NSAIDS-INDUCED REVERSAL OF AGE-RELATED DEFICITS IN LEARNING AND MEMORY: POSSIBLE INVOLVEMENT OF PRO-INFLAMMATORY CYTOKINES





M.H. Mesches, C. Gemma, L.M. Veng, C. Allgeiers, M.D. Browning, and P.C. Bickford

Medical Research Service, Denver VA Medical Center and Dept. Pharmacology, Univ. Colo. Health Sci. Ctr., Neuroscience, B138, UCHSC, 4200 East 9th Ave., Denver, CO 80262



Oxidative stress and inflammation processes have been implicated to have a role in neurodegenerative disease such as Alzheimers Disease (AD) and Parkinsons Disease. There are increased inflammatory responses in aged rats with increases in activated microglia and pro-inflammatory cytokines in the cerebellum. There are also increases in activated astrocytes in the hippocampus of aged rats. Increases in the pro-inflammatory cytokine interleukin (IL)-1B in the hippocampus of aged rats might underlie impairments in long term potentiation (LTP), a putative molecular substrate of memory, by increasing the formation of reactive oxygen species. NSAIDs inhibit inflammation by inhibiting the cycloxygenase (COX) enzyme, thereby limiting the production of pro-inflammatory prostaglandins. Chronic NSAIDs use decreases the risk for AD and decrease infarct size following ischemia reperfusion. We administered the NSAID, sulindac, to aged Fischer 344 rats for 2 mo. The rats were then trained in a win-stay version of the 12-arm radial arm water maze task followed by contextual fear conditioning. Hippocampal NMDA subunit protein levels were determined using semiquantitative Western blot analysis. Hippocampal IL-1B levels were measured by ELISA. We have previously shown that decreases in the NR2B subunit correlate with impaired water maze performance in aged rats and LTP deficits. There were age-related deficits in both behavioral tasks, and decreases in hippocampal levels of NR2B. In addition, hippocampal levels of IL-1B also increased in the aged controls. Sulindac, but not its non-COX activating metabolite, sulindac sulfone, reversed the age-related behavioral deficits and increased NR2B protein levels. There was a significant increase in IL-1B in aged rats, which was blocked by sulindac but not by sulindac sulfone. Thus, NSAIDs treatment might reverse age-related cognitive deficits, perhaps acting by rescuing age-related decreases in the NMDA NR2B subunit. Grant Support: AG04418, AG00961, & VAMRS




Key words: NSAID, memory, aging, cytokines, NMDA







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