Universitas Indonesia Conferences, Asian Federation for Pharmaceutical Sciences (AFPS) 2019

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2-(4-methyl-thiazol-5-yl) ethyl nitrate maleate (NMZM) potentiated GABAA receptor response and played a role in neuroprotection
Weiping Wang, Xiaomei Jiang, Nan Feng, Ling Wang, Xiaoliang Wang

Last modified: 2019-06-16


Background: 2-(4-methyl-thiazol-5-yl) ethyl nitrate maleate (NMZM, also called W1302), a derivative of clomethiazole (CMZ), was developed for the treatment of Alzheimer’s disease (AD) and vascular dementia (VaD) by Institute of Materia Medica, Chinese Academy of Medical Sciences. The beneficial effects of NMZM in AD included reversing cognitive deficit, improving learning and memory as well as neuroprotection. Objective: The present study aimed to clarify the pharmacological effects of NMZM on neuroprotection underlying cerebral ischemia and dementia and the relevant mechanisms related to GABAA receptors. Materials and Methods: APP/PS1 transgenic mice and Aβ1-42- and scopolamine-induced dementia animal models were used to evaluate the improvements of learning and memory deficits by NMZM and patch clamp recordings were used to observe the binding site of NMZM to GABAA receptor. Results: We demonstrated that NMZM obviously improved learning and memory deficits in APP/PS1 transgenic mice and Aβ1-42- and scopolamine-induced dementia animal models. Meanwhile, we found that NMZM directly activated GABAA receptors in hippocampus neurons at a high concentration. However, it could potentiate the response of GABAA receptors to GABA, NMZM positively modulated GABAA receptors with an EC50 value of 465 μM at 3 μM GABA. While this potentiation at low concentration of GABA (1, 3 μM) was more significant than that at high concentration (10, 30 μM). In addition, NMZM could enhance GABA currents after using diazepam and pentobarbital, the positive modulators of GABAA receptors. NMZM could not affect the etomidate-potentiated GABAA current. It suggested that the binding site of NMZM at GABAA receptors is the same as etomidate, which binds to β-subunit. NMZM potentiated GABAA receptor as a positive allosteric modulator, but it is not a direct activator. Conclusion: These results provided support for the neuroprotective effects of NMZM, which was partly dependent on the potentiation of GABAA receptors. The etomidate binding site for GABAA receptor might be a new target for neuroprotection and drug development.