Effect of NMDAR-NMNAT1/2 pathway on neuronal cell damage and cognitive impairment of sevoflurane-induced aged rats

Abstract

ABSTRACTObjective: The possible effect of NMDAR (N-methyl-D-aspartate receptor)-NMNAT1/2 (nicotinamide/nicotinic acid mono-nucleotide adenylyltransferase) signaling pathway on the neuronal cell damage and cognitive impairment of aged rats anesthetized by sevoflurane was explored.Methods: Adult male Wistar rats were selected and divided into Control, Sevo (Sevoflurane), Sevo+DCS (NMDAR agonist D-cycloserine) 30 mg/kg, Sevo+DCS 100 mg/kg, and Sevo+DCS 200 mg/kg groups. Morris water maze and fear conditioning text were used to observe cognitive function changes of rats. The inflammatory cytokines were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) assay, neuronal apoptosis by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) staining and MDAR-NMNAT1/2 pathway-related proteins by Western blotting.Results: The longer escape latency, decreased platform crossing times and reduced staying time spent in platform quadrant were found in rats from Sevo group, with decreased percentage of freezing time in contextual test and tone cued test; and meanwhile, these rats had increased inflammatory cytokines (interleukin (IL)-1β, tumor necrosis factor (TNF-α), IL-6, and IL-8) and neuronal apoptosis, but declined expressions of MDAR-NMNAT1/2 pathway-related proteins. However, the above changes were exhibited an opposite tendency in those Sevo rats treated with different concentrations of DCS (including 30, 100, and 200 mg/kg, respectively). Particularly, the improving effect of low-dose DCS on each aspect in aged rats was better than high-dose ones.Conclusion: Activation of NMDAR-NMNAT1/2 signaling pathway could not only reduce neuronal apoptosis, but also alleviate sevoflurane-induced neuronal inflammation and cognitive impairment in aged rats.