Inhibition of p53 transcriptional activity: a potential target for future development of therapeutic strategies for primary demyelination.
Oligodendrogliopathy, microglial infiltration, and lack of remyelination are detected in the brains of patients with multiple sclerosis and are accompanied by high levels of the transcription factor p53. In this study, we used the cuprizone model of demyelination, characterized by oligodendrogliopathy and microglial infiltration, to define the effect of p53 inhibition. Myelin preservation, decreased microglial recruitment, and gene expression were observed in mice lacking p53 or receiving systemic administration of the p53 inhibitor pifithrin-alpha, compared with untreated controls. Decreased levels of lypopolysaccharide-induced gene expression were also observed in vitro, in p53(-/-) primary microglial cultures or in pifithrin-alpha-treated microglial BV2 cells. An additional beneficial effect of lack or inhibition of p53 was observed in Sox2+ multipotential progenitors of the subventricular zone that responded with increased proliferation and oligodendrogliogenesis. Based on these results, we propose transient inhibition of p53 as a potential therapeutic target for demyelinating conditions primarily characterized by oligodendrogliopathy.
Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
Jiadong
J
Li
Cristina A
CA
Ghiani
Jin Young
JY
Kim
Aixiao
A
Liu
Juan
J
Sandoval
Jean
J
DeVellis
Patrizia
P
Casaccia-Bonnefil
D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D002478:Cells, Cultured; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020547:Lateral Ventricles / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D003471:Cuprizone; C121565:pifithrin