Abstract
Inflammatory processes in the central nervous system are thought to contribute to Alzheimer's disease (AD). Chronic administration of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of Alzheimer's disease. There are very few studies, however, on the cognitive impact of chronic NSAID administration. The N-methyl-d-aspartate (NMDA) receptor is implicated in learning and memory, and age-related decreases in the NMDA NR2B subunit correlate with memory deficits. Sulindac, an NSAID that is a nonselective cyclooxygenase (COX) inhibitor was chronically administered to aged Fischer 344 rats for 2 months. Sulindac, but not its non-COX active metabolite, attenuated age-related deficits in learning and memory as assessed in the radial arm water maze and contextual fear conditioning tasks. Sulindac treatment also attenuated an age-related decrease in the NR1 and NR2B NMDA receptor subunits and prevented an age-related increase in the pro-inflammatory cytokine, interleukin 1beta (IL-1beta), in the hippocampus. These findings support the inflammation hypothesis of aging and have important implications for potential cognitive enhancing effects of NSAIDs in the elderly.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aging / drug effects*
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Aging / metabolism
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Aldehyde Dehydrogenase / genetics*
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Aldehyde Dehydrogenase, Mitochondrial
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Conditioning, Psychological / drug effects
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Conditioning, Psychological / physiology
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Disease Models, Animal
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Encephalitis / drug therapy*
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Encephalitis / physiopathology
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Encephalitis / prevention & control
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Interleukin-1 / metabolism
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Male
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Maze Learning / drug effects
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Maze Learning / physiology
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Memory Disorders / drug therapy*
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Memory Disorders / metabolism
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Memory Disorders / physiopathology
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use
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Nootropic Agents / pharmacology
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Nootropic Agents / therapeutic use
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Rats
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Rats, Inbred F344
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Receptors, N-Methyl-D-Aspartate / drug effects*
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Receptors, N-Methyl-D-Aspartate / metabolism
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Sulindac / pharmacology*
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Sulindac / therapeutic use
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Treatment Outcome
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Up-Regulation / drug effects
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Up-Regulation / physiology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Interleukin-1
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NR1 NMDA receptor
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NR2B NMDA receptor
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Neuroprotective Agents
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Nootropic Agents
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Receptors, N-Methyl-D-Aspartate
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Sulindac
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ALDH2 protein, human
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Aldehyde Dehydrogenase
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Aldehyde Dehydrogenase, Mitochondrial