Jujuboside A Regulates Calcium Homeostasis and Structural Plasticity to Alleviate Depression-Like Behavior via Shh Signaling in Immature Neurons.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2024-10-12 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S479055

Ziyan Zhong, Jian Liu, Yan Luo, Mei Wu, Feng Qiu, Hongqing Zhao, Yang Liu, Yajing Wang, Hongping Long, Lei Zhao, Yuhong Wang, Yuanshan Han, Pan Meng

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Abstract

Background: Depression, a leading cause of disability worldwide, is characterized by dysfunction of immature neurons, resulting in dysregulated calcium homeostasis and impaired structural plasticity. Jujuboside A (JuA), a biologically active compound derived from Semen Ziziphi Spinosae, has demonstrated anti-anxiety and anti-insomnia properties. Recent studies suggest that JuA may be a promising antidepressant, but its underlying mechanisms remain unclear.

Methods: Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS) to induce a depression model. JuA (12.5 mg/kg, 25 mg/kg, 50 mg/kg) was administered orally for 4 weeks. Emotional and cognitive function were assessed. Monoamine neurotransmitter levels were measured using enzyme-linked immunosorbent assay (ELISA). The number of immature neurons and calcium homeostasis were evaluated by immunofluorescence. Western blotting and immunofluorescence were employed to detect the expression of Sonic hedgehog (Shh) signaling proteins. Additionally, lentiviral vector expressing Shh shRNA (LV-Shh-RNAi) were infused intracerebrally to investigate the role of Shh in JuA's antidepressant effects.

Results: JuA significantly ameliorated depressive-like behavior and cognitive dysfunction in CUMS rats, increased monoamine neurotransmitter levels in serum and hippocampal tissue, reduced the number of BrdU/DCX (bromodeoxyuridine/doublecortin)-positive immature neurons, and attenuated calcium ion (Ca²⁺) concentration and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) levels in immature neurons. JuA also markedly elevated synaptic density and prominence complexity, upregulated Shh, Gli family zinc finger 1 and 2 (Gli1/2), synaptophysin (Syn) and postsynaptic density protein-95 (PSD-95) expression in the ventral dentate gyrus (vDG). However, knockdown of Shh in the vDG counteracted JuA's therapeutic effects.

Conclusion: These findings collectively suggest that JuA improves depressive-like behavior in CUMS rats by modulating calcium homeostasis and synaptic structural plasticity in immature neurons through the Shh signaling pathway.

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大枣苷 A 通过 Shh 信号调节未成熟神经元的钙平衡和结构可塑性，从而缓解抑郁样行为

背景：抑郁症是导致全球残疾的主要原因，其特征是未成熟神经元功能失调，导致钙平衡失调和结构可塑性受损。大枣苷 A（Jujuboside A，简称 JuA）是从酸枣仁中提取的一种生物活性化合物，具有抗焦虑和抗失眠的特性。最近的研究表明，JuA 可能是一种很有前途的抗抑郁剂，但其潜在机制仍不清楚：方法：对 Sprague-Dawley 大鼠施加慢性不可预测轻度应激（CUMS）以诱导抑郁模型。连续4周口服JuA（12.5毫克/千克、25毫克/千克、50毫克/千克）。对情绪和认知功能进行评估。使用酶联免疫吸附试验（ELISA）测量单胺类神经递质水平。免疫荧光法评估了未成熟神经元的数量和钙稳态。用 Western 印迹法和免疫荧光法检测音速刺猬（Shh）信号蛋白的表达。此外，脑内注入表达Shh shRNA（LV-Shh-RNAi）的慢病毒载体，以研究Shh在JuA抗抑郁作用中的作用：结果：JuA明显改善了CUMS大鼠的抑郁样行为和认知功能障碍，提高了血清和海马组织中单胺神经递质的水平，减少了BrdU/DCX（溴脱氧尿苷/双皮质素）阳性未成熟神经元的数量，降低了未成熟神经元中钙离子（Ca2+）的浓度和Ca2+/钙调蛋白依赖性蛋白激酶II（CaMKII）的水平。JuA 还显著提高了突触密度和突起复杂性，上调了腹侧齿状回（vDG）中 Shh、Gli 家族锌指 1 和 2（Gli1/2）、突触素（Syn）和突触后密度蛋白-95（PSD-95）的表达。然而，在 vDG 中敲除 Shh 会抵消 JuA 的治疗效果：这些研究结果共同表明，JuA 可通过 Shh 信号通路调节未成熟神经元的钙稳态和突触结构可塑性，从而改善 CUMS 大鼠的抑郁样行为。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.