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. 2022 Sep 20:14:978768.
doi: 10.3389/fnagi.2022.978768. eCollection 2022.

Dexmedetomidine exerts an anti-inflammatory effect via α2 adrenoceptors to alleviate cognitive dysfunction in 5xFAD mice

Su-Mei Luo  1 , Long-Yan Li  1   2 , Li-Zhe Guo  1 , Lu Wang  1 , Yan-Feng Wang  1 , Na Chen  1 , E Wang  1   2
Affiliations

Dexmedetomidine exerts an anti-inflammatory effect via α2 adrenoceptors to alleviate cognitive dysfunction in 5xFAD mice

Su-Mei Luo et al. Front Aging Neurosci. .

Abstract

Background: Inflammation promotes the progression of Alzheimer's disease (AD). In this study, we explored the effect of dexmedetomidine on inflammation and cognitive function in a mouse model of AD. Methods: 5xFAD mice were intragastrically administered saline, dexmedetomidine, or dexmedetomidine and yohimbine for 14 days. The effects of dexmedetomidine on the acquisition and retention of memory in the Morris water-maze test and Y maze were evaluated. The deposition of amyloid beta protein (Abeta) and cytokine levels in the hippocampus were assessed. The expression of Bace1 protein and NFκB-p65 protein was assessed by Western blotting. Results: Compared with WT mice, 5xFAD mice exhibited cognitive impairment in the Morris water maze test and Y maze test. Cognitive decline was alleviated by dexmedetomidine and this was reversed by the α2 adrenoceptor antagonist yohimbine. Compared with saline treatment, dexmedetomidine led to a reduction in the Abeta deposition area (p < 0.05) and in the mean gray value (p < 0.01) in the hippocampus of 5xFAD mice. Compared with saline treatment, dexmedetomidine inhibited the activation of astrocytes and microglia in the hippocampal DG of 5xFAD mice and reduced the area of GFAP (p < 0.01) and IBA1 (p < 0.01). The level of IL-1β in the hippocampus decreased significantly after dexmedetomidine treatment compared with saline treatment in 5xFAD mice (p < 0.01). Yohimbine neutralized the effects of dexmedetomidine. Dexmedetomidine inhibited the expression of BACE1 and NF-κB p65 (p < 0.01), and these changes were reversed by yohimbine treatment. Conclusion: Dexmedetomidine alleviates cognitive decline, inhibits neuroinflammation, and prevents the deposition of Abeta in 5xFAD mice. The effect is mediated by the α2 adrenoceptor-mediated anti-inflammatory pathway. Dexmedetomidine may be effective for the treatment of AD and a better choice for the sedation of AD.

Keywords: Alzheimer’s disease; amyloid plaques; dexmedetomidine; neuroinflammation; yohimbine.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Dexmedetomidine improves learning and memory ability in 5xFAD mice. The data from the Morris water maze (A–D) and Y maze (E,F) were recorded and statistically analyzed. Panel (A) represents latency during the acquisition phase (means ± SEM, two-way repeated measures ANOVA and Bonferroni post-hoc test, *p < 0.05, AD+NC compared to the WT+NC group). Panel (B) represents the number of animals crossing the platform. Panel (C) represents swimming speed by mice in the target quadrant during the probe trial. Panel (D) represents video tracks of the probe trial. Panel (E) represents time spent in the new arm of the Y maze. Panel (F) represents the percentage of new arm entries in the Y maze (means ± SEM, ANOVA, Tukey’s test, *p < 0.05, ***p < 0.001, ****p < 0.0001). n = 12 in each group.
Figure 2
Figure 2
Dexmedetomidine alleviates the deposition of Aβ (A,B,C,D) (means ± SD, ANOVA, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). (A) Immunofluorescence staining of hippocampal sections from WT and 5xFAD mice, scale bars, 200 μm. (B) Immunofluorescence staining of the hippocampal DG sections from WT and 5xFAD mice, scale bars, 100 μm. (C) Bar graph represents Abeta expression levels in the hippocampus. (D) The bar graph represents Abeta expression levels in the hippocampus DG.
Figure 3
Figure 3
Panels (A,B) show ELISA data of IL-1β and IL-6 expression levels in the hippocampus (n = 6 in each group). (C) The expression level of Bace1 in qRT-PCR (n = 6 in each group). *p < 0.05, ***p < 0.001, ****p < 0.0001.
Figure 4
Figure 4
Dexmedetomidine inhibited glial cell activation in the hippocampus DG of 5xFADmice (means ± SD, ANOVA, **p < 0.01). (A) Representative images of GFAP-positive staining in the hippocampus DG from WT and 5xFAD mice, scale bars, 100 μm. (B) High magnification images of GFAP-positive staining in the hippocampus DG from WT and 5xFAD mice, scale bars, 50 μm. (C,D) The bar graph represents GFAP expression levels in the hippocampus DG.
Figure 5
Figure 5
Dexmedetomidine inhibited glial cell activation in the hippocampus DG of 5xFAD mice (means ± SD, ANOVA, **p < 0.01, ***p < 0.001). (A) Representative images of IBA1-positive staining in the hippocampus DG from WT and 5xFAD mice, scale bars, 100 μm. (B) High magnification images of IBA1-positive staining in the hippocampus DG from WT and 5xFAD mice, scale bars, 50 μm. (C,D) The bar graph represents IBA1 expression levels in the hippocampus DG (n = 6 in each group).
Figure 6
Figure 6
Dexmedetomidine downregulates the expression of Bace1 (A,C) and NF-κB p65 (B,D; means ± SD, ANOVA, *p < 0.05, **p < 0.01). (A) Western blotting data showing Bace1 expression levels in the hippocampus. (B) Western blotting data of NF-κB p65 expression levels in the hippocampus. (C) The bar graph represents Bace1 expression levels in the hippocampus. (D) The bar graph represents NF-κB p65 expression levels in the hippocampus (n = 6 in each group).
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