Open Access2‐(4‐methyl‐thiazol‐5‐yl) ethyl nitrate maleate‐potentiated GABA A receptor response in hippocampal neurons
Author(s) -
Jiang XiaoMei,
Wang WeiPing,
Liu ZhiHui,
Yin HuaJing,
Ma Hao,
Feng Nan,
Wang Ling,
Huang HaiHong,
Wang XiaoLiang
Publication year - 2018
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13033
Subject(s) - long term potentiation , gabaa receptor , chemistry , pharmacology , receptor , hippocampal formation , neuroprotection , long term depression , dentate gyrus , neuroscience , glutamate receptor , biochemistry , biology , ampa receptor
Summary Aims 2‐(4‐methyl‐thiazol‐5‐yl) ethyl nitrate maleate (NMZM), a derivative of clomethiazole (CMZ), had been investigated for the treatment of Alzheimer's disease (AD). The beneficial effects of NMZM in AD included reversing cognitive deficit, improving learning and memory as well as neuroprotection. The pharmacological effects of NMZM on GABA A receptors were reported previously; however, the mechanisms were unclear and were explored therefore. Results In this study, we demonstrated that NMZM improved learning and memory by alleviating scopolamine‐induced long‐term potentiation (LTP) suppression in the dentate gyrus of rats, indicating that NMZM had protective effects against scopolamine‐induced depression of LTP. Next, we investigated the action of NMZM on GABA A receptors in hippocampal neurons and the binding site of NMZM on GABA A receptors. NMZM directly activated GABA A receptors in hippocampal neurons in a weak manner. However, NMZM could potentiate the response of GABA A receptors to GABA and NMZM positively modulated GABA A receptors with an EC 50 value of 465 μmol/L at 3 μmol/L GABA while this potentiation at low concentration of GABA (1, 3 μmol/L) was more significant than that at high concentration (10, 30 μmol/L). In addition, NMZM could enhance GABA currents after using diazepam and pentobarbital, the positive modulators of GABA A receptors. NMZM could not affect the etomidate‐potentiated GABA A current. It suggested that the binding site of NMZM on GABA A receptors is the same as etomidate. Conclusions These results provided support for the neuroprotective effect of NMZM, which was partly dependent on the potentiation of GABA A receptors. The etomidate binding site might be a new target for neuronal protection and for drug development.