N-methyl-D-aspartate receptor antagonist MK-801 and radical scavengers protect cholinergic nucleus basalis neurons against beta-amyloid neurotoxicity

Previous experimental data indicate the involvement of Ca2+-related excitot oxic processes, possibly mediated by N-Methyl-D-Aspartate (NMDA) receptors, in beta-amyloid (beta A) neurotoxicity. On the other hand, other lines of evidence support the view that free radical generation is a critical step i n the beta A-induced neurodegenerative cascade. In the present study, there fore, a neuroprotective strategy was applied to explore the contributions o f each of these pathways in beta A toxicity. beta A((1-42)) was injected in to the magnocellular nucleus basalis of rats, while neuroprotection was ach ieved by either single or combined administration of the NMDA receptor anta gonist MK-801 (2.5 mg/kg) and/or a vitamin E and C complex (150 mg/kg). The degree of neurodegeneration was determined by testing the animals in conse cutive series of behavioral tasks, including elevated plus maze, passive av oidance learning, small open-field and open-field paradigms, followed by ac etylcholinesterase (AChE), cholineacetyltransferase (ChAT), and superoxide dismutase (SOD) biochemistry, beta A injected in the nucleus basalis elicit ed significant anxiety in the elevated plus maze, derangement of passive av oidance learning, and altered spontaneous behaviors in both open-field task s. A significant decrease in both AChE and ChAT accompanied by a similar de crement of MnSOD, but not of Cu/ZnSOD provided neurochemical substrates for the behavioral changes, Each of the single drug administrations protected against the neurotoxic events, whereas the combined treatment failed to ame liorate beta A toxicity. (C) 1999 Academic Press.