title: Sulindac improves memory and increases NMDA receptor subunits in aged Fischer 344 rats.
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.
authors.affiliation: Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA. michael.mesches@uchsc.edu
authors.forename: Michael H
authors.initials: MH
authors.lastname: Mesches
authors.forename: Carmelina
authors.initials: C
authors.lastname: Gemma
authors.forename: Lone M
authors.initials: LM
authors.lastname: Veng
authors.forename: Chrissy
authors.initials: C
authors.lastname: Allgeier
authors.forename: David A
authors.initials: DA
authors.lastname: Young
authors.forename: Michael D
authors.initials: MD
authors.lastname: Browning
authors.forename: Paula C
authors.initials: PC
authors.lastname: Bickford
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004660:Encephalitis / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D016194:Receptors, N-Methyl-D-Aspartate; D013467:Sulindac; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial