| Introduction With the increase in senescent population, senile dementia is among the most urgent public health problems. Apart from Alzheimer's type ( SDAT ) , the most common dementia in the elderly,vascular dementia is also a common clinical syndrome. Previous studies have revealed that, like the pathosis of Alzheimer's disease, cholinergic abnormalities are associated with the disturbance of cognitive function, such as attention and memory trauma in patients with vascular dementia. Hirohisa et al. report that the cholinergic terminals in the hippoccampal CAl subfield where the cholinergic neurons projecting to, are vulnerable to ischemia, and cholinegic deficits in the hippocampal cause memory impairment. In patients with vascular dementia, acetylcholineconcentration in the cerebrospinal fluid was significantly lower than in the controls, and showed a significantly positive correlation with dementia scale scores. These findings introduced the possibility of using cholinegic substances as therapeutic intervention in vascular dementia. It has been reported recently that cholinesterase inhaibitor ( ChEI ) could protect against ischemia, such as huperzine A and ENA713.TAK-147{ - [ 1 - ( phenylmethyl )-4-piperidinyl ]-1-(1,3,4, 5 - tetrahydro- 1H - 1 - benzazepin - 8 - yl ) - 1 - propanone fumarate } has been recently introduced to be another selective AChE inhibitor, which is indicated to selectively inhibit activity of AChE. It has been demonstrated that TAK-147 is more potent and brain-specific AChE inhibition than tacrine and physostigmine, and has been approval potentiating choline acetyltransferase ( ChAT ) activity in cultured rat septal neurons more potent than donepezil, tacrine and revastigmine. Initial behavior studies have also demonstrated that Scopolamine interferes with memory and cognitive function in both human and rodents by blocking muscarinic receptor in the brain, and the treatment with TAK-147 ameliorates learning and memory impairment in passive avoidance test induced by scopolamine. However, whether TAK-147 is effective in spatial cognitive deficit induced by scopolamine and ischemia in rodent or not, have not yet been evaluated. Aim In the present study, compared with tacrine and donepezil, we try to investigate effects of TAK-147 on the changes in behaviour after Ip of scopolamine and brain ischemia induced by four-vessel occlusion and the histological picture of the hippocampal CA1 subfield, Meanwhile to evaluate the protective effects of TAK-147 on anoxia / aglycemia brain slice.Methods Ip injection of scopolaine induced cholinegic system deficit, 4-vo induced brain ischemia. Morris water maze was used to measure spatial memory in rats, and open field test was used to analysis locomotor activity. Light microscopy showed that 4-vo yielded losses of pyramidal neurons in the hippocampal CA1 region. The brain slice activation was determined with 2, 3, 5 - triphenyltetrazolium chloride staining. One-way analysis of variance with Dunnett's test using computer software ( SigmaStat 1.01 for Windows 95, 1992, Jandel Corp, USA ) , was used for calculating a significant difference. Values are shown as means+ standard deviation ( x+sem ) . Significant difference are express as P < 0.05 vs control group, respectively.Results (1) Effects of TAX-147, donepezil and tacrine on spatial memory deficit induced by scopolamine in Morris water maze. During the process of memory acquisition, scopolamine ( 0.4 mg/kg, ip ) significantly increased the latency period in Morris Water Maze. Both TAK-147 ( 0.1, 0.3 and 1.0 mg/kg ) , E2020 ( 0.1, 0.3 and 1.0 mg/kg ) and tacrine ( 3 and 5 mg/kg ) significantly reversed scopolamine ( 0.4 mg/kg ) . A significant effect was obtained at doses of 0.3 and 1.0 mg/kg . During the process of memory retrieval, both intraperitoneal TAK-147 (0.1, 0.3 and 1.0 mg/kg ) and E2020 ( 0.3 and 1.0 mg/kg ) significantly reversed scopolamine ( 1.5 mg/kg ) increased latency in memory retrieval in a dose-related manner. Tacrine ( 3 mg/kg ) significantly reversed scopol... |
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