The impairment of cognitive function such as memory and attention has been recognized in patients with chronic mild cerebral ischemia. The hippocampal memory and long-term potentiation (LTP), a cellular correlate of learning and memory, were impaired by chronic cerebral hypoperfusion induced by permanent, bilateral occlusion of the common carotid artery (2VO).
Objectives: The purpose of present study was to evaluate the effects of renexin on the impaired LTP and expression of mRNA genes involving neuronal plasticity in the rat 2 VO model.
Methods: Adult male Sprague-Dawley rats were randomly divide three experimental groups into:1) Sham without 2VO, 2) 2VO+vehicle, 3) 2VO+renexin. The permanent ligation of bilateral common carotid arteries was performed to elicit chronically lower blood flow to the brain. Animals were treated with oral administration of renexin(gingko biloba 20 mg/kg/day + cilostazol 25 mg/kg/day) or vehicle every day from1 day after surgery for 3 weeks. We recorded LTP induced by brief high frequency stimulation to the Schaffer collateral-CA1 pathway of the hippocampus under anesthesia in vivo. Two hours after induction of LTP, the animal was sacrificed and the hippocampus was isolated for quantitative detection of mRNA for BDNF, Arc, Egr-1 and CREB using quantitative real-time RT-PCR technique.
Results: Animals of 2VO+vehicle group showed a highly significant deficit in LTP induction (15 ± 3% of control fEPSP slope; n= 7; P< 0.01) 3 weeks after 2VO. On the other hand, daily oral administration of renexin showed the marked preservation of LTP induction (98 ± 17% of control fEPSP slope; n =7; P< 0.01). On the real-time RT-PCR analysis, a significant reduction of CREB, Arc and BDNF mRNA expression was observed in the hippocampus of 2VO+vehicle group compared with that of sham group (P< 0.01). In contrast, renexin treatment increased significantly the expression of these mRNAs in the hippocampus compared with that of 2VO+vehicle group (P< 0.05).
Conclusion: These results suggest that daily oral administration of renexin can ameliorate cognitive deficit through the preservation of synaptic plasticity on the level of neural circuit in rodent model of chronic cerebral hypoperfusion.