Cell cycle proteins preceded neuronal death after chronic cerebral hypoperfusion in rats.

Objectives: To explore the re-expression of cell cycle related proteins and delayed neuronal death after chronic cerebral hypoperfusion in rats and to investigate the relationship between aberrant expression of cell cycle proteins and apoptotic cell death. Methods: Rat model of chronic cerebral hypoperfusion was established by permanent bilateral common carotid arteries occlusion (2VO) in the retired rats. The apoptotic cells were assessed by TUNEL method. The expression of cell cycle related proteins, i.e. CDK4 and cyclin B1, were detected by immunohistochemical staining and Western blotting. A cyclin-dependent kinases (CDKs) inhibitor, roscovitine, was intracerebroventricularly administered 1 day before 2VO insult. Spatial learning behavior was assessed by the Morris water maze 7, 14 and 21 days after the surgery. Results: Aberrant expression of CDK4 and cyclin B1 became present 7 days after 2VO insult surgery and last for a long period. On the other hand, TUNEL positive cells appeared as early as 14 days after the surgery and peaked at day 21. Furthermore, roscovitine significantly improve behavioral deficit in the Morris water maze test 7 and 14 days after the surgery. Conclusion: These findings indicated that aberrant expression of CDK4 and cyclin B1 takes place in the brain after chronic cerebral hy\ poperfusion in retired rat, and aberrant expression of cell cycle proteins preceded neuronal death in this model. Our data also suggest that the CDK inhibitor, roscovitine, has therapeutic potential for the treatment of dementia caused by chronic cerebral hypoperfusion. [Neurol Res 2008; 30: 932-939]