Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, PL 20-033 Lublin, Poland.
Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
Cells. 2023 Jan 9;12(2):264. doi: 10.3390/cells12020264.
The G-protein coupled receptor 39 (GPR39) is gaining increasing attention as a target for future drugs, yet there are gaps in the understanding of its pharmacology. Zinc is an endogenous agonist or an allosteric modulator, while TC-G 1008 is a synthetic, small molecule agonist. Zinc is also a positive allosteric modulator for the activity of TC-G 1008 at GPR39. Activation of GPR39 by TC-G 1008 facilitated the development of epileptogenesis in the pentylenetetrazole (PTZ)-induced kindling model of epilepsy. Congruently, TC-G 1008 decreased the seizure threshold in the maximal electroshock seizure threshold (MEST) test. Here, we investigated the effects of TC-G 1008 under the condition of zinc deficiency. Mice were fed a zinc-adequate diet (ZnA, 50 mg Zn/kg) or a zinc-deficient diet (ZnD, 3 mg Zn/kg) for 4 weeks. Following 4 weeks of dietary zinc restriction, TC-G 1008 was administered as a single dose and the MEST test was performed. Additional groups of mice began the PTZ-kindling model during which TC-G 1008 was administered repeatedly and the diet was continued. TC-G 1008 administered acutely decreased the seizure threshold in the MEST test in mice fed the ZnD diet but not in mice fed the ZnA diet. TC-G 1008 administered chronically increased the maximal seizure severity and the percentage of fully kindled mice in those fed the ZnA diet, but not in mice fed the ZnD diet. Our data showed that the amount of zinc in a diet is a factor contributing to the effects of TC-G 1008 in vivo.
G 蛋白偶联受体 39（GPR39）作为未来药物的靶点越来越受到关注，但人们对其药理学的理解仍存在空白。锌是内源性激动剂或变构调节剂，而 TC-G 1008 是一种合成的小分子激动剂。锌也是 GPR39 活性的 TC-G 1008 的正变构调节剂。TC-G 1008 激活 GPR39 促进了戊四氮（PTZ）诱导的癫痫点燃模型中癫痫发生的发展。一致地，TC-G 1008 降低了最大电休克惊厥阈值（MEST）测试中的惊厥阈值。在这里，我们在缺锌的情况下研究了 TC-G 1008 的作用。将小鼠喂食锌充足的饮食（ZnA，50 mg Zn/kg）或缺锌的饮食（ZnD，3 mg Zn/kg）4 周。在锌限制饮食 4 周后，给予 TC-G 1008 单次剂量并进行 MEST 测试。另外几组小鼠开始进行 PTZ 点燃模型，在此期间反复给予 TC-G 1008 并继续喂食饮食。急性给予 TC-G 1008 降低了喂食 ZnD 饮食的小鼠 MEST 测试中的惊厥阈值，但不降低喂食 ZnA 饮食的小鼠。慢性给予 TC-G 1008 增加了喂食 ZnA 饮食的小鼠的最大惊厥严重程度和完全点燃的小鼠百分比，但不增加喂食 ZnD 饮食的小鼠。我们的数据表明，饮食中的锌量是 TC-G 1008 在体内作用的一个因素。
