A major clinical problem encountered with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, is gastrointestinal complications. Both NSAID-dependent cyclooxygenase inhibition and gastric mucosal apoptosis are involved in NSAID-produced gastric lesions, and this apoptosis is mediated by the endoplasmic reticulum stress response and resulting activation of Bax. Heat shock proteins (HSPs) have been suggested to protect gastric mucosa from NSAID-induced lesions; here we have tested this idea genetically. The severity of gastric lesions produced by indomethacin was worse in mice lacking heat shock factor 1 (HSF1), a transcription factor for hsp genes, than in control mice. Indomethacin administration upregulated the expression of gastric mucosal HSP70. Indomethacin-induced gastric lesions were ameliorated in transgenic mice expressing HSP70. After indomethacin administration, fewer apoptotic cells were observed in the gastric mucosa of transgenic mice expressing HSP70 than in wild-type mice, whereas the gastric levels of prostaglandin E 2 for the two were indistinguishable. This suggests that expression of HSP70 ameliorates indomethacin-induced gastric lesions by affecting mucosal apoptosis. Suppression of HSP70 expression in vitro stimulated indomethacin-induced apoptosis and activation of Bax but not the endoplasmic reticulum stress response. Geranylgeranylacetone induced HSP70 at gastric mucosa in an HSF1-dependent manner and suppressed the formation of indomethacin-induced gastric lesions in wild-type mice but not in HSF1-null mice. The results of this study provide direct genetic evidence that expression of HSP70 confers gastric protection against indomethacin-induced lesions by inhibiting the activation of Bax. The HSP inducing activity of geranylgeranylacetone seems to contribute to its gastroprotective activity against indomethacin.

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We previously proposed that membrane permeabilization activity of NSAIDs is involved in NSAID-induced gastric lesions. We here synthesized derivatives of loxoprofen that have lower membrane permeabilization activity than other NSAIDs. Compared to loxoprofen, the derivatives 10a and 10b have lower membrane permeabilization activity and their oral administration produced fewer gastric lesions but showed an equivalent anti-inflammatory effect. These results suggest that 10a and 10b are likely to be therapeutically beneficial as safer NSAIDs.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, are a useful family of therapeutics.1) An inhibitory effect of NSAIDs on cyclooxygenase (COX) activity is responsible for their anti-inflammatory actions because COX is an enzyme essential for the synthesis of prostaglandins (PGs), such as PGE 2 , which have a strong capacity to induce inflammation. On the other hand, NSAID use is associated with gastrointestinal complications. [2][3][4] In 1991, two subtypes of COX, COX-1 and COX-2, which are responsible for the majority of COX activity at the gastrointestinal mucosa and in tissues with inflammation, respectively, were identified. 5,6) Since PGE 2 has a strong protective effect on the gastrointestinal mucosa, it is reasonable to speculate that selective COX-2 inhibitors maintain anti-inflammatory activity without gastrointestinal side-effects. In fact, a greatly reduced incidence of gastroduodenal lesions has been reported for selective COX-2 inhibitors (such as celecoxib and rofecoxib).7-9) However, a recently raised issue concerning the use of selective COX-2 inhibitors is their potential risk for cardiovascular thrombotic events. 10,11) This may be due to the fact that prostacyclin, a potent antiaggregator of platelets and a vasodilator, is mainly produced by COX-2 in vascular endothelial cells, while thromboxane A 2 , a potent aggregator of platelets and a vasoconstrictor, is mainly produced by COX-1 in platelets. [12][13][14] Because of this concern, rofecoxib was withdrawn from the worldwide market. Therefore, NSAIDs exhibiting gastrointestinal safety, other than selective COX-2 inhibitors, are clinically important.The inhibition of COX by NSAIDs is not the sole explanation for the gastrointestinal side-effects of NSAIDs.15) We have recently demonstrated that NSAIDs induce necrosis and apoptosis in cultured gastric mucosal cells and at gastric mucosa in a manner independent of COX inhibition. [16][17][18][19][20] We clearly showed that the primary target of NSAIDs for induction of necrosis and apoptosis is cytoplasmic membranes. 16,18) As for the molecular mechanism governing this apoptosis, we have proposed the following pathway. Permeabilization of cytoplasmic membranes by NSAIDs stimulates Ca 2ϩ influx and increases intracellular Ca 2ϩ levels, which in turn induces the endoplasmic reticulum (ER) stress response. 16,21,22) In this response, an apoptosis-inducing transcription factor, CCAAT/enhancer-binding protein (C/EBP) homologous transcription factor (CHOP), is induced and CHOP induces expression of p53 up-regulated modulator of apoptosis (PUMA) and resulting translocation and activation of Bax, mitochondrial dysfunction, activation of caspases and apoptosis.17,23) Furthermore, we have suggested that both COX inhibition and gastric mucosal cell death are required for the formation of NSAID-induced gastric lesions in vivo. 20,24) Loxoprofen has been used clinically for a long time as a standard NSAID in Japan, and clinical studies have suggested that it is safer than other NSAIDs, s...

Delayed gastric emptying and impaired gastric accommodation (decreased gastric compliance) play important roles in functional dyspepsia (FD). Here we screen for a clinically used drug with an ability to improve delayed gastric emptying in rats. Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying. Administration of allantoin, but not aluminium hydroxide, restored the gastric emptying. Both aldioxa and allantoin inhibited clonidine binding to the α-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity. Aldioxa or aluminium hydroxide but not allantoin restored gastric compliance with restraint stress, suggesting that aluminium hydroxide moiety is involved in this restoration. We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here.