الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
The present study confirms the damaging effect of cholestasis on the integrity of hepatic and biliary tissues. Ligation of the common bile duct in male rats for 3 days resulted in severe damage to the hepatobiliary system. Serum markers of hepatic damage namely; AST and ALT were markedly elevated.
Serum markers of biliary tract damage such as ALP and GGT were also significantly increased.
In addition, serum level of bilirubin and TBAs was markedly increased as a result of bile duct obstruction.All cholestatic animals exhibited spontaneous gastric ulceration (Score 3.16 ± 0.17) in the glandular portion of the stomach.
Microscopical examination of gastric specimens also showed damaged mucosa with loss of superficial epithelial layer, distorted arrangement of glands, congested blood vessels, inflammatory cell infiltration together with severe submucosal edema .Cholestasis-induced gastric damage was accompanied with increased oxidative stress manifested as increased mucosal MDA level. This oxidative stress could be linked to the elevated serum level of TBAs, which are known to have pro-oxidant effects. In addition, there was a pronounced reduction of gastric mucosal content of GSH which could result from diminished GSH synthesis or increased GSH consumption secondary to the over production of ROS. Gastric mucosal content of NO was also decreased
significantly in cholestatic animals, possibly, as a result of increased oxidative stress as ROS are known to suppress NOS activity. In addition, BDL rats showed a pronounced fall in the gastric mucosal content of VEGF level that could be secondary to the decrease in NO as it is reported to be involved in the expression of VEGF.
Moreover, there was a marked elevation of pro-inflammatory cytokine; TNF-α. This elevation could be attributed to the increased oxidative stress that is reported to activate the expression of nuclear factorkappaB (NF-KB) with a consequent increase in inflammatory cytokines synthesis.
Elevation of TNF-α could also be linked to the reported inhibitory effect of cholestasis on prostaglandin E2 synthesis which in turn enhances neutrophil activation and inflammatory cytokines synthesis and release. Oral administration of piroxicam (50 mg/kg) to male rats induced gastric ulcers in in the glandular portion of the stomach of all treated animals. The ulcerogenic effect of piroxicam is generally accepted to be mediated through inhibition of COX activity which leads to inhibition of mucosal prostaglandin E2 synthesis.
Inhibition of COX activity diverts arachidonic acid toward the formation of leukotrienes. Piroxicam-induced gastric ulceration was associated in the present study with a significant alteration in the redox system manifested as increased level of mucosal MDA along with decreased level of GSH.
These alterations could be related to the reported stimulatory effect of piroxicam on several pro-oxidant enzymes such as xanthine oxidase.
In addition, increased MDA level could be attributed to neutrophil activation secondary to diminished PGE2 synthesis and enhanced leukotrienes formation. Piroxicam-induced peptic ulceration was also accompanied by a significant decrease in mucosal NO level which could result from the inhibitory effect of ROS on NOS activity.
Decreased NO level could also be linked to piroxicam-induced up-regulation of endothelin-1 which is reported to inhibit NOS activity. In addition, there was a marked increase in mucosal TNF-α level which could be attributed to oxidative stress, decreased PG E2 synthesis and neutrophil activation.The present study reveals the aggravating effect of BDL on piroxicam-induced gastric ulceration. Oral administration of a single dose of piroxicam (50 mg/kg) to cholestatic rats produced severe gastric ulceration (score; 72.33 ± 4.75) in the glandular portion of the stomach of all treated animals.
The ulcer index was significantly higher compared to either BDL or (SO + piroxicam) treated groups. The present study points to the possible mutual synergistic damaging interaction between cholestasis and piroxicam on gastric integrity.
This mutual aggressive effect could be mediated through their additive pro-oxidant and inflammatory effect manifested as increased level of MDA and TNF-α, respectively. The aggressive effect is also mediated through additive inhibitory effect of both cholestasis and piroxicam on GSH and NO level.
In addition, cholestasis-induced aggravation of peptic ulceration is associated with depletion of gastric mucosal level of VEGF. Piroxicam showed no effect on mucosal VEGF level as piroxicam could exert opposite effects on VEGF expression; enhanced expression through increased endothelin-1 formation and decreased expression secondary to diminished mucosal NO level. In the current work, pretreatment of male rats with NAC (300 mg/kg) for 4 successive days ameliorated piroxicam-induced gastric ulceration in both control (non-BDL) and cholestatic animals.
The protection ratios afforded by NAC treatment were 100% and 60.36 % in control and cholestatic animals, respectively. The protection ratio afforded by NAC
in cholestatic animals is about 91.00% of that provided by the standard acid suppressing drug; omeprazole. The gastroprotective effect of NAC was mediated through its potent antioxidant activity manifested as a significant reduction ofMDA level and a marked elevation of GSH content.
In addition, NAC pretreatment ameliorated the reduction in the mucosal level of VEGF. AlthoughNAC failed to elevate NO level in control animals receiving piroxicam, it significantly increased its level in piroxicam-treated cholestatic group. This could be explained taking into account that the ameliorating effect of NAC on NO reduction in cholestatic rats is due to its potent antioxidant effect whereas, in piroxicam-treated control rats, NO decrease develops mainly secondary to piroxicam-induced elevation in endothelin-1 level. Moreover,the gastroprotective effect of NAC could be mediated through its observed anti-inflammatory effect. NAC pretreatment markedly elevated the anti-inflammatory cytokine; IL-10 in gastric mucosa of cholestatic animals.The present study also demonstrates the protective activity of NAC on hepatobiliary tissues. Pretreatment of cholestatic animals with NAC significantly ameliorated the damaging effect of cholestasis on biliary ductmanifested as a significant reduction of serum level of ALP and GGT.
The present study reveals for the first time the gastroprotective effect of SB against piroxicam-induced gastric ulceration in both control and cholestatic animals.Oral administration of SB (400 mg/kg) twice daily for 4 successive days with the last dose given 30 minutes before piroxicam administration attenuated gastric ulceration and afforded a protection ratio of 66.82 % and 50.46% in both control and cholestatic animals, respectively.
The protective ratio provided by SB treatment in cholestatic animals was about 76.0 % of that afforded by omeprazole. The gastroprotection exerted by SB was mediated through antioxidant and anti-inflammatory mechanisms.
Pretreatment cholestatic animals with SB resulted in a marked reduction of the gastric mucosal content of MDA and the pro-inflammatory cytokine; TNF-α. SB treatment also elevated the mucosal level of GSH and the anti-inflammatory cytokine; IL-10.
In addition, SB gastroprotective effect could be mediated through its angiogenic effect as the drug significantly elevated the mucosal level of VEGF in piroxicam-treated cholestatic animals.The present study is the first to demonstrate the hepatoprotective effects of SB in BDL animals.
This protection was evidenced by the significant reduction in serum level of AST, ALP, GGT, TBIL and DBIL. In the current study, pretreatment of control and cholestatic rats with silymarin decreased piroxicam-induced gastric mucosal lesions and afforded a protection ratio of 38.07 % and 32.25 %, respectively.
The efficacy of silymarin as a gastroprotective drug against piroxicam-induced ulceration in cholestatic animals was about half the efficacy of omeprazole. Silymarin treatment was accompanied with a marked elevation of GSH in gastric mucosa along with a significant reduction in the mucosal content of MDAin piroxicam-treated cholestatic rats.
Although silymarin failed to elevate the gastric mucosal content of NO in control animals receiving piroxicam, it significantly increased its level in piroxicam-treated cholestatic animals. This discrepancy could be explained considering that cholestasis-induced inhibition of NOS activity could be mediated through the increased oxidative stress whereas piroxicam-induced inhibition is mediated mainly from increased ynthesis of endothelin-1. Silymarin also significantly increased the gastric mucosal level of VEGF in piroxicam-treated cholestatic animals.
In the present study, silymarin showed a marked hepatoprotective effect in cholestatic rats. Silymarin pretreatment markedly reduced serum markers indicative of cholestasis and hepatic damage; namely, ALT, ALP, GGT, TBIL, DBIL and TBAs.In the present study, pioglitazone pretreatment produced a significant reduction of piroxicam-induced gastric lesions in both control and cholestatic rats and it provided a protection ratio of 53.10% and 41.00 %, respectively. The protection ratio of pioglitazone in cholestatic animals was almost 62.00 % of the protection ratio of omeprazole.The gastroprotective activity of pioglitazone was mediated through antioxidant and anti-inflammatory mechanisms.
Pioglitazone significantly reduced the gastric mucosal content of MDA and TNF-α along with an elevation of the anti-inflammatory cytokine; IL-10. The gastroprotection of pioglitazone could also be mediated through enhancement of gastric mucosal blood flow as pioglitazone elevated the mucosal content of NO and VEGF. Pioglitazone treatment also significantly mitigated cholestasis-induced elevation of the serum hepatic parameters AST, GGT, and bilirubin.
In the present work, pretreatment of control and cholestatic animals with fenofibrate resulted in a significant protection against piroxicam-induced gastric ulceration and it afforded a protection ratio of 39.39 % and 41.45 %, respectively. The protection ratio of fenofibrate in cholestatic animals was about 63.00 % of the protection ratio provided by omeprazole. The gastroprotective effect of fenofibrate could be attributed to its antioxidant and anti-inflammatory activity.
Fenofibrate markedly reduced themucosal level of MDA together with an elevation of the mucosal content of GSH. Fenofibrate treatment also significantly reduced the gastric mucosal content of TNF-α. In addition, enhancement of NO level in the gastric tissues could contribute to the gastroprotective of fenofibrate.
In the present work, fenofibrate administration to BDL animals markedly reduced the elevated serum hepatic markers; ALT, TBIL and DBIL.On the other hand, TBAs level was markedly increased in fenofibrate-treated BDL group. This increase could be attributed to the reported inhibitory effect of fenofibrate on BAs uptake transporters and its stimulatory effect on basolateral efflux pump.
In the current study, UDCA treatment markedly decreased all the elevated serum hepatic markers including AST, ALT, ALP, GGT, bilirubin and TBAs in BDL animals. Although UDCAfailed to provide any gastroprotective effect against piroxicam-induced ulceration in control animals, it significantly reduced gastric ulceration in cholestatic animals with a protection ratio of 33.87% which is almost 51.00 % of the protection ratio of omeprazole. Based on the observed differential gastroprotective activity of UDCA, it could be suggested that UDCA ameliorated the gastric damage secondary to its anticholestatic activity rather than through a direct effect on gastric tissues. Gastroprotection exerted by UDCA treatment in cholestatic animals was accompanied with a reversal of the gastric mucosal depletion of GSH, IL10, NO, and VEGF.
<According to the protection ratioagainst piroxicam-induced gastric ulceration in control animals, the investigated drugs in the present study can be arranged as follows; NAC > Omp = SB > Pio > fenofibrate = silymarin.
According to the protection ratio against piroxicam-induced gastric ulceration in cholestatic animals, the investigated drugs in the present study can be arranged as follows; Omp > NAC > SB > Pio = fenofibrate > silymarin = UDCA.