Central and peripheral emetic loci contribute to vomiting evoked by the Akt inhibitor MK-2206 in the least shrew model of emesis.
Central and peripheral emetic loci contribute to vomiting evoked by the Akt inhibitor MK-2206 in the least shrew model of emesis.
复制标题
DOI：
10.1016/j.ejphar.2021.174065
复制
发表时间：
2021-06-05
影响因子：
5
通讯作者：
Darmani NA
中科院分区：
文献类型：
--
作者：
Zhong W;Chebolu S;Darmani NA
Akt（蛋白激酶 B）信号在多种癌症中经常被激活。 Akt 抑制剂如哌立福辛和 MK-2206 已被评估为潜在的癌症化疗药物。虽然这两种药物通常耐受性良好，但最常见的副作用之一是呕吐，这是一个主要问题。在这里，我们研究了这些 Akt 抑制剂是否会在最小鼩鼱呕吐模型中引起呕吐。事实上，哌立福辛和 MK-2206 均能诱导呕吐，50 mg/kg（腹腔注射）时的最大功效分别为 90%，10 mg/kg（腹腔注射）时的最大功效分别为 100%。 MK-2206（10 mg/kg，腹腔注射）增加了鼩鼱脑干背侧迷走神经复合体（DVC）催吐核中央和空肠外周的 c-Fos 免疫反应性。 MK-2206 还在 DVC 催吐核和空肠肠神经系统中引起细胞外信号调节激酶 1/2 (ERK1/2) 的磷酸化。 ERK1/2 抑制剂 U0126 抑制 MK-2206 诱导的呕吐，剂量依赖性。然后，我们评估了多种止吐药对 MK-2206 诱发呕吐的抑制功效，包括 L 型 Ca2+ 通道拮抗剂/抑制剂（硝苯地平，2.5 mg/kg，皮下注射（皮下注射））；糖原合酶激酶 3 (GSK-3)（AR-A014418 10 mg/kg 和 SB216763 0.25 mg/kg，腹腔注射）； 5-羟色胺 5-HT3 受体（帕洛诺司琼 0.5 mg/kg，皮下注射）； P 物质神经激肽 NK1 受体（奈妥匹坦 10 mg/kg，腹腔注射）和多巴胺 D2/3 受体（舒必利 8 mg/kg，皮下注射）。所有测试的拮抗剂/阻滞剂都不同程度地减弱了催吐参数。总之，这是第一项证明 Akt 的药理学抑制如何通过中枢和外周机制引起呕吐的研究，该过程涉及多个催吐受体。
Akt (protein kinase B) signaling is frequently activated in diverse cancers. Akt inhibitors such as perifosine and MK-2206 have been evaluated as potential cancer chemotherapeutics. Although both drugs are generally well tolerated, among their most common side-effects vomiting is a major concern. Here we investigated whether these Akt inhibitors evoke emesis in the least shrew model of vomiting. Indeed, both perifosine and MK-2206 induced vomiting with maximal efficacies of 90% at 50 mg/kg (i.p.) and 100% at 10 mg/kg (i.p.), respectively. MK-2206 (10 mg/kg, i.p.) increased c-Fos immunoreactivity both centrally in the shrew brainstem dorsal vagal complex (DVC) emetic nuclei, and peripherally in the jejunum. MK-2206 also evoked phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in both the DVC emetic nuclei and the enteric nervous system in the jejunum. The ERK1/2 inhibitor U0126 suppressed MK-2206-induced emesis dose-dependently. We then evaluated the suppressive efficacy of diverse antiemetics against MK-2206-evoked vomiting including antagonists/inhibitors of the: L-type Ca2+ channel (nifedipine at 2.5 mg/kg., subcutaneously (s.c.)); glycogen synthase kinase 3 (GSK-3) (AR-A014418 at 10 mg/kg and SB216763 at 0.25 mg/kg., i.p.); 5-hydroxytryptamine 5-HT3 receptor (palonosetron at 0.5 mg/kg, s.c.); substance P neurokinin NK1 receptor (netupitant at 10 mg/kg., i.p.) and dopamine D2/3 receptor (sulpride at 8 mg/kg, s.c.). All tested antagonists/blockers attenuated emetic parameters to varying degrees. In sum, this is the first study to demonstrate how pharmacological inhibition of Akt evokes vomiting via both central and peripheral mechanisms, a process which involves multiple emetic receptors.
登录
查看更多内容
影响因子：
2.9
作者：
Darmani, Nissar A.;Crim, Jennifer L.;Ramirez, Juan
通讯作者：
Ramirez, Juan
影响因子：
3.6
作者：
Darmani, Nissar A.;Zhong, Weixia;Mercadante, Frank
通讯作者：
Mercadante, Frank
影响因子：
2.5
作者：
BULLITT, E
通讯作者：
BULLITT, E
影响因子：
3.6
作者：
Darmani, NA;Crim, JL
通讯作者：
Crim, JL
影响因子：
5
作者：
Darmani, Nissar A.;Janoyan, Jano J.;Ramirez, Juan
通讯作者：
Ramirez, Juan