PBA. 4-PBA prevented decreased myelin basic protein and neurofilament heavy chain immunoreactivity caused by cuprizone exposure. Cuprizone-induced neurobehavioral deficits were improved by 4-PBA treatment. Peroxisome injury in CNS-associated macrophages contributed to neuroinflammation and demyelination that was pre-vented by 4-PBA treatment. A peroxisome-targeted therapy might be valuable for treating inflammatory demyelination and neurode-generation in MS.

Automated summary

This study investigates the peroxisomal injury and the effects of peroxisome-restorative therapy on inflammatory demyelination in multiple sclerosis (MS) models. It reveals that peroxisomes play critical roles in CNS homeostasis and their dysfunction is associated with neuroinflammation and demyelination in MS. The therapeutic peroxisome proliferator, 4-phenylbutyrate (4-PBA), shows potential in mitigating neuroinflammation and promoting myelin repair in MS.