The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva).
The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva).
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DOI：
10.3389/fphar.2021.647021
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发表时间：
2021
影响因子：
5.6
通讯作者：
Darmani NA
中科院分区：
文献类型：
--
作者：
Zhong W;Darmani NA
超极化激活的环核苷酸门控 (HCN) 通道的亚型 (1-4) 广泛表达于中枢和周围神经系统以及许多器官的平滑肌细胞中。它们主要用于调节这些组织中的细胞兴奋性。 HCN 通道阻滞剂 ZD7288 已被证明可以减少阿朴吗啡引起的大鼠对糖精偏好的条件性味觉厌恶，表明潜在的止恶心/止吐作用。目前，在最小显示呕吐模型中，我们发现 ZD7288 以剂量依赖性方式诱导呕吐，1 mg/kg（腹腔注射）时的最大功效为 100%，10 µg（i.c.v.）时的最大功效为 83.3%。使用免疫组织化学方法评估包含催吐核（后区（AP）、孤束核和迷走神经背运动核）的最小鼩鼱脑干背侧迷走神经复合体（DVC）中的HCN通道亚型（1-4）表达。 AP 中存在高度富集的 HCN1 和 HCN4 亚型。 1 mg/kg（腹腔注射）剂量的 ZD7288 强烈诱发鼩鼱脑干 DVC 中的 c-Fos 表达和 ERK1/2 磷酸化，但不在空肠的肠神经系统中，表明对诱发呕吐有重要作用。 ZD7288 诱发的 c-Fos 表达仅发生在背侧迷走神经复合体的色氨酸羟化酶 2 阳性血清素神经元中，表明血清素神经元的激活可能导致 ZD7288 诱导的呕吐。为了揭示其催吐作用机制，我们评估了多种止吐药对 ZD7288 诱发呕吐的功效，包括 ERK1/2 (U0126)、L 型 Ca2+ 通道 (硝苯地平) 的拮抗剂/抑制剂；商店操作的 Ca2+ 输入（MRS 1845）； T型Ca2+通道（Z944）、IP3R（2-APB）、RyR受体（丹曲林）； 5-羟色胺能3型受体（帕洛诺司琼）；神经激肽 1 受体 (netupitant)、多巴胺 2 型受体 (sulpride) 和瞬时受体电位香草酸 1 受体激动剂树脂毒素。除舒必利外，所有测试的止吐药均不同程度地减轻 ZD7288 诱发的呕吐。总之，ZD7288 主要通过中枢机制具有催吐潜力，该过程涉及 Ca2+ 信号传导和多种催吐受体。据报道，HCN 通道阻滞剂在临床上具有催吐作用，因为它们目前被用作/研究作为与癌症治疗相关或无关的心力衰竭、疼痛和认知障碍的候选治疗药物。
Subtypes (1–4) of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in the central and peripheral nervous systems, as well as the cells of smooth muscles in many organs. They mainly serve to regulate cellular excitability in these tissues. The HCN channel blocker ZD7288 has been shown to reduce apomorphine-induced conditioned taste aversion on saccharin preference in rats suggesting potential antinausea/antiemetic effects. Currently, in the least shew model of emesis we find that ZD7288 induces vomiting in a dose-dependent manner, with maximal efficacies of 100% at 1 mg/kg (i.p.) and 83.3% at 10 µg (i.c.v.). HCN channel subtype (1–4) expression was assessed using immunohistochemistry in the least shrew brainstem dorsal vagal complex (DVC) containing the emetic nuclei (area postrema (AP), nucleus tractus solitarius and dorsal motor nucleus of the vagus). Highly enriched HCN1 and HCN4 subtypes are present in the AP. A 1 mg/kg (i.p.) dose of ZD7288 strongly evoked c-Fos expression and ERK1/2 phosphorylation in the shrew brainstem DVC, but not in the in the enteric nervous system in the jejunum, suggesting a central contribution to the evoked vomiting. The ZD7288-evoked c-Fos expression exclusively occurred in tryptophan hydroxylase 2-positive serotonin neurons of the dorsal vagal complex, indicating activation of serotonin neurons may contribute to ZD7288-induced vomiting. To reveal its mechanism(s) of emetic action, we evaluated the efficacy of diverse antiemetics against ZD7288-evoked vomiting including the antagonists/inhibitors of: ERK1/2 (U0126), L-type Ca2+ channel (nifedipine); store-operated Ca2+ entry (MRS 1845); T-type Ca2+ channel (Z944), IP3R (2-APB), RyR receptor (dantrolene); the serotoninergic type 3 receptor (palonosetron); neurokinin 1 receptor (netupitant), dopamine type 2 receptor (sulpride), and the transient receptor potential vanilloid 1 receptor agonist, resiniferatoxin. All tested antiemetics except sulpride attenuated ZD7288-evoked vomiting to varying degrees. In sum, ZD7288 has emetic potential mainly via central mechanisms, a process which involves Ca2+ signaling and several emetic receptors. HCN channel blockers have been reported to have emetic potential in the clinic since they are currently used/investigated as therapeutic candidates for cancer therapy related- or unrelated-heart failure, pain, and cognitive impairment.
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影响因子：
3.6
作者：
DARMANI, NA;MOCK, OB;GERDES, GF
通讯作者：
GERDES, GF
影响因子：
3.7
作者：
Casillas-Espinosa, Pablo Miguel;Hicks, Ashleigh;Powell, Kim L.
通讯作者：
Powell, Kim L.
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