Divison of Neuroscience & Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
ACS Chem Neurosci. 2024 Sep 18;15(18):3286-3297. doi: 10.1021/acschemneuro.4c00175. Epub 2024 Aug 27.
Treatment-resistant depression (TRD) occurs in almost 50% of the depressed patients. Central kappa opioid receptor (KOR) agonism has been demonstrated to induce depression and anxiety, while KOR antagonism alleviates depression-like symptoms in rodent models and TRD in clinical studies. Previously, we have shown that sustained KOR activation leads to a TRD-like phenotype in mice, and modulation of brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex (PFC) appears to be one of the molecular determinants of the antidepressant response. In the present study, we observed that sustained KOR activation by a selective agonist, U50488, selectively reduced the levels of transcripts , , and CDS (protein-coding Exon IX) in the PFC and cultured primary cortical neurons, which was blocked by selective KOR antagonist, . Considering the crucial role of epigenetic pathways in BDNF expression, we further investigated the role of various epigenetic markers in KOR-induced BDNF downregulation in mice. We observed that treatment with U50488 resulted in selective and specific downregulation of acetylation at the ninth lysine residue of the histone H3 protein (H3K9ac) and upregulation of histone deacetylase 5 (HDAC5) expression in the PFC. Further, using anti-H3K9ac and anti-HDAC5 antibodies in the chromatin immune precipitation assay, we detected decreased enrichment of H3K9ac and increased HDAC5 binding at II and IV transcripts after U50488 treatment, which were blocked by a selective KOR antagonist, . Further mechanistic studies using HDAC5 selective inhibitor, LMK235, in primary cortical neurons and adeno-associated viral shRNA-mediated HDAC5-knockdown in the PFC of mice demonstrated an essential role of HDAC5 in KOR-mediated reduction of expression the PFC and in depression-like symptoms in mice. These results suggest that KOR engages multiple pathways to induce depression-like symptoms in mice and provide novel insights into the mechanisms by which activation of KOR regulates major depressive disorders.
治疗抵抗性抑郁症（TRD）发生在近 50%的抑郁症患者中。已证实中枢κ阿片受体（KOR）激动剂可诱发抑郁和焦虑，而 KOR 拮抗剂可减轻啮齿动物模型中的抑郁样症状和临床研究中的 TRD。先前，我们已经表明，持续的 KOR 激活会导致小鼠出现 TRD 样表型，而前额叶皮层（PFC）中脑源性神经营养因子（BDNF）表达的调节似乎是抗抑郁反应的分子决定因素之一。在本研究中，我们观察到，选择性激动剂 U50488 持续激活 KOR 可选择性降低 PFC 和培养的原代皮质神经元中 、 和 CDS（蛋白编码外显子 IX）的水平，这一作用被选择性 KOR 拮抗剂 阻断。考虑到表观遗传途径在 BDNF 表达中的关键作用，我们进一步研究了各种表观遗传标记在 KOR 诱导的 BDNF 下调中的作用。我们观察到，U50488 治疗导致 PFC 中组蛋白 H3 蛋白第九赖氨酸残基（H3K9ac）的乙酰化选择性和特异性下调，以及组蛋白脱乙酰酶 5（HDAC5）表达上调。此外，在染色质免疫沉淀测定中使用抗 H3K9ac 和抗 HDAC5 抗体，我们检测到 U50488 治疗后 II 和 IV 转录物的 H3K9ac 富集减少，HDAC5 结合增加，这一作用被选择性 KOR 拮抗剂 阻断。在原代皮质神经元中使用 HDAC5 选择性抑制剂 LMK235 和在小鼠 PFC 中使用腺相关病毒 shRNA 介导的 HDAC5 敲低进行的进一步机制研究表明，HDAC5 在 KOR 介导的 PFC 中 表达减少和小鼠的抑郁样症状中发挥重要作用。这些结果表明，KOR 通过多种途径在小鼠中引发抑郁样症状，并为 KOR 激活调节重度抑郁症的机制提供了新的见解。
