Font Size: 

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 GABA_A receptors. Materials and Methods: APP/PS1 transgenic mice and Aβ_1-42- 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 GABA_A receptor. Results: We demonstrated that NMZM obviously improved learning and memory deficits in APP/PS1 transgenic mice and Aβ_1-42- and scopolamine-induced dementia animal models. Meanwhile, we found that NMZM directly activated GABA_A receptors in hippocampus neurons at a high concentration. However, it could potentiate the response of GABA_A receptors to GABA, NMZM positively modulated GABA_A 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 GABA_A receptors. NMZM could not affect the etomidate-potentiated GABA_A current. It suggested that the binding site of NMZM at GABA_A 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 GABA_A receptors. The etomidate binding site for GABA_A receptor might be a new target for neuroprotection and drug development.