Roscovitine reduces neuronal loss, glial activation, and neurologic deficits after brain trauma.
Traumatic brain injury (TBI) causes both direct and delayed tissue damage. The latter is associated with secondary biochemical changes such as cell cycle activation, which leads to neuronal death, inflammation, and glial scarring. Flavopiridol--a cyclin-dependent kinase (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 mins 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 accumulation of glial fibrillary acidic protein. 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 multifactorial 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.
Hilton
Genell D
GD
Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia 20057, USA.
Stoica
Bogdan A
BA
Byrnes
Kimberly R
KR
Faden
Alan I
AI
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects; D003071:Cognition; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009043:Motor Activity; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine
D018696:Neuroprotective Agents; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases