Ketamine reduces amyloid β-protein degradation by suppressing neprilysin expression in primary cultured astrocytes

Pathological accumulation of cortical amyloid beta-protein (A beta) is an early and consistent feature of Alzheimer's disease (AD). A beta levels in the brain are determined by production and catabolism. Previous studies have suggested that deficits in the brain expression of neprilysin (NEP) and the insulin-degrading enzyme (IDE), which are both proteases involved in amyloid degradation, may promote A beta deposition in patients with sporadic late-onset AD. Because the incidence of AD increases after surgical intervention, we examined whether ketamine, which is a general anaesthetic with neuroprotective properties for excitotoxic ischaemic damage, is associated with A beta degradation by inducing NEP and IDE expression. The non-competitive N-methyl-D-aspartate receptor antagonist ketamine and MK801 significantly decreased the expression of NEP, but not IDE, in a concentration-and time-dependent manner through the dephosphorylation of p38 mitogen-activated protein kinase (MAPK) in cultured rat astrocytes. Furthermore, NEP-reduced reagents significantly suppressed the degradation of exogenous A beta in cultured astrocytes. These results suggested that ketamine suppresses the A beta degradation of NEP by reducing p38 MAPK-mediated pathway activity. (C) 2013 Elsevier Ireland Ltd. All rights reserved.