Aspirin-like drugs inhibit arachidonic acid metabolism via lipoxygenase and cyclo-oxygenase in rat neutrophils from carrageenan pleural exudates

Aspirin-like drugs inhibit the metabolism of arachidonic acid via lipoxygenase and cyclo-oxygenase in rat neutrophils from carrageenan pleural exudates. These non-steroidal anti-inflammatory drugs inhibit the formation of 11-hydroxy- and 15-hydroxy-eicosatetraenoic acid (HETE) as well as prostaglandins. In addition, the concentration- and time-dependent irreversible inhibition of lipoxygenase by aspirin and indomethacin parallels closely the patterns observed for inhibition of cyclo-oxygenase. The results suggest that some common steps may exist for the synthesis of HETE and prostaglandins from arachidonic acid in rat neutrophils. The ability of aspirin-like drugs to inhibit the formation of the chemotactic hydroxy-fatty acids may contribute to their anti-inflammatory activity.     

Some new aspects of gastric mucosal protection and damage

Much of the research on gastric mucosal protection has concerned prostaglandins. Some of the recent studies consolidate aspects first investigated a few years ago, but whose importance is now becoming established more clearly. This short review will mention some of the more recent work demonstrating the importance of prostaglandins in preventing stasis of gastric mucosal blood flow, effects on cell senescence and exfoliation, and the protection of a severe mucosal lesion by a mucus-containing plug which facilitates healing. The leukotrienes are other substances formed in the gastric mucosa from the same precursors as the prostaglandins. Their roles are not well understood, but may include participation in gastric inflammation, and in mucosal damage by nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol. The NSAIDs may damage the gastric mucosa not only by reducing the formation of protective prostaglandins, but also by increasing the metabolism of prostaglandin precursors into leukotrienes. Another factor is thromboxane A2, a substance that is damaging to the gastric mucosa but whose synthesis is inhibited by NSAIDs. The prostaglandin analogues produced for the treatment of peptic ulcer may find a major use in the protection against damage by NSAIDs. Not only may they act as 'replacement therapy' for the inhibited prostaglandins, but they protect against damage from substances that do not inhibit prostaglandin synthesis. In doses that raise the gastric pH, the prostaglandins reduce the local absorption of NSAIDs by increasing their ionisation. In rats, paracetamol protects against damage by aspirin, but whether this occurs in man is controversial. Work not previously published demonstrates that paracetamol does not affect the inhibition of prostaglandin formation by indomethacin in human isolated gastric mucosa.     

Prostaglandin biosynthesis in rabbit kidney medulla: inhibition in-vitro vs. in-vivo by aspirin, indomethacin and meclofenamic acid.

The non-steroidal anti-inflammatory drugs aspirin, indomethacin and meclofenamic acid were compared for their potency and duration of inhibition of prostaglandin biosynthesis in rabbit kidney medulla. Indomethacin and meclofenamic acid showed equal potency of inhibition in-vitro (IC50 0.88 micron and 0.85 micron respectively) while aspiring was a much weaker inhibitor (IC50 120 micron). In-vivo, indomethacin was the most powerful inhibitor (ID50 0.034 mg/kg) followed by meclofenamic acid (0.45 mg/kg) and aspirin (2.35 mg/kg). Studies on the duration of in-vivo inhibition by these compounds showed the effect of indomethacin and meclofenamic acid to be completely reversed within 4-6 hours. In contrast, return of kidney prostaglandin biosynthetic activity following aspirin inhibition is very slow and significant inhibition is still present 48 hours after a single aspiring injection. The inhibitory effect of aspirin in-vivo could be blocked by pretreatment with indomethacin, indicating that both drugs interact with related sites on the cyclo-oxygenase enzyme. The irreversible inhibition of the cyclo-oxygenase by aspirin as demonstrated in studies of other investigators suggests that the return of kidney prostaglandin synthetase activity after aspirin inhibition represents synthesis of new cyclo-oxygenase protein.     

Prostaglandin biosynthesis in rabbit kidney medulla: Inhibition vs. by aspirin, indomethacin and meclofenamic acid

The non-steroidal anti-inflammatory drugs aspirin, indomethacin and meclofenamic acid were compared for their potency and duration of inhibition of prostaglandin biosynthesis in rabbit kidney medulla. Indomethacin and meclofenamic acid showed equal potency of inhibition (IC₅₀ 0.88 μM and 0.85 μM respectively) while aspirin was a much weaker inhibitor (IC₅₀ 120 μM). , indomethacin was the most powerful inhibitor (ID₅₀ 0.034 mg/kg) followed by meclofenamic acid (0.45 mg/kg) and aspirin (2.35 mg/kg).Studies on the duration of inhibition by these compounds showed the effect of indomethacin and meclofenamic acid to be completely reversed within 4–6 hours. In contrast, return of kidney prostaglandin biosynthetic activity following aspirin inhibition is very slow and significant inhibition is still present 48 hours after a single aspirin injection. The inhibitory effect of aspirin could be blocked by pretreatment with indomethacin, indicating that both drugs interact with related sites on the cyclo-oxygenase enzyme. The irreversible inhibition of the cyclo-oxygenase by aspirin as demonstrated in studies of other investigators suggests that the return of kidney prostaglandin synthetase activity after aspirin inhibition represents synthesis of new cyclo-oxygenase protein.     

Synthesis and anti-inflammatory activity of benzophenone analogues

A series of substituted benzophenone analogues has been synthesized and evaluated as orally active anti-inflammatory agents with reduced side effects. The anti-inflammatory and ulcerogenic activities of the compounds were compared with naproxen, indomethacin, and phenylbutazone. In carrageenan-induced foot pad edema assay, benzophenone analogues showed an interesting anti-inflammatory activity. In the air-pouch test, some of the analogues reduced the total number of leukocytes of the exudate, which indicates inhibition of prostaglandin production. Side effects of the compounds were examined on gastric mucosa, in the liver and stomach. None of the compounds showed significant side effects compared with nonsteroidal anti-inflammatory drugs such as indomethacin and naproxen.     

Profiles of eicosanoid production from 14C-arachidonic acid and prostaglandin metabolism by rabbit esophageal mucosa and muscularis

In an attempt to elucidate the possible involvements of eicosanoids in esophageal functions and disorders, we have investigated the formation of both cyclooxygenase and lipoxygenase metabolites from 14C-arachidonic acid by rabbit esophageal tissues. Homogenates of rabbit esophageal mucosa and muscularis were incubated with 14C-arachidonic acid and after ether extraction eicosanoids were separated and quantified by reverse phase high performance liquid chromatography. The predominant cyclooxygenase products were 6-keto-PGF1 alpha, PGF2 alpha, and PGE2 for mucosa and 6-keto-PGF1 alpha, and PGE2 for muscularis. The formation of these products was inhibited both by indomethacin and the dual pathway inhibitor, nordihydrogualaretic acid (NDGA). In mucosa the major eicosanoid was 12-HETE (12-hydroxyeicosatetraenoic acid) which was inhibited by NDGA but not by indomethacin which on the contrary enhanced its formation. Additionally four polar products were synthesized which appeared to be lipoxygenase-dependent as their formation was inhibited by NDGA but not by indomethacin. Muscularis produced as a minor lipoxygenase product only 12-HETE, which was inhibited by NDGA but unchanged in the presence of indomethacin. In addition, both tissues, but mucosa more than muscularis, possessed large prostaglandin catabolizing capacity. The present findings indicate that rabbit esophageal tissues can convert 14C-arachidonic acid into lipoxygenase as well cyclo-oxygenase products which may have a role in esophageal physiology and pathophysiology.     

Suppression of cholesteryl ester accumulation in cultured human monocyte-derived macrophages by lipoxygenase inhibitors

Atherosclerotic lesions and xanthomas are characterized by the occurrence of cholesteryl ester (CE)-laden foam cells, which partly originate from macrophages. Little is known about the role of cyclo-oxygenase or lipoxygenase metabolites of arachidonic acid in the development of foam cells. In this study we investigated the influence of prostaglandins and inhibitors of the cyclo-oxygenase or the lipoxygenase pathway on CE accumulation in cultured human monocyte-derived macrophages. Accumulation of CE was achieved by incubation of the cells with acetylated low density lipoprotein (AcLDL). The stable prostacyclin analogue ZK 36 374 and prostaglandin E2 showed no effect on cellular CE storage. Similarly, the cyclo-oxygenase inhibitor indomethacin failed to influence AcLDL-induced CE accumulation. By contrast, however, the inhibitors of lipoxygenase activity nordihydroguaiaretic acid (NDGA) and BW 755 C markedly suppressed the accumulation of CE in monocyte-derived macrophages. The inhibitory effect of NDGA was dose-dependent. Incubation of the cells with the anti-oxidant vitamin E gave no significant reduction of CE accumulation. Our results indicate that inhibition of the lipoxygenase pathway of arachidonic acid metabolism in cultured monocyte-derived macrophages effectively decreases the rate of experimentally-induced CE accumulation.     

Nonsteroidal anti-inflammatory drugs inhibit gastric peroxidase activity

The peroxidase activity of the mitochondrial fraction of rat gastric mucosa was inhibited with various nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro. Indomethacin was found to be more effective than phenylbutazone (PB) or acetylsalicylic acid (ASA). Mouse gastric peroxidase was also very sensitive to indomethacin inhibition. Indomethacin has no significant effect on submaxillary gland peroxidase activity of either of the species studied. Purified rat gastric peroxidase activity was inhibited 75% with 0.15 mM indomethacin showing half-maximal inhibition at 0.04 mM. The inhibition could be withdrawn by increasing the concentration of iodide but not by H2O2. NSAIDs inhibit gastric peroxidase activity more effectively at acid pH (pH 5.2) than at neutral pH. Spectral studies showed a bathochromic shift of the Soret band of the enzyme with indomethacin indicating its interaction at or near the heme part of the enzyme.     

Cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal anti-inflammatory drugs and gastric mucosal responses.

Occurrence of gastrointestinal damage and delayed healing of pre-existing ulcer are commonly observed in association with clinical use of nonsteroidal antiinflammatory drugs (NSAIDs). We examined the effects of NS-398, the cyclooxygenase (COX)-2 selective inhibitor, and nitric oxide (NO)- releasing aspirin (NCX-4016) on gastric mucosal ulcerogenic and healing responses in experimental animals, in comparison with those of nonselective COX inhibitors such as indomethacin and aspirin. Indomethacin and aspirin given orally were ulcerogenic by themselves in rat stomachs, while either NS-398 or NCX-4016 was not ulcerogenic at the doses which exert the equipotent antiinflammatory action with indomethacin or aspirin. Among these NSAIDs, only NCX-4016 showed a dose-dependent protection against gastric lesions induced by HCl/ethanol in rats. On the other hand, the healing of gastric ulcers induced in mice by thermal-cauterization was significantly delayed by repeated administration of these NSAIDs for more than 7 days, except NCX-4016. Gastric mucosal prostaglandin contents were reduced by indomethacin, aspirin and NCX-4016 in both normal and ulcerated mucosa, while NS-398 significantly decreased prostaglandin generation only in the ulcerated mucosa. Oral administration of NCX-4016 in pylorus-ligated rats and mice increased the levels of NO metabolites in the gastric contents. In addition, both NS-398 and NCX-4016 showed an equipotent anti-inflammatory effect against carrageenan-induced paw edema in rats as compared with indomethacin and aspirin. These results suggest that both indomethacin and aspirin are ulcerogenic by themselves and impair the healing of pre-existing gastric ulcers as well. The former action is due to inhibition of COX-1, while the latter effect may be accounted for by inhibition of COX-2 and mimicked by NS-398, the COX-2 selective NSAID. NCX-4016, despite inhibiting both COX-1 and COX-2, protects the stomach against damage and preserves the healing response of gastric ulcers, probably because of the beneficial action of NO.     

Arachidonate metabolism in the mouse thyroid implication of the lipoxygenase pathway in thyrotropin action

The present study of compares the effects of various inhibitors of arachidonate metabolism on mouse thyroid cyclo-oxygenase and lipoxygenase activities and thyrotropin-augmented cyclic-AMP accumulation. Mouse thyroid homogenate converts [1-14C]- arachidonate to several products of the cyclo-oxygenase pathway as well as one major product of the lipoxygenase pathway, 12-L-hydroxyeicosatetraenoic acid (12-Hete). Prostaglandin (PG) formation in thyroid homogenates is inhibited by 1-10 microM indomethacin and etya. 12-HETE accumulation is reduced by 91%, 83% and 20% by 5 microM ETYA, 15-HETE, and indomethacin, respectively. Thyrotropin-stimulated cyclic-AMP accumulation, measured in whole thyroid lobes by radioimmunoassay, is reduced by 45% and 73% by 50 microM and 100 microM ETYA, respectively; indomethacin is without effect at these concentrations. 15-HETE reduces thyrotropin-augmented cyclic-AMP accumulation by 57% and 100 microM. In product inhibition studies, 10 microM 12-HETE reduced the formation of radiolabeled 12-HETE by 20%. 10 microM PGE2, PGF2 alpha or PGD2 had no effect on [1-14C]-PG formation. 12-HETE, however, reduced PG synthesis by 76% at 10 microM. This is the first report implicating the arachidonate lipoxygenase pathway in thyrotropin action at the level of cyclic-AMP regulation. Additionally, our finding that 12-HETE inhibits prostaglandin synthesis suggests that the cyclo-oxygenase and lipoxygenase pathways in the mouse thyroid may be highly integrated.     

Glucose-stimulated protein phosphorylation in the pancreatic islet

The effect of inhibitors of the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism on steroidogenesis in rat testis Leydig cells and rat tumour Leydig cells has been investigated. In the presence of nordihydroguaiaretic acid [NDGA; 4,4'-(2,3- dimethylbutan -1,4- diyl )bis[1,2- benzendiol ]], 5,8,11,14-eicosatetraynoic acid (ETYA), BW 755C [3-amino-1-[3-(trifluoromethyl)phenyl]-2-pyrazoline hydrochloride] and benoxaprofen [ Opren ; 2-(2-p-chlorophenyl- benzoxazol -5-yl)propionic acid)] (which inhibit lipoxygenase activity), but not indomethacin and aspirin (which inhibit cyclo-oxygenase activity), a dose-related inhibition of lutropin (LH)-stimulated testosterone and pregnenolone production was obtained (ID50 values of 2.5, 30, 25 and 30 microM for NDGA, ETYA, BW 755C and benoxaprofen were obtained, respectively). BW 755C and benoxaprofen had no significant effect on LH-stimulated cyclic AMP production except at the highest concentrations examined (330 and 380 microM, respectively), whereas NDGA and ETYA inhibited LH-stimulated cyclic AMP production in a dose-dependent manner (ID50 7.0 and 22 microM respectively). However, NDGA and ETYA also caused a dose-dependent inhibition of dibutyryl cyclic AMP-stimulated testosterone and pregnenolone production. The metabolism of exogenous ( 22R )-hydroxycholesterol or pregnenolone to testosterone by Leydig cells was not inhibited by either NDGA, ETYA or indomethacin. At low concentrations of NDGA and ETYA a significant increase in the conversion of both pregnenolone and ( 22R )-hydroxycholesterol to testosterone was obtained. Studies in which the metabolism of [14C]arachidonic acid by purified rat tumour Leydig cells was investigated indicate that products are formed by tumour Leydig cells that have similar mobilities in a thin layer chromatography system to 5-L-hydroxy-6,8,11,14-eicosatetraenoic acid, 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid and leukotriene B4. The formation of these products was inhibited to varying degrees by NDGA, BW 755C and benoxaprofen but not by aspirin and indomethacin. These studies demonstrate for the first time that inhibition of lipoxygenase activity but not cyclo-oxygenase activity causes an inhibition of LH- and dibutyryl cyclic AMP-stimulated steroid production and suggest a stimulatory role for products of the lipoxygenase pathway of arachidonic acid metabolism in steroidogenesis. The site of this stimulation is apparently distal to the production of cyclic AMP and before the side chain cleavage of cholesterol.     

Effects of nimesulide, a preferential cyclooxygenase-2 inhibitor, on carrageenan-induced pleurisy and stress-induced gastric lesions in rats

Intrapleural injection of carrageenan in rats increased prostaglandin E₂ (PGE₂) production and induced newly synthesized cyclooxygenase-2 (COX-2) in pleural exudate cells without affecting COX-1 levels. Nimesulide, a preferential inhibitor of COX-2, reduced pleural PGE₂ production and was almost as active as indomethacin and 10 times more active than ibuprofen. Only COX-1, and no COX-2, was detected in gastric mucosal cells, and PGE₂ concentration of gastric mucosa was significantly decreased by indomethacin and ibuprofen. The decrease in gastric PGE₂ production induced by indomethacin and ibuprofen was enhanced in stressed rats, resulting in aggravation of stress-induced gastric lesions at anti-inflammatory doses. However, nimesulide did not produce stress-induced gastric lesions even at 30 times the anti-inflammatory dose. This supports the hypothesis that inhibition of COX-1 causes unwanted side effects and inhibition of COX-2 produces anti-inflammatory effects.     

Salicylate fails to prevent the inhibitory effect of 5,8,11,14-eicosatetraynoic acid on human platelet cyclo-oxygenase and lipoxygenase activities

Sodium salicylate is inactive both on cyclo-oxygenase and lipoxygenase prepared from human platelets. It prevents the inhibition of cyclo-oxygenase induced by aspirin, but does not counteract the inhibitory effect of 5,8,11,14-eicosatetraynoic acid on both enzymes. It also fails to interfere with the inhibitory activity of nordihydroguaiaretic acid on lipoxygenase. These data indicate that, unlike eicosatetraynoic acid, non-steroidal anti-inflammatory drugs interact with a site on cyclo-oxygenase distinct from the catalytic site, although related to it. Such a supplementary binding site is lacking on lipoxygenase.     

Role of cyclooxygenase-2 in Helicobacter pylori- induced gastritis in Mongolian gerbils

Cyclooxygenase (COX)-2 expression is induced in the gastric mucosa of Helicobacter pylori-infected patients, but its role remains unclear. We examined the effects of NS-398 and indomethacin on gastric pathology in H. pylori-infected Mongolian gerbils. COX-1 was detected in both normal and H. pylori-infected mucosa, whereas COX-2 was expressed only in the infected mucosa. PGE(2) production was elevated by H. pylori infection, and the increased production was reduced by NS-398, which did not affect PGE(2) production in normal mucosa. Indomethacin inhibited PGE(2) production in both normal and infected mucosa. Hemorrhagic erosions, neutrophil infiltration, lymphoid follicles, and epithelium damage were induced by H. pylori infection. NS-398 and indomethacin aggravated these pathological changes but did not increase viable H. pylori number. H. pylori-increased production of neutrophil chemokine and interferon-gamma was potentiated by NS-398 and indomethacin. Neither NS-398 nor indomethacin caused any pathological changes or cytokine production in normal animals. These results indicate that COX-2 as well as COX-1 might play anti-inflammatory roles in H. pylori-induced gastritis.     

Stereoisomeric relationships among anti-inflammatory activity, inhibition of platelet aggregation, and inhibition of prostaglandin synthetase

This study compares the affects of a new non-steroidal anti-inflammatory drug, d,l-6-chloro-alpha-methyl-carbazole-2-acetic acid, its enantiomers, and indomethacin on platelet aggregation, prostaglandin synthetase, adjuvant arthritis, gastric ulceration and arachidonic acid induced diarrhea. In the adjuvant arthritic rat, doses producing anti-inflammatory activity were similar for all compounds with the exception of the l-isomer which was much less active. On the other hand, indomethacin was 10 to 25 times more potent with regard to inhibition of platelet aggregation, inhibition of prostaglandin synthetase, inhibition of arachidonic acid induced diarrhea, and induction of gastric ulceration than the racemate and its isomers. Such divergence of potencies suggests that the racemate, unlike indomethacin, would have no affect on platelet aggregation and, hence, produce no prolongation of bleeding time at doses possessing anti-inflammatory activity. The data also suggest that the racemate and d-isomer have greater specificity toward anti-arthritic activity and are less ulcerogenic than indomethacin. The d-isomer apparently is the more active component of the racemate in all the systems tested since: (a) the d-isomer has 2 to 3 times the inhibitory potency of the racemate and (b) the l-isomer, at high dosages or high concentrations had considerably less affect. Comparison of potencies relative to inhibition of platelet aggregation and of prostaglandin synthetase, are quite close; therefore, mechanistically, the anti-aggregatory affects of these drugs, or lack thereof, may be related to inhibition of prostaglandin synthetase.     

Stereoisomeric relationships among anti-inflammatory activity, inhibition of platelet aggregation, and inhibition of prostaglandin synthetase

This study compares the affects of a new non-steroidal anti-inflammatory drug, d,1-6-chloro-alpha-methyl-carbazole-2-acetic acid, its enantiomers, and indomethacin on platelet aggregation, prostaglandin synthetase, adjuvant arthritis, gastric ulceration and arachidonic acid induced diarrhea. In the adjuvant arthritic rat, doses producing anti-inflammatory activity were similar for all compounds with the exception of the I-isomer which was much less active. On the other hand, indomethacin was 10 to 25 times more potent with regard to inhibition of platelet aggregation, inhibition of prostaglandin synthetase, inhibition of arachidonic acid induced diarrhea, and induction of gastric ulceration than the racemate and its isomers. Such divergence of potencies suggests that the racemate, unlike indomethacin, would have no affect on platelet aggregation and, hence, produce no prolongation of bleeding time at doses possessing anti-inflammatory activity. The data also suggest that the racemate and d-isomer have greater specificity toward anti-arthritic activity and are less ulcerogenic than indomethacin. The d-isomer apparently is the more active component of the racemate in all the systems tested since: (a) the d-isomer has 2 to 3 times the inhibitory potency of the racemate and (b) the I-isomer, at high dosages or high concentrations had considerably less affect. Comparison of potencies relative to inhibition of platelet aggregation and of prostaglandin synthetase, are quite close; therefore, mechanistically, the anti-aggregatory affects of these drugs, or lack thereof, may be related to inhibition of prostaglandin synthetase.     

NSAIDs counteract H. pylori VacA toxin-induced cell vacuolation in MKN 28 gastric mucosal cells

The relationship between nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori-induced gastric mucosal injury is still under debate. VacA toxin is an important H. pylori virulence factor that causes cytoplasmic vacuolation in cultured cells. Whether and how NSAIDs affect VacA-induced cytotoxicity is unclear. This study was designed to evaluate the effect of NSAIDs on H. pylori VacA toxin-induced cell vacuolation in human gastric mucosal cells in culture (MKN 28 cell line). Our data show that 1) NSAIDs (indomethacin, aspirin, and NS-398) inhibit VacA-induced cell vacuolation independently of inhibition of cell proliferation and prostaglandin synthesis; 2) NSAIDs impair vacuole development/maintenance without affecting cell binding and internalization of VacA; and 3) NSAIDs, as well as the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid, also inhibit cell vacuolation induced by ammonia. We thus hypothesize that NSAIDs might protect MKN 28 cells against VacA-induced cytotoxicity by inhibiting VacA channel activity required for vacuole genesis.     

The protective action of melatonin on indomethacin-induced gastric and testicular oxidative stress in rats

Reactive oxygen species and lipid peroxidation play a role in the pathogenesis induced by the non-steroidal anti-inflammatory drug indomethacin. Melatonin (MLT) protection against indomethacin-induced oxidative tissue injury was investigated in gastric mucosa and testis of rats. MLT was administered intragastrically (i.g.) 30 min before the administration to fasted rats of 20 mg indomethacin/kg rat given i.g.. The area of gastric lesion as well as thiobarbituric acid reactive substances (TBARS) and lactate dehydrogenase (LDH) activity were found to be significantly increased 4 h after administration of indomethacin in rat gastric mucosa and testis indicating acute oxidative injury. MLT pretreatment reduced gastric lesion area to 80% of the indomethacin-treated rats and reduced the rise in TBARS concentration. MLT treatment reduced the LDH activity increase in testis but not in gastric mucosa. In indomethacin-treated rats, both the cytosolic Cu,Zn superoxide dismutase (Cu,Zn-SOD) and mitochondrial Mn-SOD activities were significantly diminished in gastric mucosa as well as the total SOD activity in testis. In addition, glutathione (GSH) content in both tissues was markedly decreased following indomethacin treatment. Pretreatment with MLT significantly ameliorated both the inhibition of SOD activity and the decreased GSH content in both tissues. Thus, these results show the effective antiperoxidative and preventive actions of MLT against indomethacin-induced gastric mucosal damage and testicular oxidative injury and we propose that this action might be relevant for its use with other free radical generating drugs.     

The role of prostaglandins in the regulation of gastric mucosal blood flow

It has been postulated that endogenous gastric prostaglandin activity contributes to the maintenance of non-stimulated gastric mucosal blood flow. Prostacyclin and PGE₂ increase mucosal blood flow in the non-stimulated canine stomach. Inhibition of prostaglandin synthesis by aspirin or indomethacin causes a reduction of 30% to 50% in non-stimulated gastric mucosal blood flow in dog and rat. These observations are consistent with the hypothesis that endogenous prostaglandin activity within the gastric mucosa contributes to the maintenance of its blood flow.Also it has been postulated that endogenous prostaglandins may, in part, mediate the vasodilation associated with stimulated gastric acid secretion. Exogenous prostacyclin and PGE₂ inhibit stimulated acid secretion while increasing mucosal blood flow. Indomethacin and aspirin-inhibited endogenous prostaglandin synthesis has been reported to increase stimulated acid secretion and reduce mucosal blood flow in anesthetized rat and dog. In gastric secretory fluid, prostaglandins have been detected during gastrin stimulation by some investigators and a dose response relationship between rate of secretion and fluid prostaglandin output has been observed. These observations are consistent with the hypothesis that endogenous prostaglandins may, in part, contribute to the regulation of mucosal blood flow during stimulated acid secretion. Further studies, directly measuring specific endogenous prostaglandins and their metabolic products within the gastric mucosa during stimulated and inhibited acid secretion will be necessary to prove or disprove this hypothesis.     

Sulindac inhibits activation of the NF-kappaB pathway.

Sulindac is a non-steroidal anti-inflammatory agent that is related both structurally and pharmacologically to indomethacin. In addition to its anti-inflammatory properties, sulindac has been demonstrated to have a role in the prevention of colon cancer. Both its growth inhibitory and anti-inflammatory properties are due at least in part to its ability to decrease prostaglandin synthesis by inhibiting the activity of cyclooxygenases. Recently, we demonstrated that both aspirin and sodium salicylate, but not indomethacin, inhibited the activity of an IkappaB kinase beta (IKKbeta) that is required to activate the nuclear factor-kappaB (NF-kappaB) pathway. In this study, we show that sulindac and its metabolites sulindac sulfide and sulindac sulfone can also inhibit the NF-kappaB pathway in both colon cancer and other cell lines. Similar to our previous results with aspirin, this inhibition is due to sulindac-mediated decreases in IKKbeta kinase activity. Concentrations of sulindac that inhibit IKKbeta activity also reduce the proliferation of colon cancer cells. These results suggest that the growth inhibitory and anti-inflammatory properties of sulindac may be regulated in part by inhibition of kinases that regulate the NF-kappaB pathway.