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

Drug Des Devel Ther. 2024 Nov 23:18:5351-5365. doi: 10.2147/DDDT.S489860. eCollection 2024.

Abstract

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.

Keywords: Alzheimer’s disease; anxiety; behavioral Tests; chemokine CXCL2; cognitive dysfunction; dexamethasone.

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Anxiety* / drug therapy
  • Cell Death / drug effects
  • Chemokine CXCL2* / metabolism
  • Cognitive Dysfunction* / drug therapy
  • Dexmedetomidine* / administration & dosage
  • Dexmedetomidine* / pharmacology
  • Disease Models, Animal*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons* / drug effects
  • Neurons* / metabolism
  • Neurons* / pathology
  • Neuroprotective Agents / pharmacology

Substances

  • Dexmedetomidine
  • Chemokine CXCL2
  • Cxcl2 protein, mouse
  • Neuroprotective Agents
  • Amyloid beta-Peptides

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82001493, from Ma KG; No. 82171308 from Chen XL), China Postdoctoral Science Foundation (No.2019M653662, from Ma KG). Fundamental Research Funds for the Central Universities (No. xzy012022098, from Zhu K); Natural Science Basic Research Plan in Shaanxi Province of China (No. 2023-JC-QN-0862, from Zhu K). Science and Technology Talent Support Program of Shaanxi Provincial People’s Hospital (No. 2023BJ-02, from Zhang YM), Research Incubation Fund of Shaanxi Provincial People’s Hospital (No. 2023YJY-01, from Zhang YM).