ArticlesThe effects of a novel NSAID on chronic neuroinflammation are age dependent☆☆
Introduction
Alzheimer’s disease (AD) is associated with a distinct pattern of neuropathological changes [29] and a dense distribution of highly activated astrocytes and microglia [35]. Due to glia activation, AD is associated with increased levels of the proinflammatory cytokines, interleukin-1β (IL-1β), IL-6, S100β, and tumor necrosis factor-α (TNF-α) [4], [7], [13], [51], [52], [54]. Increased cytokine expression in the AD brain tends to occur at sites of pathology, e.g., temporal lobe structures, and not to occur in brain regions that demonstrate little or no neurodegeneration. Activated microglia are present in diffuse amyloid beta deposits [14], [40] and may drive the conversion of the diffuse plaques into compacted neuritic plaques [14], [31], [35], [55], [58], [59]. The cytokine S-100β has also been implicated in neuritic plaque formation [39], [40] and in the AD-like neuropathological changes seen in advanced cases of Down’s syndrome [15]. Interestingly, the cytokine IL-1β can be expressed by microglia within hours after head injury in humans, which has been shown to be a significant risk factor for AD [12]. These results suggest that inflammatory mediators might interact with amyloid beta deposits in neuritic plaques, leading over many years to the regional neurodegeneration that characterizes AD [6], [9], [10], [32], [39], [45], [48], [62].
Temporal lobe structures, particularly the hippocampus, demonstrate significant neuropathological and neurochemical changes associated with aging and AD [11], [21], [38], [44]. The hallmarks of the AD pathology develop extensively throughout these brain regions. The number of activated microglia and S100β-containing astrocytes have been shown to correlate significantly with the burden of neurofibrillary tangles and neuritic plaques within the subiculum and hippocampus [8], [60]. It is conceivable that one consequence of the temporal lobe pathology induced by the chronic neuroinflammation may be a significant memory deficit [2].
Because of these unique interactions of inflammatory processes with the pathological hallmarks associated with AD, it is not surprising that conventional anti-inflammatory therapy using nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to slow the progress, or delay the onset, of AD [33], [47]. Overall, the results of recent clinical studies suggest that long-term anti-inflammatory therapy may be beneficial in AD [1], [3], [24], [26], [27], [33], [34], [43], [46], [57]. In one study, untreated elderly demented and non-demented patients with senile plaques had almost three times more activated microglia than did those patients with senile plaques chronically taking NSAIDs [27]. In addition, recent evidence suggests that neuronal cyclooxygenase-2 (COX-2) is elevated in the brains of AD patients; the long-term inhibition of this enzyme might underlie the beneficial effects of NSAID therapy in AD [42].
We have shown previously that chronic infusion of the proinflammagen lipopolysaccharide (LPS) into the fourth ventricle of young rats could reproduce many of the behavioral, inflammatory, neurochemical, and neuropathological changes associated with AD [18], [19], [20]. These inflammatory, neurochemical, behavioral, and neuropathological changes include, but are not limited to, the following: 1) an increase in the number of activated astrocytes; 2) an increase in the number and density of OX-6-positive reactive microglia, particularly within the hippocampus, entorhinal cortex, and basal forebrain; 3) an increase in the levels of IL-1β, TNF-α, and β-amyloid precursor protein mRNA, particularly within the temporal lobe regions and basal forebrain; 4) the degeneration of hippocampal pyramidal neurons; and 5) a significant impairment in working memory [18], [19], [20]. These inflammation-induced changes were restricted to the central nervous system; the rats did not have a fever and plasma cytokine levels were not elevated. LPS injections into the periphery [30] or brain [5] will produce fever when administered acutely and at very high doses.
NO-Flurbiprofen (2-fluoro-a-methyl [1,1′-biphenyl]-4-acetic acid, 4-(nitrooxy)butyl ester, NFP) is a novel NSAID that shows a significant attenuation of the gastrointestinal side effects [61]. This novel drug was produced by the incorporation of a nitric oxide (NO) moiety through an ester linkage to the carboxyl group of the common anti-inflammatory drug flurbiprofen. NO plays an important role in gastric mucosal defense; drugs that generate NO reduce the severity of gastric mucosal injury in vivo and ex vivo [23], [28]. The rationale underlying the development of this compound was the recognition that the NO released from these derivatives would prevent the pathogenic events that occur subsequent to the suppression of prostaglandin synthesis, in particular the reduced blood flow to the gastric mucosa. Previous experiments have demonstrated that this novel NSAID has good anti-inflammatory efficacy and gastrointestinal tolerability in rats [61]. We have determined previously that daily peripheral administration of NFP can significantly reduce the number of activated microglial cells in young rats [20].
The purpose of the present study was to compare the effects of chronic neuroinflammation upon spatial memory in young (3 months), adult (9 months), and old (24 months) rats. In addition, we also investigated whether NFP could attenuate the neuroinflammatory reaction and reduce the learning and memory deficit associated with the chronic infusion of LPS into the fourth ventricle.
Section snippets
Subjects
Male F-344 rats were obtained at 3 months of age (young, n = 14), 9 months of age (adults, n = 16), and 23 months of age (old, n = 22) from Harlan Sprague–Dawley (Indianapolis, IN). The rats were singly housed in Plexiglas cages with free access to food and water and maintained on a 12/12-h light-dark cycle in a temperature-controlled room (22°C). All rats were given health checks and handled upon arrival and were given at least 3 weeks to adapt to their new environment before surgery. The age
Results
Overall, the chronic infusion of LPS was well tolerated by all of the rats. Initially after surgery all of the LPS-treated rats lost a few grams of weight. Within a few days, however, all of the rats had regained weight and continued to grow normally for the duration of the study.
Discussion
LPS produced an extensive inflammatory reaction within the brain, particularly within the cingulate gyrus, hippocampus, subiculum, and the entorhinal and piriform cortexes. The inflammatory response was characterized by a significant increase in the number of reactive microglial cells that expressing MHC class II antigens. Overall, the effects of LPS infusions into the fourth ventricle of young rats upon microglial activation were consistent with our previous reports [18], [19]. In addition,
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☆ Supported by the U.S. Public Health Service, Contract Grant Number AG10546, the Alzheimer’s Association, IIRG-95-004, and by an unrestricted grant from NicOx S.A., France, to GLW.