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The Journal of Neuroscience, June 11, 2008, 28(24):6118-6127; doi:10.1523/JNEUROSCI.0184-08.2008

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Development/Plasticity/Repair
Inhibition of p53 Transcriptional Activity: A Potential Target for Future Development of Therapeutic Strategies for Primary Demyelination

Jiadong Li,¹ Cristina A. Ghiani,² Jin Young Kim,¹ Aixiao Liu,¹ Juan Sandoval,¹ Jean DeVellis,² and Patrizia Casaccia-Bonnefil¹

¹Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and ²Departments of Psychiatry and Neurobiology, Mental Retardation Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095

Correspondence should be addressed to Dr. Patrizia Casaccia-Bonnefil at her present address: Department of Neuroscience, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1065, New York, NY 10069. Email: patrizia.casaccia{at}mssm.edu

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-, compared with untreated controls. Decreased levels of lypopolysaccharide-induced gene expression were also observed in vitro, in p53^–/– primary microglial cultures or in pifithrin--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.

Key words: myelin repair; oligodendrocyte; microglia; transcription; myelin; demyelination

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Received Sept. 17, 2007; revised March 23, 2008; accepted April 29, 2008.

Correspondence should be addressed to Dr. Patrizia Casaccia-Bonnefil at her present address: Department of Neuroscience, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1065, New York, NY 10069. Email: patrizia.casaccia{at}mssm.edu

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