Inhibition of p53 transcriptional activity: a potential target for future development of therapeutic strategies for primary demyelination
| Autor: | Juan Sandoval, Aixiao Liu, Jiadong Li, Patrizia Casaccia-Bonnefil, Jean DeVellis, Jin Young Kim, Cristina A. Ghiani |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Transcription
Genetic Subventricular zone Biology Article Myelin Cuprizone Mice Lateral Ventricles Gene expression medicine Animals Benzothiazoles Remyelination Enzyme Inhibitors Cells Cultured Oligonucleotide Array Sequence Analysis Mice Knockout Microglia General Neuroscience Multiple sclerosis medicine.disease Oligodendrocyte Mice Inbred C57BL Disease Models Animal Oligodendroglia medicine.anatomical_structure Immunology Systemic administration Cancer research Tumor Suppressor Protein p53 Demyelinating Diseases Toluene |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|