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Brain Advance Access published online on August 9, 2007
Brain, doi:10.1093/brain/awm179
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cell cycle activation contributes to post-mitotic cell death and secondary damage after spinal cord injury

Kimberly R. Byrnes1, Bogdan A. Stoica1, Stanley Fricke1, Simone Di Giovanni2 and Alan I. Faden1

1Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA and 2Hertie Institute for Clinical Brain Research, University of Tuebingen, Germany

Correspondence to: Kimberly R. Byrnes, PhD, Georgetown University Medical Center, Department of Neuroscience, Research Building, Room EP16A 3970 Reservoir Rd., NW, Washington, DC 20057 E-mail: krb27{at}georgetown.edu

Spinal cord injury (SCI) causes delayed secondary biochemical alterations that lead to tissue loss and associated neurological dysfunction. Up-regulation of cell cycle proteins occurs in both neurons and glia after SCI and may contribute to these changes. The present study examined the role of cell cycle activation on secondary injury after severe SCI in rat. SCI caused cell cycle protein up-regulation associated with neuronal and oligodendroglial apoptosis, glial scar formation and microglial activation. Treatment with the cell cycle inhibitor flavopiridol reduced cell cycle protein induction and significantly improved functional recovery versus vehicle-treated controls at 21 and 28 days post-injury. Treatment also significantly reduced lesion volume, as measured by MRI and histology, decreased astrocytic reactivity, attenuated neuronal and oligodendroglial apoptosis and reduced the production of factors associated with microglial activation. Thus, flavopiridol treatment improves outcome after SCI by inhibiting cell cycle pathways, resulting in beneficial multifactorial actions on neurons and glia.

Key Words: apoptosis; astrocyte; inflammation; microglia; neuron

Abbreviations: CDKIs, cyclin-dependent kinase inhibitors; CDKs, cyclin-activated kinases; MRI, magnetic resonance imaging; PRb, phosphorylated retinoblastoma protein; SCI, spinal cord injury

Received March 21, 2007. Revised June 29, 2007. Accepted July 9, 2007.


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