Roscovitine reduces neuronal loss, glial activation and neurological deficits after brain trauma

• Published in: Journal of cerebral blood flow and metabolism 2008-07, Vol.28 (11), p.1845-1859
• Main Authors: Hilton, Genell D., Stoica, Bogdan A., Byrnes, Kimberly R., Faden, Alan I.
• Format: Article
• Language: English
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2008.75

TBI causes both direct and delayed tissue damage. The latter is associated with secondary biochemical changes such as cell cycle activation that lead to neuronal death, inflammation and glial scarring. Flavopiridol — a CDK inhibitor that is neither specific nor selective — is neuroprotective. To examine the role of more specific CDK inhibitors as potential neuroprotective agents, we studied the effects of roscovitine in TBI. Central administration of roscovitine 30 minutes after injury resulted in significantly decreased lesion volume, as well as improved motor and cognitive recovery. Roscovitine attenuated neuronal death and inhibited activation of cell cycle pathways in neurons after TBI, as indicated by attenuated cyclin G1 accumulation and phosphorylation of retinoblastoma protein. Treatment also decreased microglial activation after TBI, as reflected by reductions in ED1, Galectin-3, p22 PHOX and Iba-1 levels, and attenuated astrogliosis as shown by decreased GFAP accumulation. In primary cortical microglia and neuronal cultures, roscovitine and other selective CDK inhibitors attenuated neuronal cell death, as well as decreasing microglial activation and microglial-dependent neurotoxicity. These data support a multi-factorial neuroprotective effect of cell cycle inhibition after TBI-likely related to inhibition of neuronal apoptosis, microglial-induced inflammation and gliosis-and suggest that multiple CDKs are potentially involved in this process.