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Effect of Resveratrol on GABA_A-mediated Current in Cultured Rat Cortical Neurons

Author: SunYu
Tutor: LuYaPing
School: Anhui Normal University
Course: Neurobiology
Keywords: Resveratrol GABAA receptor Whole cell patch clamp Primary cultured Cortical neurons
CLC: R285.5
Type: Master's thesis
Year: 2010
Downloads: 57
Quote: 0
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Abstract


Ligand-gated ion channels in the nervous system mediates fast synaptic transmission to changes in the external environment so that the cells can respond quickly. gamma aminobutyric acid type A receptor (GABAA Receptors, GABAARs) is the major inhibitory receptors in the adult mammalian central nervous system (CNS), they belong to the ligand-gated ion superfamily. GABAA receptor activation caused by chloride ion influx, intracellular membrane potential increase hyperpolarization, thereby inhibiting neuronal excitability. Therefore, the GABAA receptor has an important role in regulating neuronal excitability. Resveratrol (3,4 ', 5 - trihydroxy - stilbene) is a polyphenolic compound present in plants, grapes and red wine contain large quantities of this material. The experiments show that plays an effective neuroprotective effect of resveratrol in vivo and in vitro models. Resveratrol has anti-inflammatory, anti-cancer, anti-platelet aggregation and estrogen. However, other studies examined the pharmacological effects of resveratrol on ion channels and receptors. For example, the effect of resveratrol on vascular endothelial cells Ca2 activated K channel has a stimulating effect and strengthen the activation of large conductance potassium channel. It can also inhibit ventricular myocytes L-type calcium current, to reduce dorsal root ganglion cells TTX-sensitive and TTX-resistant Na current, inhibition of lymphocytes and hippocampal neurons voltage-activated potassium current, inhibition of acute rat hippocampal film AMPA / NMDA receptor neurons mediated excitatory postsynaptic current. However, no resveratrol reported the influence of the chloride ion channel, especially in the central nervous system GABAARs reported. In the present study, we use the whole-cell patch-clamp recording method, detection of resveratrol on rat cortical cultured cells GABAA receptor. In the present study, we found that resveratrol concentration-dependent manner reversibly inhibit the GABAA receptor-mediated current, semi-potent inhibition concentration of 48.7 ± 2.4μM. Resveratrol reduced the maximum value of the GABA-induced current and significant change in EC50 values ??and Hill coefficient. Therefore, resveratrol GABAA receptor antagonism on rat cortical neurons in a non-competitive way. Resveratrol inhibited GABAA receptor process is very fast, and this inhibitory effect of drug-eluting within 4 minutes to fully recover. These features Resveratrol is a direct effect on the GABAA receptor. Dynamics analysis showed that resveratrol accelerate the GABAA receptor desensitization, a mechanism to accelerate receptor desensitization is a non-competitive way. In this experiment, resveratrol inhibited GABAA receptor-mediated current in the GABA and resveratrol was eluted at the same time does not appear tail current, the tail current of the emergence of open-channel blocking port (open channel block ) theory of a direct evidence. The same time, in a different mode, resveratrol GABAA receptor mediated effect of suppressing the type of conduction current is stronger inhibitory effect of resveratrol in the pre-administration mode. In the order of the mode of administration, resveratrol still be able to produce effective inhibition of the GABAA receptor mediated currents, which showed that resveratrol in the channel is not open and the receptor binding and final suppression GABAA receptor-mediated currents, suggesting that resveratrol binding sites not in the middle of the channel, these results are more supportive of non-channel port blocking mechanism speculated. Based on the above facts, we hypothesized that Resveratrol may inhibit the GABAA receptor by allosteric regulation. Resveratrol not compete with GABA binding site of the GABAA receptor, which may reduce the affinity of the GABAA receptor for GABA and allosteric modulators and the other sites on the GABAA receptor binding. In summary, our results suggest that resveratrol noncompetitive antagonist of GABAA receptors on cortical neurons. Resveratrol and its metabolites can be through the blood-brain barrier, so resveratrol may have a direct role of GABAA receptors in the cerebral cortex, thereby to adjust the balance of excitatory and inhibitory cortical nervous system as well as between the two, which is the We study resveratrol receptor pharmacology accumulated information.

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