Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury.
Traumatic brain injury (TBI) causes neuronal apoptosis, inflammation, and reactive astrogliosis, which contribute to secondary tissue loss, impaired regeneration, and associated functional disabilities. Here, we show that up-regulation of cell cycle components is associated with caspase-mediated neuronal apoptosis and glial proliferation after TBI in rats. In primary neuronal and astrocyte cultures, cell cycle inhibition (including the cyclin-dependent kinase inhibitors flavopiridol, roscovitine, and olomoucine) reduced up-regulation of cell cycle proteins, limited neuronal cell death after etoposide-induced DNA damage, and attenuated astrocyte proliferation. After TBI in rats, flavopiridol reduced cyclin D1 expression in neurons and glia in ipsilateral cortex and hippocampus. Treatment also decreased neuronal cell death and lesion volume, reduced astroglial scar formation and microglial activation, and improved motor and cognitive recovery. The ability of cell cycle inhibition to decrease both neuronal cell death and reactive gliosis after experimental TBI suggests that this treatment approach may be useful clinically.
Di Giovanni
Simone
S
Department of Neuroscience, Georgetown University School of Medicine, 3900 Reservoir Road NW, Washington, DC 20057, USA.
Movsesyan
Vilen
V
Ahmed
Farid
F
Cernak
Ibolja
I
Schinelli
Sergio
S
Stoica
Bogdan
B
Faden
Alan I
AI
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002921:Cicatrix / Q000473:pathology / Q000517:prevention & control*; D019938:Cyclin D1 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009457:Neuroglia / Q000166:cytology* / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D005419:Flavonoids; D018696:Neuroprotective Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D019938:Cyclin D1; C077990:alvocidib; D005047:Etoposide; D018844:Cyclin-Dependent Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases