Neuroprotective effect of dexmedetomidine on autophagy in mice administered intracerebroventricular injections of Aβ25–35

Frontiers in Pharmacology

Pharmacology

Youn Young Lee¹  Kyung Eun Lee²  Eun Cheng Suh²  Jong In Han³  Sooyoung Cho³ 

[1] Department of Anesthesiology and Pain Medicine, Ewha Womans University Seoul Hospital, Seoul, Republic of Korea;Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea;Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea;Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea;Department of Anesthesiology and Pain Medicine, Ewha Womans University Seoul Hospital, Seoul, Republic of Korea;

关键词: dexmedetomidine;    autophagy;    Alzheimer’s disease;    amyloid β-protein;    behavioral test;   

DOI  :  10.3389/fphar.2023.1184776

 received in 2023-03-12, accepted in 2023-08-08,  发布年份 2023

来源: Frontiers

【 摘 要 】

Alzheimer’s disease (AD), one of the most prevalent neurodegenerative diseases is associated with pathological autophagy-lysosomal pathway dysfunction. Dexmedetomidine (Dex) has been suggested as an adjuvant to general anesthesia with advantages in reducing the incidence of postoperative cognitive dysfunction in Dex-treated patients with AD and older individuals. Several studies reported that Dex improved memory; however, evidence on the effects of Dex on neuronal autophagy dysfunction in the AD model is lacking. We hypothesized that Dex administration would have neuroprotective effects by improving pathological autophagy dysfunction in mice that received an intracerebroventricular (i.c.v.) injection of amyloid β-protein fragment 25–35 (Aβ25–35) and in an autophagy-deficient cellular model. In the Y-maze test, Dex reversed the decreased activity of Aβ25–35 mice. Additionally, it restored the levels of two memory-related proteins, phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII) and postsynaptic density-95 (PSD-95) in Aβ25–35 mice and organotypic hippocampal slice culture (OHSC) with Aβ25–35. Dex administration also resulted in decreased expression of the autophagy-related microtubule-associated proteins light chain 3-II (LC3-II), p62, lysosome-associated membrane protein2 (LAMP2), and cathepsin D in Aβ25–35 mice and OHSC with Aβ25–35. Increased numbers of co-localized puncta of LC3-LAMP2 or LC3-cathepsin D, along with dissociated LC3-p62 immunoreactivity following Dex treatment, were observed. These findings were consistent with the results of western blots and the transformation of double-membrane autophagosomes into single-membraned autolysosomes in ultrastructures. It was evident that Dex treatment alleviated impaired autolysosome formation in Aβ mice. Our study demonstrated the improvement of memory impairment caused by Dex and its neuroprotective mechanism by investigating the role of the autophagy-lysosomal pathway in a murine Aβ25–35 model. These findings suggest that Dex could be used as a potential neuroprotective adjuvant in general anesthesia to prevent cognitive decline.

【 授权许可】

Unknown   
Copyright © 2023 Lee, Han, Lee, Cho and Suh.