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 1β (IL-1β), 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.

Introduction

Several lines of evidence indicate that inflammatory processes underlie neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease [1], [2], [41], [43]. Chronic inflammation also occurs with normal aging. In the periphery, there are increased levels of pro-inflammatory cytokines, delayed termination of inflammatory activity, and prolonged fever response in humans [10]. Inflammatory responses increase in aged rats along with increases in activated microglia [50] and activated astrocytes [35]. Pro-inflammatory cytokine levels also increase in the aged brain [22], [33], [67]. These and similar findings led Chung et al. to propose the inflammation hypothesis of aging [12]. The cognitive impact of inflammation is not known, but acute inflammation induced by lipopolysaccharides impairs memory in young rats [25], [26]. This inflammation-induced memory deficit is prevented by administration of a nonsteroidal anti-inflammatory drug (NSAID) [27].

Increases in the pro-inflammatory cytokine interleukin (IL)-1β in the hippocampus of aged rats underlie impairments in long-term potentiation (LTP), a putative molecular substrate of memory [8], by increasing the formation of reactive oxygen species (ROS) [46]. Increases in ROS might be involved in the pathology of many neurodegenerative disorders [2]. Antioxidants decrease pro-inflammatory cytokines and improve age-related deficits in LTP [38], [45], [49]. Aged rats fed diets with high antioxidant capacity demonstrate a reversal in age-related behavioral and neurochemical deficits, including elevated cytokines [7], [22], [23], [30]. Thus, there is a link between inflammatory processes and oxidative stress. In addition, oxidative stress is implicated in the aging process [24].

NSAIDs decrease inflammation by inhibiting the cyclooxygenase (COX) enzyme, thereby limiting the production of pro-inflammatory prostaglandins [61], however, other mechanisms are also postulated [59], [65]. While chronic use of NSAIDs decreases the risk for AD [28], the cognitive effects of NSAIDs in the elderly are not well understood. Indomethacin, a non-specific COX inhibitor, enhances sensorimotor coordination and short-term memory in elderly subjects [9]. Chronic administration of aspirin [54] or celecoxib [11] enhances learning in aged rats.

The N-methyl-d-aspartate (NMDA) receptor is implicated in some types of LTP that might underlie spatial learning and memory [60]. The NMDA NR2B subunit decreases in aged rats and these decreases are correlated with impaired performance in a spatial memory task [13], [14], [55]. Treatments that attenuate age-related declines in NR2B subunit levels also attenuate memory deficits [36].

Sulindac is an NSAID that inhibits the two COX isoforms, the constitutively expressed COX I and the inducible COX II [18]. Sulindac is metabolized into its sulfide form, which has COX inhibitory activity, and a sulfone form, which does not have COX inhibitory activity [18]. The present study was designed to investigate the actions of chronic NSAID administration on cognitive performance in aged rats and to extend these findings to putative biochemical correlates of learning and memory and levels of pro-inflammatory cytokines.