2-(4-methyl-thiazol-5-yl) ethyl nitrate maleate-potentiated GABA A receptor response in hippocampal neurons

• Published in: CNS neuroscience & therapeutics 2018-12, Vol.24 (12), p.1231-1240
• Main Authors: Jiang, Xiao-Mei, Wang, Wei-Ping, Liu, Zhi-Hui, Yin, Hua-Jing, Ma, Hao, Feng, Nan, Wang, Ling, Huang, Hai-Hong, Wang, Xiao-Liang
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Animals; Animals, Newborn; Bicuculline - pharmacology; Cells, Cultured; Chlormethiazole - chemistry; Chlormethiazole - pharmacology; Cholinergic Antagonists - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Flumazenil - pharmacology; GABA Modulators - chemistry; GABA Modulators - pharmacology; GABA-A Receptor Antagonists - pharmacology; gamma-Aminobutyric Acid - pharmacology; Hippocampus - cytology; Long-Term Potentiation - drug effects; Neurons - drug effects; Patch-Clamp Techniques; Rats; Rats, Wistar; Receptors, GABA - metabolism; Scopolamine - pharmacology; Time Factors
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.13033

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 receptors were reported previously; however, the mechanisms were unclear and were explored therefore. 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 receptors in hippocampal neurons and the binding site of NMZM on GABA receptors. NMZM directly activated GABA receptors in hippocampal neurons in a weak manner. However, NMZM could potentiate the response of GABA receptors to GABA and NMZM positively modulated GABA receptors with an EC 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 receptors. NMZM could not affect the etomidate-potentiated GABA current. It suggested that the binding site of NMZM on GABA receptors is the same as etomidate. These results provided support for the neuroprotective effect of NMZM, which was partly dependent on the potentiation of GABA receptors. The etomidate binding site might be a new target for neuronal protection and for drug development.