Influence of Nitric Oxide–Cyclic GMP and Oxidative STRESS on Amyloid-β Peptide Induced Decrease of Na,K-ATPase Activity in Rat Hippocampal Slices

Amyloid-β peptide (Aβ) has been shown to cause synaptic dysfunction and can render neurons vulnerable to excitotoxicity and oxidative stress. Na,K-ATPase plays an important role to maintain cell ionic equilibrium and it can be modulated by N-methyl- d -aspartate (NMDA)–nitric oxide (NO)–cyclic GMP pathway. Disruption of NO synthase (NOS) activity and reactive oxygen species (ROS) production could lead to changes in Na,K-ATPase isoforms’ activities that may be detrimental to the cells. Our aim was to evaluate the signaling pathways of Aβ in relation to NMDA–NOS–cyclic GMP versus oxidative stress on α 1 -/α 2,3 -Na,K-ATPase activities in rat hippocampal slices. Aβ 1–40 induced a concentration-dependent increase of NOS activity and increased cyclic guanosine monophosphate (cGMP), TBARS (thiobarbituric acid reactive substances), and 3-Nitrotyrosine (3-NT)-modified protein levels in rat hippocampal slices. The increase in NOS activity and cyclic GMP levels induced by Aβ 1–40 was completely blocked by MK-801 (inhibitor of NMDA receptor) and L-NAME (inhibitor of NOS) pre-treatment but changes in TBARS levels were only partially blocked by both compounds. The Aβ treatment also decreased Na,K-ATPase activity which was reverted by N-nitro- l -arginine methyl ester hydrochloride (L-NAME) but not by MK-801 pre-treatment. The decrease in enzyme activity induced by Aβ was isoform-specific since only α 1 -Na,K-ATPase was affected. These findings suggest that the activation of NMDA–NOS signaling cascade linked to α 2,3 -Na,K-ATPase activity may mediate an adaptive, neuroprotective response to Aβ in rat hippocampus. Graphic Abstract