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

Neurobiol Dis. 1999 Apr;6(2):109-21. doi: 10.1006/nbdi.1998.0230.

Abstract

Previous experimental data indicate the involvement of Ca(2+)-related excitotoxic 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 in the beta A-induced neurodegenerative cascade. In the present study, therefore, a neuroprotective strategy was applied to explore the contributions of each of these pathways in beta A toxicity. beta A(1-42) was injected into the magnocellular nucleus basalis of rats, while neuroprotection was achieved by either single or combined administration of the NMDA receptor antagonist 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 consecutive series of behavioral tasks, including elevated plus maze, passive avoidance learning, small open-field and open-field paradigms, followed by acetylcholinesterase (AChE), choline-acetyltransferase (ChAT), and superoxide dismutase (SOD) biochemistry. beta A injected in the nucleus basalis elicited significant anxiety in the elevated plus maze, derangement of passive avoidance learning, and altered spontaneous behaviors in both open-field tasks. A significant decrease in both AChE and ChAT accompanied by a similar decrement 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 ameliorate beta A toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Anxiety / pathology
  • Anxiety / physiopathology
  • Avoidance Learning / drug effects
  • Behavior, Animal / drug effects
  • Choline O-Acetyltransferase / metabolism
  • Dizocilpine Maleate / pharmacology*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Free Radical Scavengers / pharmacology*
  • Male
  • Microinjections
  • Neurons / drug effects*
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Somatosensory Cortex / enzymology
  • Substantia Innominata / drug effects*
  • Substantia Innominata / pathology
  • Substantia Innominata / physiopathology
  • Superoxide Dismutase / metabolism

Substances

  • Amyloid beta-Peptides
  • Excitatory Amino Acid Antagonists
  • Free Radical Scavengers
  • Neuroprotective Agents
  • Receptors, N-Methyl-D-Aspartate
  • Dizocilpine Maleate
  • Superoxide Dismutase
  • Choline O-Acetyltransferase
  • Acetylcholinesterase