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Mechanism of Inhibition of Bis(7)-tacrine on GABA-activated Current in Cultured Rat Hippocampal Neurons and the Modulation of Extracellular pH

Author: ZhouLi
Tutor: LiChaoYing;LiZhiWang
School: Huazhong University of Science and Technology
Course: Physiology
Keywords: GABA_A receptor Acetylcholinesterase inhibitors Competitive inhibition PA2 Activation Inactivation Desensitization Dynamics Whole-cell patch clamp Bis (7)-tacrine Suppression Proton Hippocampal Rats
CLC: Q42
Type: PhD thesis
Year: 2009
Downloads: 54
Quote: 0
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Abstract


On the first part of Bis (7)-tacrine inhibition in cultured rat hippocampal neurons, GABA current mechanism Bis (7)-tacrine is a new type of origin in the tacrine dimer acetylcholinesterase inhibitor. The current study found that its potential therapeutic role in Alzheimer's disease. Our previous studies have reported that bis (7)-tacrine inhibits GABA A receptor-mediated ion current. The experiments using whole cell patch clamp recording techniques were studied bis (7)-tacrine inhibition in cultured rat hippocampal neurons, GABA A receptor function mechanism. The experimental results showed: bis (7)-tacrine inhibition of GABA-activated currents, and gradually increased its role. But this does not indicate that this effect has a use-dependent, because when the bis (7)-tacrine in advance on the GABA application, the suppression of its peak current, and the steady state current is not a significant difference, do not exhibit this gradual increase of the inhibition. Moreover, the presence of bis (7)-tacrine inhibition unwanted agonist GABA - current is suppressed in the case of agonist does not exist, completely restored. Bis (7)-tacrine This slow inhibition apparently not because of their sites of action in the cells, as given in the recording electrode 25μM bis (7)-tacrine given without changing the extracellular 2.5μM BIS (7) - The inhibition rate of tacrine on GABA current. Bis (7)-tacrine GABA concentration response curve parallel moved rightward, Schild plot analysis of the resultant bis (7)-tacrine antagonistic parameters (i.e. PA 2 )) is 5.7. Bis (7)-tacrine increased GABA current activation time constant without affecting inactivation time constants and to the sensitive time constant. These experimental results show that bis (7)-tacrine inhibition of GABA-activated currents to a slow mode of action, and this effect is a competitive inhibition. Bis (7)-tacrine competitive inhibition of hippocampal neurons GABA A receptor may be one of the reasons for its enhanced memory. Modulation of GABA current role in the second part of the extracellular pH of bis (7)-tac rine inhibition in cultured rat hippocampal neurons under physiological and pathological conditions, the pH of the brain tissue can be changed. Under acidic conditions, the extracellular pH has inhibitory effects on NMDA currents in cultured rat hippocampal neurons, we previously reported that bis (7)-tacrine can inhibit NMDA currents in cultured rat hippocampal neurons. and its inhibition rate increased with the rise of the extracellular pH decreased. The experiment found that bis (7)-tacrine slow mode of action of competitive inhibition of GABA currents in cultured rat hippocampal neurons. However, pH bis (7)-tacrine inhibit GABA currents in cultured rat hippocampal neurons with modulation effects is not clear, so we make use of the whole-cell patch clamp technique further study of the extracellular pH of culture the role of GABA currents in hippocampal neurons and pH modulation of bis (7)-tacrine inhibition. The results showed that: the extracellular pH in the acidic range, protons having a concentration-dependent inhibition of GABA currents in 70% (63/90) of subjects on the cells having an enhanced role in the alkaline range. 30% (27/90) of the neurons examined had no significant effect. , Bis (7)-tacrine inhibition of GABA currents decreases with the increase of pH within the range of pH 6.0-8.8. pH 6.0, and bis (7)-tacrine on GABA current inhibition concentration-response curve with respect to the parallel Left at pH 7.4 and bis (7) the the the-tacrine Inhibition IC 50 < / sub> value by 5.61 ± 0.45μM to 1.79 ± 0.12μM. Furthermore, bis (7)-tacrine pH GABA currents parallel to the inhibition curve is moved to the alkaline direction. These results show that, under acidic conditions, the extracellular pH on GABA currents in cultured hippocampal neurons from inhibition and bis (7)-tacrine can be modulated by extracellular pH on GABA currents in cultured rat hippocampal neurons inhibition, on the other hand, bis (7)-tacrine GABA currents increased sensitivity to pH inhibition. In certain pathological conditions such as ischemic, bis (7)-tacrine better play the role of great significance.

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