Glycogen synthase kinase 3 (GSK-3) is a constitutively active multifunctional serine-threonine kinase which is involved in diverse physiological processes. GSK-3 has been implicated in a wide range of diseases including neurodegeneration, inflammation, diabetes and cancer. GSK-3 is a downstream target for protein kinase B (Akt) which phosphorylates GSK-3 and suppresses its activity. Based upon our preliminary findings, we postulated Akt's involvement in emesis. The aim of this study was to investigate the participation of GSK-3 and the antiemetic potential of two GSK-3 inhibitors (AR-A014418 and SB216763) in the least shrew model of vomiting against fully-effective emetic doses of diverse emetogens, including the nonselective and/or selective agonists of serotonin type 3 (e.g. 5-HT or 2-Methyl-5-HT)-, neurokinin type 1 receptor (e.g. GR73632), dopamine D2 (e.g. apomorphine or quinpirole)-, and muscarinic 1 (e.g. pilocarpine or McN-A-343) receptors, as well as the L-type Ca2+ channel agonist (FPL64176), the sarco/endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin, and the chemotherapeutic agent, cisplatin. We first determined if these emetogens could regulate the phosphorylation level of GSK-3 in the brainstem emetic loci of least shrews and then investigated whether AR-A014418 and SB216763 could protect against the evoked emesis. Phospho-GSK-3α/β Ser21/9 levels in the brainstem and the enteric nerves of jejunum in the small intestine were upregulated following intraperitoneal (i.p.) administration of all the tested emetogens. Furthermore, administration of AR-A014418 (2.5-20 mg/kg, i.p.) dose-dependently attenuated both the frequency and percentage of shrews vomiting in response to i.p. administration of 5-HT (5 mg/kg), 2-Methyl-5-HT (5 mg/kg), GR73632 (5 mg/kg), apomorphine (2 mg/kg), quinpirole (2 mg/kg), pilocarpine (2 mg/kg), McN-A-343 (2 mg/kg), FPL64176 (10 mg/kg), or thapsigargin (0.5 mg/kg). Relatively lower doses of SB216763 exerted antiemetic efficacy, but both inhibitors barely affected cisplatin (10 mg/kg)-induced vomiting. Collectively, these results support the notion that vomiting is accompanied by a downregulation of GSK-3 activity and pharmacological inhibition of GSK-3 protects against pharmacologically evoked vomiting.

中文翻译：

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糖原合酶激酶3（GSK-3）在呕吐中由最少的rew（隐孢子虫）中的特定雌激素引起的关键作用。

糖原合酶激酶3（GSK-3）是一种组成型活性多功能丝氨酸-苏氨酸激酶，参与多种生理过程。GSK-3与多种疾病有关，包括神经变性，炎症，糖尿病和癌症。GSK-3是蛋白激酶B（Akt）的下游靶标，它使GSK-3磷酸化并抑制其活性。根据我们的初步发现，我们推测Akt参与呕吐。这项研究的目的是研究GSK-3的参与以及两种GSK-3抑制剂（AR-A014418和SB216763）在最小剂量的呕吐模型中的呕吐作用，该模型针对各种有效的催吐剂（包括3型5-羟色胺的非选择性和/或选择性激动剂（例如5-HT或2-甲基-5-HT），1型神经激肽受体（例如GR73632），多巴胺D2（例如阿扑吗啡或喹吡罗）和毒蕈碱1（例如毛果芸香碱或McN-A-343）受体，以及L型Ca2 +通道激动剂（FPL64176），肌浆/内质网Ca2 + -ATPase抑制剂thapsigargin，和化学治疗剂顺铂。我们首先确定这些雌激素是否可以调节最少敏锐的脑干催吐位点中GSK-3的磷酸化水平，然后研究AR-A014418和SB216763是否可以预防诱发的呕吐。腹膜内（ip）施用所有测试的致敏剂后，小肠的脑干和空肠肠神经中的磷酸化GSK-3α/βSer21 / 9水平上调。此外，AR-A014418（2.5-20 mg / kg，ip ）剂量依赖性地降低腹膜内注射5-HT（5 mg / kg），2-甲基-5-HT（5 mg / kg），GR73632（5 mg / kg）时sh呕吐的频率和百分比，阿扑吗啡（2 mg / kg），喹吡罗（2 mg / kg），毛果芸香碱（2 mg / kg），McN-A-343（2 mg / kg），FPL64176（10 mg / kg）或毒胡萝卜素（0.5 mg /公斤）。相对较低剂量的SB216763具有止吐作用，但两种抑制剂几乎都不会影响顺铂（10 mg / kg）引起的呕吐。总的来说，这些结果支持了呕吐伴有GSK-3活性下调和GSK-3的药理抑制作用防止药理诱发的呕吐的观点。或毒胡萝卜素（0.5 mg / kg）。相对较低剂量的SB216763具有止吐作用，但两种抑制剂几乎都不会影响顺铂（10 mg / kg）引起的呕吐。总的来说，这些结果支持了呕吐伴有GSK-3活性下调和GSK-3的药理抑制作用防止药理诱发的呕吐的观点。或毒胡萝卜素（0.5 mg / kg）。相对较低剂量的SB216763具有止吐作用，但两种抑制剂几乎都不会影响顺铂（10 mg / kg）引起的呕吐。总的来说，这些结果支持了呕吐伴有GSK-3活性下调和GSK-3的药理抑制作用防止药理诱发的呕吐的观点。