An Experimental Study Of The Effect Of Ginaton On Hippocampal α,β-secretase Of Old Rats After Chronic Cerebrohypoperfusion

Background:Alzheimer disease (AD) is the most common cause of dementia among people over 65 yeas old. One of the biggest stumbling blocks in developing effective drug therapy for Alzheimer disease has been the lack of a comprehensive hypothesis that explains the mechanism behind all of the histopathological changes seen in patients suffering from AD. Considerable researches had shown that brain ischemia, particularly chronic cerebrohypoperfusion prevailing in the elderly strongly associated with AD and resulted in an increase of amyloid protein(Aβ),the core substance of AD. But how does it work remains obscure.α-secretase (TACE)andβ-secretase(BACE1)as two key enzymes directly affect the generation of Aβto study their changes after chronic cerebrohypoperfusion are essential to clarify the cause of Aβincrease and the further exploration of AD etiology. standard Ginkgo Biloba extract(Egb761) is one of the therapies of AD nowadays, but if it had infulence on Aβproduction remains unclear. Objective: 1.To explore the impact of Chronic cerebrohypoperfusion on old rat hippocampalα,β-secretase mRNA expression and activities. 2.To investigate the possible treatment mechanism of Egb761 by observing it's effects on Chronic cerebrohypoperfusion rats. Methods: Old Wistar rats were randomly divided into sham group, hypoperfusion group and the Egb761 treatment group. Each group was further divided into 1 week, 2 weeks, 4 weeks and 16 weeks sub-groups. Permanent bilateral carotid artery occlusion(2VO) models were estabilished to mimic the chronic cerebrohypoperfusion, and Ginaton was administered 100mg/(kg*d) orally via gastrictube. The spatial memory function were measured by Y-maze before operation and execution. Rats were sacrificed in each time point to harvest the hippocampus. Real-time PCR and fluorescence detection were applied respectively to assay the mRNA and activity ofα,β-secretase. Results:1.TACE mRNA had no significant differences(p>0.05)between 2VO group and sham group only at one week after operation,but significantly dropped at the following time points(p<0.01). BACE1 mRNA decreased at the first week(p<0.05) but reached the lowest level at the second week after operation(p<0.01), at the following time points, their were no considerable difference with sham group(p>0.05). Egb761 attenuates the changes of TACE mRNA, but not BACE1 mRNA. 2.The chonic cerebrohypoperfusion caused decreased TACE activity(p<0.01) and increased BACE1 activity(p<0.01 or p<0.05) from sham group and Egb761 plays an opposite role. Conclusions:1.The chonic cerebrohypoperfusion can influence the hippocampalα,β-secretase expression and activity of old rats. 2.Egb761 plays a protective role when chronic cerebrohypoperfusion maybe under it's influence onα,β-secretase.