Opposite effects of flurbiprofen and the nitroxybutyl ester of flurbiprofen on apoptosis in cultured guinea‐pig gastric mucous cells

Johal, Kamaljit; Hanson, Peter J.

doi:10.1038/sj.bjp.0703383

Cited by 14 publications

(21 citation statements)

References 32 publications

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“…Blockade of protein synthesis was verified by abolished Hsp60 expression. Our results are supported by previous findings in guinea pig gastric mucosal cells in vitro, where CHX inhibited caspase-3 activity [35]. The effect of CHX on the integrity of the tissue is thereby considered beneficial since previously we have shown that it was also capable of blocking the inhibition of restitution and cell proliferation induced by heat shock preconditioning [9][10][11].…”

Section: Discussionsupporting

confidence: 80%

Heat Shock Preconditioning and Eicosanoid Pathways Modulate Caspase 3-Like Activity in Superficially Injured Isolated Guinea Pig Gastric Mucosa

Oksala

Alhava²,

Paimela³

2004

Eur Surg Res

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Background: After superficial mucosal injury, the disturbed gastric epithelial continuity is restored by cellular migration. Caspase-3 is an enzyme responsible for the execution of stress-induced apoptosis. Interestingly, heat shock proteins (Hsp) including Hsp60 are capable of modulating caspase-3 activity. Interestingly, we have demonstrated that heat shock preconditioning upregulates Hsp synthesis and inhibits restitution and cell proliferation via mechanisms related to de novo protein synthesis and eicosanoid pathways, both of which are crucial in the regulation of apoptosis and gastric mucosal defense systems. Aims: To assess whether caspase-3 activity is affected by heat shock preconditioning and associated pharmacological modulations after standard superficial injury to allow development of cytoprotective strategies. Methods: Guinea pig gastric mucosae were mounted and perfused in paired Ussing chambers. After heat shock (HS) preconditioning (42°C) for 30 min, a superficial injury was induced (1.25 mol/l NaCl) followed by 3 h recovery. For mechanistic studies, the mucosa was exposed to 30 µmol/l arachidonic acid (AA) as a substrate for eicosanoid pathways, to 50 µmol/l quercetin (Q) to inhibit lipoxygenases, to 50 µmol/l indomethacin (In) to inhibit cyclo-oxygenases, or to 150 µmol/l cycloheximide (CHX) to inhibit de novo protein synthesis. After the experiment, the mucosa was prepared for analysis of caspase-3 activity. Hsp60 expression was analyzed to monitor the induction of heat shock response. Results: HS upregulated Hsp60 expression, indicating induction of the heat shock response without an effect on basal caspase-3 activity. Superficial injury itself did not affect caspase-3 activity nor Hsp60 synthesis. In all the experiments, exposure to CHX abolished caspase-3 activity and Hsp60 synthesis. AA+Q increased, Q decreased, while In+AA and In+AA+Q abolished caspase-3 activity independent of alterations in Hsp60 synthesis. Upon exposure to In+Q, HS decreased caspase-3 activity and upregulated Hsp60 synthesis. Conclusion: Caspase-3 activity in isolated guinea pig gastric mucosa is regulated by mechanisms dependent on de novo protein synthesis and eicosanoid pathways but is not strictly related to Hsp synthesis. Upon modulation of the eicosanoid pathways, HS may be utilized to simultaneously decrease caspase-3 activity and increase Hsp synthesis. Modulations of the eicosanoid pathways may be utilized to reduce caspase-3 activity also upon normothermic conditions suggesting a novel mechanism by which caspase-3 is regulated in the gastric mucosa.

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Section: Discussionsupporting

confidence: 80%

Heat Shock Preconditioning and Eicosanoid Pathways Modulate Caspase 3-Like Activity in Superficially Injured Isolated Guinea Pig Gastric Mucosa

Oksala

Alhava²,

Paimela³

2004

Eur Surg Res

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“…NO is an important biological mediator in maintaining the physiological condition in animals and humans. While NO at high levels is cytotoxic (23), at low levels it inhibits apoptosis in several cell models via post-translational S-nitrosylation /inactivation of caspase 1 and 3 (24,25). A role for caspase activation and for caspase-mediated apoptotic death of neurones in AD and other neurodegenerative diseases has been supported by several recent studies (26,27).…”

Section: Discussionmentioning

confidence: 73%

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

Prosperi

Scali

Pepeu

et al. 2001

Japanese Journal of Pharmacology

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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...

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“…In addition to these mechanisms, a lower cytotoxicity on gastric mucosal cells was reported for one NO-NSAID, NO-flurbiprofen, whose use resulted in reduced apoptosis compared to that seen with standard flurbiprofen (24). Furthermore, NO-flurbiprofen suppressed the extent of TNFα-or ceramide-induced apoptosis by inhibiting caspases in vitro (24,25).…”

mentioning

confidence: 94%

Low Direct Cytotoxicity and Cytoprotective Effects of Nitric Oxide Releasing Indomethacin

Tomisato

Tanaka

Tsutsumi³

et al. 2005

Dig Dis Sci

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Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) have shown a marked reduction of gastrointestinal side effects and we here examined the cytotoxicity of NCX 530 (NO-indomethacin). Under conditions where indomethacin clearly induced both necrosis and apoptosis, NCX 530 induced neither. NCX 530 protected cells from celecoxib-induced necrosis and apoptosis. NCX 530 partially suppressed celecoxib-dependent membrane permeabilization and an inhibitor for guanylate cyclase suppressed the cytoprotective effect of NCX 530 against celecoxib. In vivo, NCX 530 alone produced fewer gastric lesions in rats than did indomethacin. A combination of the oral administration of celecoxib together with the intraperitoneal administration of indomethacin, but not of NCX 530, clearly resulted in the production of gastric lesions. The low direct cytotoxicity and the cytoprotective effect of NCX 530 observed in vitro may also act in vivo, thus ensuring that NCX 530 is safe for use on the gastric mucosa.

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Opposite effects of flurbiprofen and the nitroxybutyl ester of flurbiprofen on apoptosis in cultured guinea‐pig gastric mucous cells

Cited by 14 publications

References 32 publications

Heat Shock Preconditioning and Eicosanoid Pathways Modulate Caspase 3-Like Activity in Superficially Injured Isolated Guinea Pig Gastric Mucosa

Heat Shock Preconditioning and Eicosanoid Pathways Modulate Caspase 3-Like Activity in Superficially Injured Isolated Guinea Pig Gastric Mucosa

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

Low Direct Cytotoxicity and Cytoprotective Effects of Nitric Oxide Releasing Indomethacin

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