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

Abstract Current evidence suggests that dexmedetomidine (Dex) can be used as an adjuvant to general anesthesia for the elderly with or without neurodegenerative diseases, such as Alzheimer's disease (AD), since it has perioperative analgesic properties and can prevent postoperative delirium. Dysfunction involving the autophagy-lysosomal pathway is thought to underlie the pathological mechanism of AD. Evidence regarding the effects of Dex on neuronal autophagy dysfunction in mice with AD is lacking. Therefore, we hypothesized that administration of Dex could exert neuroprotective effects by ameliorating 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. Low dose Dex treatment reversed decreases in percentage of alternation in the Y-maze test. It restored levels of phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII) and postsynaptic density-95 (PSD-95), both memory-related proteins. Dex also protected synapses from Aβ-induced toxicity in mice injected with Aβ25−35. Furthermore, increased expression of the autophagy-related microtubule-associated protein light chain3- II (LC3-II), p62, and lysosome-associated membrane protein2 (LAMP2) in Aβ25−35 mice was reduced after low-dose Dex treatment, ameliorating aberrant autophagic reflux. The present study demonstrated that low-dose Dex treatment ameliorated memory and learning impairments. It’s neuroprotective mechanism was associated with autophagic flux in a murine Aβ25−35 model. These findings suggest that Dex could represent an effective clinical approach for AD patients as a neuroprotective adjuvant in anesthesia.