A Brief Ischemic Postconditioning Protects Against Amyloid-β Peptide Neurotoxicity by Downregulating MLK3-MKK3/6-P38MAPK Signal in Rat Hippocampus

Background: Oligomeric amyloid-beta peptide (A beta) is associated with dysfunctional neuronal networks and neuronal loss in the development of Alzheimer's disease (AD). Ischemic postconditioning protects against post-ischemic excitotoxicity, oxidative stress, and inflammatory process that have also been implicated in the pathogenesis of AD. Evaluating the roles of ischemic postconditioning in oligomeric A beta-induced neurotoxicity and underlying signal events may provide potential strategy for medical therapy in AD. Objectives: The aim of the present study was to explore whether and how a brief ischemic postconditioning protects against A beta neurotoxicity in rat hippocampus. Methods: Oligomeric A beta(25-35) (20 nmol/rat) or A beta(1-4)(2 )(5 nmol/rat) was infused by intracerebroventricular injection in adult male Sprague-Dawley rats. Ischemic postconditioning, a brief episode of global brain ischemia (3 min), was conducted at 1, 3, or 7 days after A beta treatment, respectively. Results: A brief ischemic postconditioning reduced neuronal loss and inhibited the activation of MLK3, MKK3/6, and P38MAPKs in rat hippocampal CA1 and CA3 subfields after A beta oligomer infusion. An N-methyl-D-aspartate (NMDA) receptor antagonist amantadine, but not non-NMDA receptor antagonist CNQX, reversed the MLK3-MKK3/6-P38MAPK signal events and beneficial effect of ischemic postconditioning on neuronal survival. Such reversion was also realized by NVP-AAM077, a GluN2A-subunit-selective NMDA receptor antagonist. Moreover, posttreatment with low doses of NMDA (5 nmol-40 nmol/rat) suppressed the A beta-induced P38MAPK signaling and imitated the neuroprotection of ischemic postconditioning against A beta neurotoxicity. Conclusions: Ischemic postconditioning provides neuroprotection against A beta neurotoxicity by moderate upregulation of NMDA receptor signaling, especially GluN2A-containing NMDA receptor pathway, and thereafter downregulation of MLK3-MKK3/6-P38MAPK signal events.