Characterizing antidepressant-like effects of a novel peptide HCN channel inhibitor

表征新型肽 HCN 通道抑制剂的抗抑郁样作用

• 批准号: 9617909
• 负责人: Dane M Chetkovich
• 金额: $ 7.77万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-23 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9617909
• 关键词: Characterizing; antidepressant; like; effects; novel

Major depressive disorder (MDD) affects millions of people worldwide. Most drugs available to treat MDD target brain pathways involving monoaminergic neurotransmitters. Because up to fifty percent of patients do not improve in response to existing therapies, new treatments that target novel mechanisms are needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate Ih, an important current for controlling neuronal excitability. Brain HCN channels are tightly regulated by an auxiliary subunit, TRIP8b (tetratricopeptide repeat-containing Rab8b-interacting protein). Animals lacking TRIP8b and other HCN subunits exhibit an antidepressant-like phenotype, suggesting that inhibiting HCN channels could effectively treat depression. Because the channels are critical in controlling heart rate, directly targeting HCN channels throughout the body is not a viable therapeutic approach. We recently demonstrated that viral overexpression of TRIP8b in the hippocampus leads to changes in HCN channel function with concomitant changes in behaviors associated with antidepressant use. In particular, restoring TRIP8b expression in the hippocampi of TRIP8b knockout mice promoted depression- like behaviors, while a version of TRIP8b with impaired binding to HCN channel pore-forming subunits increased antidepressant-like behavior. These results indicate that the TRIP8b-HCN interaction might be a novel pharmacological target for treating MDD. Although our recent studies with viral gene therapy strengthen the evidence that inhibiting brain HCN might be useful for depression treatment, the approach requires surgery and the technology is not readily translatable to human patients with MDD. On the other hand, inhibitors of the TRIP8b-HCN interaction offer increased ease of use in probing the role of HCN channels in behavior as well as greater translatability as potential therapies. Along theses lines, we have synthesized a small (11 amino acids) peptide capable of binding TRIP8b and blocking the TRIP8b-HCN interaction in vitro. A cell permeable version of this peptide (SNL-CP) was synthesized to allow the peptide to penetrate the blood-brain barrier and cell membranes. In preliminary studies, we show that SNL-CP crosses the plasma membrane of CA1 neurons. We hypothesize that peptide mediated inhibition of TRIP8b's interaction with HCN pore-forming subunits will promote antidepressant-like behavior. In aim 1, we will assess the ability of SNL-CP to disrupt the TRIP8b-HCN interaction after chronic intrahippocampal delivery in mice. These experiments will determine the dosing strategy necessary for therapeutic intervention. In aim 2, we will evaluate the ability of SNL-CP to promote antidepressant-like behavior in mice. The work described in this proposal will evaluate a novel approach to producing antidepressant-like behaviors in mice and could pave the way for a new approach to treating MDD in human patients refractory to existing therapies.

重度抑郁症（MDD）影响全球数百万的人。大多数可用于治疗MDD的药物 涉及单胺能神经递质的靶向脑途径。因为多达50％的患者 不要对现有疗法有所改善，针对新型机制的新疗法是 需要。超极化激活的循环核苷酸门控（HCN）通道介导了IH，这是一个重要的 控制神经元兴奋性的电流。脑HCN通道由辅助机构严格调节 亚基，Trip8b（四肽重复含Rab8b相互作用蛋白）。缺乏Trip8b的动物 其他HCN亚基表现出抗抑郁药样表型，表明抑制HCN通道 可以有效治疗抑郁症。因为这些通道对于控制心率至关重要，所以直接 靶向HCN通道遍布整个身体不是可行的治疗方法。我们最近 证明Trip8b在海马中的病毒过表达导致HCN变化 与抗抑郁药相关的行为变化的通道功能。在 特别是，在TRIP8B敲除小鼠海马中恢复Trip8b表达促进了抑郁症 - 像行为一样，而trip8b的版本与HCN通道孔形成亚基的结合受损 增加抗抑郁药样行为。这些结果表明TRIP8B-HCN相互作用可能是 治疗MDD的新型药理靶标。 尽管我们最近对病毒基因疗法的研究加强了抑制脑HCN的证据 对于抑郁症治疗有用，该方法需要手术，并且该技术不容易 可翻译成MDD的人类患者。另一方面，TRIP8B-HCN相互作用的抑制剂提供 提高了探测HCN通道在行为中的作用以及更大的转换性的易用性 潜在疗法。沿这些线条，我们合成了一个小（11个氨基酸）肽 结合TRIP8B并在体外阻塞TRIP8B-HCN相互作用。该肽的细胞渗透性版本 （SNL-CP）合成以使肽可以穿透血脑屏障和细胞膜。在 初步研究，我们表明SNL-CP越过CA1神经元的质膜。我们 假设肽介导的Trip8b与HCN孔形成的相互作用的抑制作用 亚基将促进抗抑郁药样行为。在AIM 1中，我们将评估SNL-CP的能力 小鼠慢性膜体内递送后，破坏TRIP8B-HCN相互作用。这些实验会 确定治疗干预所需的给药策略。在AIM 2中，我们将评估 SNL-CP促进小鼠抗抑郁样行为。本提案中描述的工作将评估 一种新颖的方法，用于在小鼠中产生类似抗抑郁药的行为，并为新的方式铺平了道路 对现有疗法难治性治疗MDD的方法。