Department/Institute of Neurobiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, People's Republic of China.
Department of Anesthesiology, Shaanxi Provincial People's Hospital, Xi'an, 710068, People's Republic of China.
Drug Des Devel Ther. 2024 Nov 23;18:5351-5365. doi: 10.2147/DDDT.S489860. eCollection 2024.
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.
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.
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.
Our results suggest that Dex exerts neuroprotective effects by downregulating CXCL2. Dex shows potential as a therapeutic drug for AD.
β-淀粉样蛋白（Aβ）过载诱导的神经炎症和神经元丢失是阿尔茨海默病（AD）进展过程中的关键病理变化。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 在 AD 小鼠中的作用尚不清楚，其神经保护调节机制需要进一步研究。本研究旨在揭示 Dex 如何防止 AD 小鼠的 Aβ 诱导的神经病理学变化和行为功能障碍。
通过将 Aβ 注射到小鼠大脑中建立 AD 小鼠模型，然后腹腔注射 Dex。使用 CXCL2 过表达和 Dex 抑制剂育亨宾来研究 Dex 和 CXCL2 在调节 AD 小鼠神经元丢失、认知下降和焦虑样行为中的作用。进行行为测试以评估小鼠的认知和焦虑状态。进行尼氏染色和免疫荧光实验评估海马神经元和星形胶质细胞的状态。进行 qRT-PCR 检测 CXCL2、IL-1β、iNOS、SPHK1、Bcl2、IFN-γ 和 Caspase 1 的表达。使用 ELISA 试剂盒检测丙二醛（MDA）水平。进行末端 TUNEL 和 Fluoro-Jade C（FJC）染色以测量细胞凋亡率。
在 AD 小鼠中，Dex 治疗显著改善了认知下降和焦虑样行为。与 AD 组相比，Dex+AD 组的神经元数量增加，两组间星形胶质细胞数量无显著差异。Dex 处理的 AD 小鼠的 CXCL2、IL-1β、iNOS 和 SPHK1 水平明显低于 AD 小鼠。CXCL2 过载或育亨宾逆转了 Dex 对 AD 小鼠神经元数量以及认知和焦虑症状的保护作用。
我们的结果表明，Dex 通过下调 CXCL2 发挥神经保护作用。Dex 有望成为 AD 的治疗药物。
