Gastric Tolerability and Prolonged Prostaglandin Inhibition in the Brain with a Nitric Oxide-Releasing Flurbiprofen Derivative, NCX-2216 [3-[4-(2-Fluoro-α-methyl-[1,1′-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester]

Wallace, John L.; Muscará, Marcelo Nícolas; Nucci, Gilberto De; Zamunér, Stella Regina; Cirino, Giuseppe; Soldato, Piero Del; Ongini, Ennio

doi:10.1124/jpet.103.063453

Cited by 33 publications

(19 citation statements)

References 31 publications

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“…Overall, our data demonstrate a clear cognitive benefit of long-term administration, but are inconclusive with respect to the relationship between effects on Aβ deposition and behavioural improvements. Previous studies have shown that chronic treatment with nitric oxide-releasing flurbiprofen derivatives do lower Aβ accumulation in APP mice, but it is not clear if this effect is due to the prodrug (which is not likely to affect Aβ42 production) or flurbiprofen released following metabolism [27,53]. In this study we see trends towards reduced Aβ deposition in the prevention studies and small but significant decrease in Aβ deposition in the therapeutic study.…”

Section: Discussionsupporting

confidence: 46%

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

et al. 2007

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Background: Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil) as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice.

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Section: Discussionsupporting

confidence: 46%

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

et al. 2007

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“…Activation of microglia and astrocytes is closely associated with the neuroinflammatory response that contributes to neurodegeneration. In an amyloid transgenic mouse, NCX-2216 was observed to activate microglia in a manner leading to clearance of amyloid, but not to neurotoxic inflammation; and in a further study to inhibit COX-2 expression and prostaglandin synthesis in the rat brain for a prolonged period compared to flurbiprofen, although NCX-2216 was not detected in brain tissue (Wallace et al 2004). Administration of HCT-1026 to amyloid transgenic mice was reported to inhibit microglial activation surrounding plaques (van Groen & Kadish 2005), and a direct comparison of flurbiprofen, HCT-1026 and NCX-2216 in adult rats injected in the nucleus basalis with Aβ 1–42 , showed a reduction in inflammatory markers including iNOS (Prosperi et al 2004).…”

Section: Discussionmentioning

confidence: 99%

NO‐flurbiprofen reduces amyloid‐β, is neuroprotective in cell culture, and enhances cognition in response to cholinergic blockade

Abdul-Hay¹,

Luo²,

Ashghodom³

et al. 2009

Journal of Neurochemistry

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The non‐steroidal anti‐inflammatory drug flurbiprofen is a selective amyloid lowering agent which has been studied clinically in Alzheimer’s disease. HCT‐1026 is an ester prodrug of flurbiprofen incorporating a nitrate carrier moiety that in vivo provides NO bioactivity and an improved safety profile. In vitro, HCT‐1026 retained the cyclooxygenase inhibitory and non‐steroidal anti‐inflammatory drug activity of flurbiprofen, but at concentrations at which levels of amyloid‐β 1–42 amino acid were lowered by flurbiprofen, amyloid‐β 1–42 amino acid levels were elevated 200% by HCT‐1026. Conversely, at lower concentrations, HCT‐1026 behaved as a selective amyloid lowering agent with greater potency than flurbiprofen. The difference in concentration–responses between flurbiprofen and HCT‐1026 in vitro suggests different cellular targets; and in no case did a combination of nitrate drug with flurbiprofen provide similar actions. In vivo, HCT‐1026 was observed to reverse cognitive deficits induced by scopolamine in two behavioral assays; activity that was also shown by a classical nitrate drug, but not by flurbiprofen. The ability to restore aversive memory and spatial working and reference memory after cholinergic blockade has been demonstrated by other agents that stimulate NO/cGMP signaling. These observations add positively to the preclinical profile of HCT‐1026 and NO chimeras in Alzheimer’s disease.

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“…Peak levels in the CSF occur between 1 and 3 h for flurbiprofen in the rat (Matoga et al . 1999; Wallace et al . 2004) and at 3 h for ibuprofen in humans (Bannwarth et al .…”

Section: Clinical Relevance Of Non‐cox Mediated Effects Of Nsaids: Camentioning

confidence: 99%

“…1995) and their levels rapidly decline thereafter. Interestingly, one NO‐releasing derivative of flurbiprofen, NCX 2216, shows a long‐lasting suppression of prostaglandin production in the brain and CSF (Wallace et al . 2004).…”

Section: Clinical Relevance Of Non‐cox Mediated Effects Of Nsaids: Camentioning

confidence: 99%

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Non‐steroidal anti‐inflammatory drugs (NSAIDs) in Alzheimer's disease: old and new mechanisms of action

Gasparini¹,

Ongini²,

Wenk³

2004

Journal of Neurochemistry

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211

123

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Alzheimer's disease (AD) is characterized by cerebral deposits of b-amyloid (Ab) peptides and neurofibrillary tangles (NFT) which are surrounded by inflammatory cells. Epidemiological studies have shown that prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays the onset of the disease. It has been postulated that some NSAIDs target pathological hallmarks of AD by interacting with several pathways, including the inhibition of cyclooxygenases (COX) and activation of the peroxisome proliferator-activated receptor c. A variety of experimental studies indicate that a subset of NSAIDs such as ibuprofen, flurbiprofen, indomethacin and sulindac also possess Ab-lowering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. While COX inhibition occurs at low concentrations in vitro (nM-low lM range), the Ab-lowering activity is observed at high concentrations (£ 50 lM). Nonetheless, studies with flurbiprofen or ibuprofen in AD transgenic mice show that the effects on Ab levels or deposition are attained at plasma levels similar to those achieved in humans at therapeutic dosage. Still, it remains to be assessed whether adequate concentrations are reached in the brain. This is a crucial aspect that will allow defining the dose-window and the length of treatment in future clinical trials. Here, we will discuss how the combination of anti-amyloidogenic and anti-inflammatory activities of certain NSAIDs may produce a profile potentially relevant to their clinical use as disease-modifying agents for the treatment of AD.

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Gastric Tolerability and Prolonged Prostaglandin Inhibition in the Brain with a Nitric Oxide-Releasing Flurbiprofen Derivative, NCX-2216 [3-[4-(2-Fluoro-α-methyl-[1,1′-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester]

Cited by 33 publications

References 31 publications

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

NO‐flurbiprofen reduces amyloid‐β, is neuroprotective in cell culture, and enhances cognition in response to cholinergic blockade

Non‐steroidal anti‐inflammatory drugs (NSAIDs) in Alzheimer's disease: old and new mechanisms of action

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