Abstract: Objective To investigate the neuroprotective effect of dexmedetomidine(Dex)on isoflurane-induced postoperative cognitive dysfunction(POCD)in mice and elucidate its underlying mechanism. Methods Fifty SPF-grade aged mice were randomly divided into five groups:control,model,Dex,SFN(Nrf2 activator),and Dex+SFN.Except for the control group,all mice underwent open abdominal surgery under isoflurane anesthesia to establish the POCD model.Cognitive function was assessed using the open field test and Morris water maze test.Hematoxylin-eosin(HE)staining was used to observe morphological changes in hippocampal neurons.TUNEL staining was employed to detect hippocampal neuronal apoptosis.Western blotting was performed to measure the expression levels of Nrf2 and HO-1 proteins in hippocampal tissue. Results Compared with the control group,the model group exhibited significant behavioral inhibition:Reduced total distance traveled[(13.45±1.01)vs.(16.35±1.08)m,P<0.01]and decreased time spent in the center of the open field[(11.05±1.07)vs.(14.21±1.14)s,P<0.01].The model group also showed severe spatial learning and memory impairment:Increased escape latency[(52.34±3.25)vs.(11.45±0.52)s,P<0.01]and decreased number of platform crossings[(2.45±0.13)vs.(8.63±0.41),P<0.01].Degenerative changes were observed in hippocampal neurons,including disordered arrangement,reduced cell count,and structural alterations.The neuronal apoptosis rate was significantly higher in the model group[(51.05 ± 2.58)%vs.(0.12 ± 0.01)%,P<0.01],and Nrf2 and HO-1 protein expression were reduced(both P<0.01).Compared with the model group,all treatment groups exhibited a significant amelioration in behavioral inhibition:The Dex group showed increased distance traveled[(14.50±1.03)m,P<0.05]and increased center time[(12.58±1.08)s,P<0.05];the SFN group also showed increased distance traveled[(14.87±1.02)m,P<0.05]and increased center time[(12.69±1.09)s,P<0.05)].All treatment groups showed significant improvement in cognitive function:The Dex group exhibited decreased latency[(30.43±1.82)s,P<0.01]and increased crossings[(4.85±0.22)times,P<0.01];the SFN group showed decreased latency[(28.74±1.76)s,P<0.01]and increased crossings[(5.12±0.25)times,P<0.01).Hippocampal neuronal damage was markedly ameliorated in all treatment groups.The Dex group had a reduced apoptosis rate[(14.71 ± 1.15)%vs.(51.05 ± 2.58)%,P<0.01];the SFN group also had a reduced apoptosis rate[(18.13 ± 1.32)%vs.(51.05 ± 2.58)%,P<0.01].Both the Dex and SFN group showed increased Nrf2 and HO-1 expressions(P<0.05,P<0.01).Compared with the Dex group,the Dex+SFN group showed further increased distance traveled[(15.68±1.05)m,P<0.05],increased center time[(13.71±1.12)s,P<0.05],decreased latency[(20.03±1.17)s,P<0.01],and increased crossings[(6.74±0.36)times,P<0.01];more significant improvement in hippocampal neuronal damage was observed,along with further reduced apoptosis rate[(10.81 ± 0.94)%vs.(14.71 ± 1.15)%,P<0.01],and further increased Nrf2 and HO-1 expression(both P<0.05). Conclusion Dex exerts a significant neuroprotective effect against isoflurane-induced POCD in mice,which may be associated with the regulation of Nrf2/HO-1 signaling pathway.

Key words: dexmedetomidine, Nrf2/HO-1, isoflurane, cognitive dysfunction, neuroprotective effect