Zhong W, Darmani N A
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States.
Front Pharmacol. 2021 Apr 29;12:647021. doi: 10.3389/fphar.2021.647021. eCollection 2021.
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 Ca channel (nifedipine); store-operated Ca entry (MRS 1845); T-type Ca channel (Z944), IPR (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 Ca 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.
超极化激活的环核苷酸门控（HCN）通道的亚型（1 - 4）在中枢和外周神经系统以及许多器官的平滑肌细胞中广泛表达。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已被证明可减少阿扑吗啡诱导的大鼠对糖精偏好的条件性味觉厌恶，提示其可能具有抗恶心/止吐作用。目前，在最小的呕吐模型中，我们发现ZD7288以剂量依赖性方式诱导呕吐，腹腔注射1 mg/kg时最大有效率为100%，脑室内注射10 μg时为83.3%。使用免疫组织化学方法评估了包含催吐核（最后区（AP）、孤束核和迷走神经背运动核）的最小鼩鼱脑干迷走神经背侧复合体（DVC）中HCN通道亚型（1 - 4）的表达。AP中存在高度富集的HCN1和HCN4亚型。腹腔注射1 mg/kg剂量的ZD7288可强烈诱发鼩鼱脑干DVC中的c-Fos表达和ERK1/2磷酸化，但在空肠的肠神经系统中未出现，提示对诱发呕吐有中枢性作用。ZD7288诱发的c-Fos表达仅发生在迷走神经背侧复合体中色氨酸羟化酶2阳性的5-羟色胺能神经元中，表明5-羟色胺能神经元的激活可能促成ZD7288诱导的呕吐。为揭示其催吐作用机制，我们评估了多种止吐药对ZD7288诱发呕吐的疗效，包括以下拮抗剂/抑制剂：ERK1/2（U0126）、L型钙通道（硝苯地平）；储存操纵性钙内流（MRS 1845）；T型钙通道（Z944）、肌醇1,4,5-三磷酸受体（2-APB）、兰尼碱受体（丹曲林）；5-羟色胺能3型受体（帕洛诺司琼）；神经激肽1受体（奈妥吡坦）、多巴胺2型受体（舒必利）以及瞬时受体电位香草酸亚型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了ZD7288诱发的呕吐。总之，ZD7288主要通过中枢机制具有催吐潜力，这一过程涉及钙信号传导和多种催吐受体。由于HCN通道阻滞剂目前被用作/正在被研究作为癌症治疗相关或不相关的心力衰竭、疼痛和认知障碍的治疗候选药物，因此在临床上已有关于其具有催吐潜力的报道。
