右美托咪定通过抑制AD小鼠CA1区的CXCL2减轻神经元死亡、认知能力下降和焦虑样行为

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-11-23 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S489860

Kaige Ma, Chanyuan An, Mai Li, Yuming Zhang, Minghe Ren, Yuyang Wei, Wenting Xu, Ruoxi Wang, Yudan Bai, Hanyue Zhang, Xiyue Liu, Shengfeng Ji, Xinlin Chen, Kun Zhu

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引用次数: 0

摘要

目的：β-淀粉样蛋白超载引起的神经炎症和神经元丢失是阿尔茨海默病（AD）进展过程中出现的关键病理变化。右美托咪定（Dex）对神经系统具有神经保护和抗炎作用。然而，Dex对AD小鼠的影响仍不清楚，其神经保护调节机制也有待进一步研究。本研究旨在揭示Dex如何保护AD小鼠免受Aβ诱导的神经病理学改变和行为功能障碍的影响：方法：向小鼠脑内注射Aβ，然后腹腔注射Dex，建立AD小鼠模型。用CXCL2过表达和Dex抑制剂育亨宾研究Dex和CXCL2在调节AD小鼠神经元丢失、认知能力下降和焦虑样行为中的作用。行为测试用于评估小鼠的认知和焦虑状况。通过 qRT-PCR 检测 CXCL2、IL-1β、INOS、SPHK1、Bcl2、IFN-γ 和 Caspase 1 的表达。用酶联免疫吸附试剂盒检测丙二醛（MDA）水平。末端 TUNEL 和荧光玉 C（FJC）染色用于测量细胞凋亡率：结果：Dex治疗后，AD小鼠的认知能力下降和焦虑样行为明显改善。与AD组相比，Dex + AD组小鼠的神经元数量有所增加，而星形胶质细胞的数量在两组间无明显差异。经 Dex 处理的 AD 小鼠的 CXCL2、IL-1β、iNOS 和 SPHK1 水平明显低于 AD 小鼠。CXCL2或育亨宾的超载逆转了Dex对AD小鼠神经元数量、认知和焦虑症状的保护作用：我们的研究结果表明，Dex通过下调CXCL2发挥神经保护作用。结论：我们的研究结果表明，Dex 可通过下调 CXCL2 发挥神经保护作用。

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Dexmedetomidine Attenuated Neuron Death, Cognitive Decline, and Anxiety-Like Behavior by Inhibiting CXCL2 in CA1 Region of AD Mice.

Purpose: β-amyloid overload-induced neuroinflammation and neuronal loss are key pathological changes that occur during the progression of Alzheimer's disease (AD). Dexmedetomidine (Dex) exhibits neuroprotective and anti-inflammatory effects on the nervous system. However, the effect of Dex in AD mice remains unclear, and its neuroprotective regulatory mechanism requires further investigation. This study aimed to reveal how Dex protects against Aβ induced neuropathological changes and behavior dysfunction in AD mice.

Methods: An AD mouse model was established by the injection of Aβ into the brains of mice, followed by intraperitoneal injection with Dex. CXCL2 overexpression and Yohimbine, a Dex inhibitor, were used to investigate the role of Dex and CXCL2 in the regulation of neuronal loss, cognitive decline, and anxiety-like behavior in AD mice. Behavioral tests were performed to evaluate the cognitive and anxiety status of the mice. Nissl staining and immunofluorescence experiments were conducted to evaluate the status of the hippocampal neurons and astrocytes. qRT-PCR was performed to detect the expression of CXCL2, IL-1β, INOS, SPHK1, Bcl2, IFN-γ, and Caspase 1. The malondialdehyde (MDA) level was detected using an ELISA kit. Terminal TUNEL and Fluoro-Jade C (FJC) staining were used to measure the cell apoptosis rate.

Results: In AD mice, cognitive decline and anxiety-like behaviors were significantly improved by the Dex treatment. The number of neurons was increased in mice in the Dex + AD group compared to those in the AD group, and the number of astrocytes was not significantly different between the two groups. CXCL2, IL-1β, iNOS, and SPHK1 levels were significantly lower in Dex-treated AD mice than those in AD mice. Overloading of CXCL2 or Yohimbine reversed the protective effect of Dex on neuron number and cognitive and anxiety symptoms in AD mice.

Conclusion: Our results suggest that Dex exerts neuroprotective effects by downregulating CXCL2. Dex shows potential as a therapeutic drug for AD.

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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.