NO-Flurbiprofen Attenuates Excitotoxin-Induced Brain Inflammation, and Releases Nitric Oxide in the Brain

Abstract

ABSTRACT-Brain inflammation underlies the pathogenesis of Alzheimer's disease (AD) and nonsteroidal anti-inflammatory drug therapy may delay the onset of AD. We investigated, in vivo, the effects of NOflurbiprofen on brain inflammation in rats injected with quisqualic acid into the nucleus basalis and on the release of nitric oxide from the drug in naive rat brains. We showed that the excitotoxin-induced microglia reaction, the expression of inducible nitric oxide synthase-positive cells and the production of interleukin1b and prostaglandin-E2 in the injected area were attenuated by the NO-flurbiprofen (15 mg / kg, p.o.) treatment. An oral administration of NO-flurbiprofen (25, 50 and 100 mg/kg) to naive rats was followed by significant increases in cortical nitrite levels. This drug may have important therapeutic implications for the treatment of AD.Keywords: Nucleus basalis, Alzheimer's disease, Nitric oxide-releasing nonsteroidal anti-inflammatory drug,Inflammatory mediatorRecent studies have demonstrated a role for immune activation in the most common neurodegenerative disease in aging humans, namely Alzheimer's disease (AD) (1). Abnormal deposition of complement components, acutephase reactants, as well as various cytokines, and up-regulation of inducible cyclooxygenase (COX-2) are among the features detected in AD brain (2, 3). The neuritic plaques, a histopathological hallmark of the disease, are typically surrounded by reactive astrocytes and microglia, which are capable of producing and releasing proteases, complement components, reactive oxygen and nitrogen intermediates and cytokines. Epidemiological studies (1) reporting that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk and delays the clinical expression of AD (4, 5) and that AD and rheumatoid arthritis are diagnosed in the same individuals less frequently than expected (6) support the hypothesis that inflammation is closely related to the clinical manifestation of AD. Most NSAIDs have numerous gastrointestinal side effects (7) that significantly limit their usefulness in the long-term therapy that is necessary for AD patients (8).A new class of nitric oxide (NO)-releasing NSAID derivatives, including NO-flurbiprofen (HCT-1026), generated by the incorporation of a nitroxybutyl moiety through an ester linkage to the parent NSAID, exhibits, in experiments in animals and healthy volunteers, a reduced gastrointestinal toxicity when compared with the corresponding parent NSAID (9 -11). NO plays an important role in gastric mucosal defense, and it is believed that NO-NSAIDs spare the gastrointestinal tract by local release of NO. This leads to an increase in mucosal blood flow and thus to the prevention of the pathogenic events subsequent to the suppression of prostaglandin synthesis (11,12).We showed that quisqualic acid injection into the nucleus basalis (NB) of rats induces an intense glia reaction and the production of inflammatory mediators and that the administration of the NSAID nimesulide significantly attenuates th...

Treatment with a Nitric Oxide-Donating NSAID Alleviates Functional Muscle Ischemia in the Mouse Model of Duchenne Muscular Dystrophy

“…Furthermore, our data showing a consistent effect of high dose, but not low dose, HCT 1026 to improve muscle blood flow regulation in the mdx mice suggest that a threshold level of NO bioactivity in blood or muscle is required to rescue the blood flow phenotype. As previous rat studies have shown dose-dependent increases in NOx in blood and brain after oral administration of HCT 1026 in doses ranging from 10 to 50 mg/kg, we speculate that in our study NOx was elevated to a greater extent in mice treated with the high versus the low dose of HCT 1026 (≈ 45 vs. 15 mg/kg) [27], [36].…”

“…These observations argue against a general vasodilatory action of HCT 1026 and suggest a more specific mechanism by which the drug affects vascular regulation only in the active muscles. One such mechanism could involve conversion of NO derived from HCT 1026 to more stable compounds such as nitrosylhemoglobin or NOx that can circulate in the blood and, in the case of NOx, accumulate in tissues [22], [28], [31], [35], [36]. Release of NO from these compounds is greatly facilitated by physiological levels of hypoxia and acidosis, providing a plausible mechanism to deliver NO bioactivity to ischemic tissue [37]–[39].…”

Inhibition of Amyloidogenesis by Nonsteroidal Anti-inflammatory Drugs and Their Hybrid Nitrates

“…39 Hydrolysis of HCT-1026 yields 4-hydroxybutyl nitrate, and it is possible that this metabolite has brain bioavailaibility since animal studies have shown that the level of inorganic nitrite in the brain increases after oral administration of HCT-1026. 29, 40 It was of interest both to confirm the increased stability of the amide linked hybrid nitrate 27 relative to the ester linked homolog, 2 , and to determine if unlike 2 , the NO-flurbiprofen, 27 , was detectable in the brain. Therefore, 27 (10 mg/kg) was delivered by i.p.…”

1,3-Selenazol-4-one Derivatives Inhibit Inducible Nitric Oxide-Mediated Nitric Oxide Production in Lipopolysaccharide-Induced BV-2 Cells

“…It was reported that NO demonstrated a neuroprotective effect through the S-nitrosylation of cysteine in caspase, which plays an important role in neuronal cell apoptosis. 18) On the other hand, NO was reported to induce neuronal cell death following DNA damage and disruption of mitochondrial function. NO reacts with superoxide anion to yield peroxynitrite, which is a strong oxidative stress agent.…”