Abstract
Huperzine A, a promising therapeutic agent for Alzheimer's disease, was examined for its potential to antagonize the deleterious neurochemical, structural, and cognitive effects of infusing beta-amyloid protein-(1-40) into the cerebral ventricles of rats. Daily intraperitoneal administration of huperzine A for 12 consecutive days produced significant reversals of the beta-amyloid-induced deficit in learning a water maze task. This treatment also reduced the loss of choline acetyltransferase activity in cerebral cortex, and the neuronal degeneration induced by beta-amyloid protein-(1-40). In addition, huperzine A partly reversed the down-regulation of anti-apoptotic Bcl-2 and the up-regulation of pro-apoptotic Bax and P53 proteins and reduced the apoptosis that normally followed beta-amyloid injection. The present findings confirm that huperzine A can alleviate the cognitive dysfunction induced by intracerebroventricular infusion of beta-amyloid protein-(1-40) in rats. The beneficial effects are not confined to the cholinergic system, but also include favorable changes in the expression of apoptosis-related proteins and in the extent of apoptosis in widespread regions of the brain.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids
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Amyloid beta-Peptides / administration & dosage*
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Amyloid beta-Peptides / adverse effects
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Animals
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Apoptosis / drug effects
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Cerebral Cortex / drug effects
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Cerebral Cortex / metabolism
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Cerebral Cortex / pathology
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Choline O-Acetyltransferase / drug effects
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Choline O-Acetyltransferase / metabolism
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Cognition Disorders / chemically induced
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Cognition Disorders / drug therapy*
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Cognition Disorders / physiopathology
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Dose-Response Relationship, Drug
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Hippocampus / drug effects
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Hippocampus / metabolism
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Hippocampus / pathology
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Humans
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In Situ Nick-End Labeling
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Infusion Pumps
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Injections, Intraventricular
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Male
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Maze Learning / drug effects
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Memory Disorders / chemically induced
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Memory Disorders / drug therapy
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Memory Disorders / physiopathology
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Microscopy, Electron
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Nerve Degeneration / chemically induced
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Nerve Degeneration / drug therapy*
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Neurons / drug effects
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Neurons / pathology
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Neurons / ultrastructure
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Neuroprotective Agents / pharmacology*
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Peptide Fragments / administration & dosage*
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Peptide Fragments / adverse effects
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / drug effects
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Psychomotor Performance / drug effects
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Rats
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Rats, Sprague-Dawley
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Sesquiterpenes / pharmacology*
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Tumor Suppressor Protein p53 / drug effects
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Tumor Suppressor Protein p53 / metabolism
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bcl-2-Associated X Protein
Substances
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Alkaloids
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Amyloid beta-Peptides
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BAX protein, human
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Bax protein, rat
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Neuroprotective Agents
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Peptide Fragments
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Sesquiterpenes
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Tumor Suppressor Protein p53
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amyloid beta-protein (1-40)
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bcl-2-Associated X Protein
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huperzine A
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Choline O-Acetyltransferase