The Effect Of Bis(7)-tacrine And Aβ Self-aggregation Inhibitor On Modulation Of Synaptic Plasticity Mediated By Aβ

Objective: 1. To investigate the effects of bis(7)-tacrine on LTP (long term potentiation )and overturn of inhibition of LTP by Aβ(β-Amyloid protein). Furthermore, to investigate dose-response relationship of bis(7)-tacrine and its mechanism, this part lays emphasis on investigating its pharmacological effects on NMDAR (N-methyl-D-aspartate receptor) to offer pharmacological basis for its clinical application. 2. To illustrate the difference in toxicity and concentration among several kinds of Aβon the inhibition of LTP, and the effects of two aggregation inhibitors on Aβ-mediated inhibition of LTP induction.Methods: The fresh transverse slices of wistar rat (3-4 weeks) hippocampus placed in cold oxygenated (95% O2/5% CO2) ACSF (Artificial cerebrospinal fluid) were continuously superfused in control groups and experimental groups. Standard electroneurophysiological techniques were used to record EPSP (excitatory postsynaptic potential) and LTP in the hippocampal dentate gyrus. For LTP experiment, the peak value of EPSP and amplitude of LTP were measured and analyzed. All values were normalized to this baseline and all values of LTP reported here were calculated as the changes in fEPSP amplitude. Electrophysiological values are the means±S.E.M. for n slices. EPSP was analyzed by pClamp software. Measurment data were used by two-tailed Student's test and two-way ANOVA for statistical comparison.Results: 1. Bis(7)-tacrine enhances LTP with a higher efficiency than other acetylcholinesterase (AChE) inhibitors; bis(7)-tacrine but not tacrine reverse Aβ? inhition on LTP inα7 nACh receptor independent manner; bis(7)-tacrine reverses Aβinhibition on LTP in a dose-dependent manner with double mechanism; bis(7)-tacrine in low concentration block Aβinhibition by preventing calcium overload via NMDA and VDCC (Voltage-dependent calcium channel). 2. Synthetic and naturally secreted human soluble Aβboth inhibit the control LTP; Aβtreated by M1 and M2 is deprived of the effects on inhibition of LTP induction.Conclusions: 1. Bis(7)-tacrine shows multiple-targets action which is analogue to several drugs in mediating Aβinhibition of LTP, whose properties provide the powerful basis and supportment for clinical drug and remedy for neurodegenerative diseases. 2. The studies show that the blockade of Aβself aggregation prevents the Aβinhibition of LTP. These findings indicate that therapeutic treatment for AD may include agents that block Aβself aggregation.