Effect of nonselective and selective COX-2 inhibitors on memory dysfunction, glutathione system, and tumor necrosis factor alpha level against cerebral ischemia reperfusion injury

Involvement of the glutathione system is well established in stroke-induced memory dysfunction. The aim of the present study was to investigate the effects of celecoxib (a selective cyclooxygenase-2 [COX-2] inhibitor), nimesulide (a preferential COX-2 inhibitor), and ibuprofen (a nonselective COX-2 inhibitor) against bilateral common carotid artery occlusion (BCCAO)-induced memory dysfunction. BCCAO for 30 minutews, followed by 24-hour reperfusion, significantly delayed transfer latency in the plus-maze performance task and shortened fall-off time in the hanging-wire experimental test. Besides significant alterations in glutathione defense (i.e., glutathione S-transferase and redox ratio), increased acetylcholinesterase activity and proinflammatory marker (tumor necrosis factor alpha TNF-α) in the hippocampus was seen. Seven days of treatment with celecoxib (3 and 10?mg/kg, p.o.), nimesulide (10?mg/kg, p.o.), and ibuprofen (30?mg/kg, p.o.) significantly improved behavioral alterations and glutathione defense and attenuated acetylcholinesterase activity and TNF-α levels, as compared to the control (i.e., ischemic reperfusion) group. The present study highlights the neuroprotective effect of celecoxib and nimesulide against ischemia reperfusion injury-induced memory dysfunction, neuroinflammation, and oxidative damage.     

Ibuprofen administration attenuates serum TNF-alpha levels, hepatic glutathione depletion, hepatic apoptosis and mouse mortality after Fas stimulation

Fas stimulation recruits neutrophils and activates macrophages that secrete tumor necrosis factor-α (TNF-α), which aggravates Fas-mediated liver injury. To determine whether nonsteroidal anti-inflammatory drugs modify these processes, we challenged 24-hour-fasted mice with the agonistic Jo2 anti-Fas antibody (4 µg/mouse), and treated the animals 1 h later with saline or ibuprofen (250 mg/kg), a dual cyclooxygenase (COX)-1 and COX-2 inhibitor. Ibuprofen attenuated the Jo2-mediated recruitment/activation of myeloperoxidase-secreting neutrophils/macrophages in the liver, and attenuated the surge in serum TNF-α. Ibuprofen also minimized hepatic glutathione depletion, Bid truncation, caspase activation, outer mitochondrial membrane rupture, hepatocyte apoptosis and the increase in serum alanine aminotransferase (ALT) activity 5 h after Jo2 administration, to finally decrease mouse mortality at later times. The concomitant administration of pentoxifylline (decreasing TNF-α secretion) and infliximab (trapping TNF-α) likewise attenuated the Jo2-mediated increase in TNF-α, the decrease in hepatic glutathione, and the increase in serum ALT activity 5 h after Jo2 administration. The concomitant administration of the COX-1 inhibitor, SC-560 (10 mg/kg) and the COX-2 inhibitor, celecoxib (40 mg/kg) 1 h after Jo2 administration, also decreased liver injury 5 h after Jo2 administration. In contrast, SC-560 (10 mg/kg) or celecoxib (40 or 160 mg/kg) given alone had no significant protective effects. In conclusion, secondary TNF-α secretion plays an important role in Jo2-mediated glutathione depletion and liver injury. The combined inhibition of COX-1 and COX-2 by ibuprofen attenuates TNF-α secretion, glutathione depletion, mitochondrial alterations, hepatic apoptosis and mortality in Jo2-treated fasted mice.     

Effect of celecoxib and L-NAME on global ischemia-reperfusion injury in the rat hippocampus

Abstract

Transient global ischemia continues to be an important clinical problem with limited treatment options. The present study aimed to investigate the possible protective effects of celecoxib [a selective cyclooxygenase (COX-2) inhibitor] and N-omega-nitro-L-arginine methyl ester (L-NAME) [a nonselective nitric oxide synthase (NOS) inhibitor] against global ischemia-reperfusion (IR) induced biochemical and histological alterations in the rat hippocampus. Global ischemia was induced by bilateral clamping of the common carotid arteries for 60 minutes. Hippocampal cysteinyl aspartate-specific protease-3 (caspase-3) activity, nitrite/nitrate contents (NO_X), as well as COX-2 immunoreactivity in the hippocampal Cornu Ammonis 1 (CA1) subregion were dramatically increased 24 hours after global ischemia. After 72-hour of reperfusion, ischemia induced a selective, extensive neuronal loss in the hippocampus CA1 subregion. Celecoxib (3 and 5?mg/kg, intraperitoneally; i.p.), administered 30 minutes before ischemia and at 6, 12, and 22 hours of 24-hour reperfusion, caused significant reductions in hippocampal caspase-3 activity as well as the number of COX-2 immunoreactive (COX-2 ir) neurons in the CA1 subregion. Further, celecoxib (3 or 5?mg/kg, i.p.), administered 30 minutes before ischemia and at 6, 12, 22, and 48 hours of 72-hour reperfusion, provided a notable histological protection of hippocampal CA1 neurons. Meanwhile, L-NAME (3?mg/kg, i.p.), administered twice (immediately after ischemia and 45 minutes after starting the reperfusion period), effectively reduced the elevated NO_X level, decreased hippocampal caspase-3 activity and COX-2 immumoreactivity, and ameliorated ischemia-induced damage in the hippocampal CA1 subregion. The present study indicates that celecoxib and L-NAME might be neuroprotective agents of potential benefit in the treatment of cerebral ischemia.     

Modulation of nitrergic signalling pathway by American ginseng attenuates chronic unpredictable stress-induced cognitive impairment, neuroinflammation, and biochemical alterations

Prolonged stress causes extensive loss of neurons leading to deficits in cognitive performance. Increasing evidence indicates that accumulation of intercellular messenger, nitric oxide (NO), plays a crucial role in the pathogenesis of memory disorders. American ginseng (AG) is known to show protection in different animal models of neurological diseases; however, its exact mechanism of action is not clearly understood. Therefore, the current study was designed to investigate the interaction of AG against chronic unpredictable stress (CUS)-associated behavioral and biochemical alterations and the probable role of nitrergic pathway in this effect. Male Laca mice were exposed to a series of stressors along with drug/vehicle treatment daily for 28 days. CUS paradigm caused significant impairment in both acquisition and retention memory as measured in Morris water maze and elevated plus maze task. This was coupled with alterations in oxidative stress markers, mitochondrial enzyme complex activities, pro-inflammatory cytokine (TNF-α), and acetylcholinesterase levels in the hippocampus as compared with naïve group. Besides, there was a marked increase in serum corticosterone levels. AG (100, 200 mg/kg; p.o.) treatment significantly improved cognitive impairment; reduced TNF-α, acetylcholinesterase, and corticosterone levels; and attenuated oxidative–nitrergic stress. Furthermore, pre-treatment of l-arginine (100 mg/kg; i.p.), a nitric oxide donor, with subeffective dose of AG (100 mg/kg; p.o.) reversed its protective effects. However, l-NAME (10 mg/kg, i.p.), a non-specific NO synthase inhibitor, potentiated the effects of AG. Our findings suggest that modulation of nitrergic signalling cascade is involved in the protective effects of AG against CUS-induced cognitive dysfunction, oxidative stress, and neuroinflammation.     

Acute studies on safety index of nonsteroidal anti-inflammatory drugs in rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammation. Their use is frequently limited by gastrointestinal side effects, ranging from dyspeptic symptoms to life threatening bleeding or perforations of gastroduodenal ulcers. The present study mainly aimed to establish a safety index of NSAIDs in experimental animals. Safety index is based on the ratio of ulcerogenic dose (UD₅₀) and anti-inflammatory dose (ED₅₀). The safety index of preferential COX-2 inhibitor (nimesulide, meloxicam) was investigated using carrageenan-induced paw oedema and acute ulcerogenic model in rats, compared with the classical NSAIDs (naproxen, indomethacin). Meloxicam was found to be the most potent NSAID (ED₅₀ 1.07 mg/kg, p.o.) followed by nimesulide (2.42 mg/kg, p.o.), indomethacin (2.72 mg/kg, p.o.) and naproxen (6.82 mg/kg, p.o.) after 240 min of carrageenan challenge. In acute ulcerogenic study naproxen, indomethacin and meloxicam were found to be ulcerogenic at lower doses (UD₅₀ 14.0, 3.80 and 3.21 mg/kg, p.o.) in comparison to nimesulide (UD₅₀ 24.52 mg/kg, p.o.). Meloxicam, naproxen and indomethacin also produced damage to gastric epithelium (disruption of mucus layer and damage to parietal cells) at ED₅₀ dose level when it was viewed under scanning electron microscope, but nimesulide did not distrub gastric mucosal integrity at ED₅₀ dose. Based on the safety index (Ulcerogenic dose₅₀ /Effective anti-inflammatory dose₅₀) the order of safety of these agents was nimesulide > meloxicam > naproxen > indomethacin.     

Protective effects of nimesulide (COX Inhibitor), AKBA (5-LOX Inhibitor), and their combination in aging-associated abnormalities in mice

Several inflammatory processes play a critical role in brain aging and are associated with increased vulnerability to neurodegeneration. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), two enzymes involved in the oxygenation of the arachidonic acid, are upregulated in the central nervous system during aging and are associated with different aging-related brain pathologies. The present experiment was performed to study the effects of 5-LOX inhibitor, acetyl-11-keto-beta-boswellic acid (AKBA), nimesulide (preferential COX-2 inhibitor), and their combination on cognitive performance of young and aged mice, using elevated plus maze test. Chronic administration of AKBA (100 mg/kg, p.o.) and nimesulide (2.42 mg/kg, p.o.) for 15 days significantly reversed the aging-induced retention deficit in mice. Coadministration of AKBA and nimesulide enhanced the cognitive performance in aged mice when compared with that in per se treatment. The aging-related increase in oxidative damage (increased LPO and decreased GSH) was reversed by AKBA, nimesulide, and their combination. Further, per se COX and LOX inhibitors and their combination did not produce any alteration in gastrointestinal parameters; they also reversed the aging-induced motor dysfunction in the aged animals. On the basis of these observations, present findings indicated that the combination of COX and LOX inhibitors (dual inhibitors) may provide a new therapeutic innovation for the treatment of aging-related brain disorders such as Alzheimer's disease and different motor dysfunctions with adequate gastrointestinal tolerability.     

Central ghrelin gastroprotection involves nitric oxide/prostaglandin cross-talk

BACKGROUND AND PURPOSE: Ghrelin, a gut-brain peptide, is considered a gastroprotective factor in gastric mucosa. We investigated the role of prostaglandins (PG) and the possible interplay between PGs and nitric oxide (NO) in ghrelin gastroprotection against ethanol (EtOH)-induced gastric lesions. EXPERIMENTAL APPROACH: We examined the effects of (1) central ghrelin (4 mug per rat) injection on PGE(2) accumulation in normal or EtOH-lesioned gastric mucosa, (2) pretreatment with indomethacin (10 mg kg(-1), p.o.), a non-selective cyclooxygenase (COX) inhibitor, and with a selective COX-1, SC560 (5 mg kg(-1), p.o.) or COX-2 inhibitor, celecoxib (3.5 mg kg(-1), p.o.) on ghrelin gastroprotection against 50% EtOH (1 mL per rat)-induced gastric lesions, (3) the NO synthase inhibitor, L-NAME (70 mg kg(-1), s.c), on gastric PGE(2) content in ghrelin-treated rats and (4) central ghrelin on the expression of constitutive and inducible NOS and COX mRNA and on the localization of the immunoreactivity for COX-2 in the gastric mucosa exposed to EtOH. KEY RESULTS: Ghrelin increased PGE(2) in normal mucosa, whereas, it reversed the EtOH-induced PGE(2) surge. Ghrelin had no effect on mucosal COX-1 expression but reduced the EtOH-induced increase in COX-2 expression and immunoreactivity. Indomethacin and SC560, but not celecoxib, removed ghrelin gastroprotection. L-NAME prevented the PGE(2) surge induced by ghrelin and, like indomethacin, reduced EtOH-induced PGE(2) increase. Ghrelin enhanced eNOS expression and reduced iNOS mRNA. CONCLUSIONS AND IMPLICATIONS: This study shows that COX-1-derived PGs are mainly involved in ghrelin gastroprotection and that the constitutive-derived NO together with PGE(2) are involved in ghrelin gastroprotective activity.     

Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction

The present study was designed to explore the mechanism of hesperidin action via the nitric oxide pathway in the protection against ischemic reperfusion cerebral injury-induced memory dysfunction. Male Wistar rats (200-220 g) were subjected to bilateral carotid artery occlusion for 30 min followed by 24 h reperfusion. Hesperidin (50 and 100 mg/kg, po) pretreatment was given for 7 days before animals were subjected to cerebral I/R injury. Various behavioral tests (rotarod performance and memory retention), biochemical parameters (lipid peroxidation, nitrite concentration, glutathione levels, superoxide dismutase activity and catalase activity), mitochondrial complex enzyme dysfunctions (complex I, II, III and IV) and histopathological alterations were subsequently assessed in hippocampus. Seven days of hesperidin (50 and 100 mg/kg) treatment significantly improved neurobehavioral alterations (delayed fall off time and increased memory retention), oxidative defense and mitochondrial complex enzyme activities in hippocampus compared to control (I/R) animals. In addition, hesperidin treatment significantly attenuated histopathological alterations compared to control (I/R) animals. L-arginine (100 mg/kg) pretreatment attenuated the protective effect of the lower dose of hesperidin on memory behavior, biochemical and mitochondrial dysfunction compared with hesperidin alone. However, L-NAME pretreatment significantly potentiated the protective effect of hesperidin. The present study suggests that the L-arginine-NO signaling pathway is involved in the protective effect of hesperidin against cerebral I/R-induced memory dysfunction and biochemical alterations in rats.     

Cholinesterase inhibitors,donepezil and rivastigmine,attenuate spatial memory and cognitive flexibility impairment induced by acute ethanol in the Barnes maze task in rats

Central cholinergic dysfunction contributes to acute spatial memory deficits produced by ethanol administration. Donepezil and rivastigmine elevate acetylcholine levels in the synaptic cleft through the inhibition of cholinesterases—enzymes involved in acetylcholine degradation. The aim of our study was to reveal whether donepezil (acetylcholinesterase inhibitor) and rivastigmine (also butyrylcholinesterase inhibitor) attenuate spatial memory impairment as induced by acute ethanol administration in the Barnes maze task (primary latency and number of errors in finding the escape box) in rats. Additionally, we compared the influence of these drugs on ethanol-disturbed memory. In the first experiment, the dose of ethanol (1.75 g/kg, i.p.) was selected that impaired spatial memory, but did not induce motor impairment. Next, we studied the influence of donepezil (1 and 3 mg/kg, i.p.), as well as rivastigmine (0.5 and 1 mg/kg, i.p.), given either before the probe trial or the reversal learning on ethanol-induced memory impairment. Our study demonstrated that these drugs, when given before the probe trial, were equally effective in attenuating ethanol-induced impairment in both test situations, whereas rivastigmine, at both doses (0.5 and 1 mg/kg, i.p.), and donepezil only at a higher dose (3 mg/kg, i.p.) given prior the reversal learning, attenuated the ethanol-induced impairment in cognitive flexibility. Thus, rivastigmine appears to exert more beneficial effect than donepezil in reversing ethanol-induced cognitive impairments—probably due to its wider spectrum of activity. In conclusion, the ethanol-induced spatial memory impairment may be attenuated by pharmacological manipulation of central cholinergic neurotransmission.     

Quercetin along with piperine prevents cognitive dysfunction,oxidative stress and neuro-inflammation associated with mouse model of chronic unpredictable stress

Stress occurs in everyday life and persistence of it causes memory loss. Bioflavonoids like quercetin are reported to have poor bioavailability and limited therapeutic potential against stress induced neurological disorders. Therefore, the present study is an attempt to elucidate the therapeutic potency of combination of quercetin with piperine; a bioavailability enhancer against chronic unpredictable stress (CUS)-induced behavioral and biochemical alterations. Laca mice were subjected to a series of stressful events for a period of 28 days. Quercetin (20, 40 and 80 mg/kg, p.o.), piperine (20 mg/kg, p.o.) and their combinations were administered daily 30 min before CUS procedure. Piracetam (100 mg/kg, i.p.) served as a standard control. CUS caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Further, there was significant increase in brain oxidative stress markers and neuro-inflammation (TNF-α). This was coupled with marked rise in acetylcholinesterase and serum corticosterone levels. Co-administration of piperine with quercetin significantly elevated their potential to restore these behavioral, biochemical and molecular changes associated with mouse model of CUS. These results suggest that piperine enhances the neuroprotective effects of quercetin against CUS-induced oxidative stress, neuro-inflammation and memory deficits.     

Chrysin alleviates testicular dysfunction in adjuvant arthritic rats via suppression of inflammation and apoptosis: Comparison with celecoxib

Long standing rheumatoid arthritis (RA) is associated with testicular dysfunction and subfertility. Few studies have addressed the pathogenesis of testicular injury in RA and its modulation by effective agents. Thus, the current study aimed at evaluating the effects of two testosterone boosting agents; chrysin, a natural flavone and celecoxib, a selective COX-2 inhibitor, in testicular impairment in rats with adjuvant arthritis, an experimental model of RA. Chrysin (25 and 50 mg/kg) and celecoxib (5 mg/kg) were orally administered to Wistar rats once daily for 21 days starting 1 h before arthritis induction. Chrysin suppressed paw edema with comparable efficacy to celecoxib. More important, chrysin, dose-dependently and celecoxib attenuated the testicular injury via reversing lowered gonadosomatic index and histopathologic alterations with preservation of spermatogenesis. Both agents upregulated steroidogenic acute regulatory (StAR) mRNA expression and serum testosterone with concomitant restoration of LH and FSH. Furthermore, they suppressed inflammation via abrogation of myeloperoxidase, TNF-α and protein expression of COX-2 and iNOS besides elevation of IL-10. Alleviation of the testicular impairment was accompanied with suppression of oxidative stress via lowering testicular lipid peroxides and nitric oxide. With respect to apoptosis, both agents downregulated FasL mRNA expression and caspase-3 activity in favor of cell survival. For the first time, these findings highlight the protective effects of chrysin and celecoxib against testicular dysfunction in experimental RA which were mediated via boosting testosterone in addition to attenuation of testicular inflammation, oxidative stress and apoptosis. Generally, the 50 mg/kg dose of chrysin exerted comparable protective actions to celecoxib.     

Differential effects of cyclooxygenase inhibitors on intracerebroventricular colchicine-induced dysfunction and oxidative stress in rats

Alzheimer's disease is a progressive neurological and psychiatric disorder. Oxidative stress and neuroinflammation have been implicated in pathophysiology of Alzheimer's disease. Inflammatory cells, such as astrocytes and microglia, are activated in areas of the brain affected by amyloid plaques and inflammatory mediators including cytokines, chemokines, prostaglandins, oxygen free radicals and reactive nitrogen species may have a crucial role in Alzheimer's disease pathogenesis. Central administration of colchicine, a microtubule-disrupting agent, causes loss of cholinergic neurons and cognitive dysfunction that is associated with excessive free radical generation. The present study was aimed to evaluate the effects of cyclooxygenase inhibitors against colchicine-induced cognitive dysfunction and oxidative stress in rats. Following intracerebroventricular (i.c.v.) administration of colchicine (15 microg/5 microl), rats exhibited poor retention of memory in Morris water maze and elevated plus maze task paradigms and oxidative stress in rats. Chronic treatment with naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) daily respectively for a period of 25 days beginning 4 days prior to colchicine injection significantly improved colchicine-induced cognitive impairment. Intracerebroventricular colchicine injection resulted in free radical generation characterized by alterations in oxidative stress markers with a significant increase in malondialdehyde and nitrite levels and depletion of reduced glutathione levels in the brains of rats. It also caused a decrease in acetylcholinesterase activity. Besides, improving cognitive dysfunction, chronic administration of cyclooxygenase inhibitors (naproxen and valdecoxib) significantly reduced elevated malondialdehyde, nitrite levels and restored reduced glutathione levels and acetylcholinesterase activity. The results of the present study indicated that naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) treatment has a neuroprotective role against colchicine-induced cognitive impairment and associated oxidative stress. The present findings further support the potential use of cyclooxygenase inhibitors in treatment of neurodegenerative diseases such as Alzheimer's disease.     

Anti-inflammatory effects of selective COX-2 inhibitors

In this study, effects of rofecoxib, celecoxib, nimesulide on the acute phase of inflammation were studied in the carrageenan-induced paw edema model and their influence on the chronic phase of inflammation was evaluated in the cotton pellet granuloma tests. Additionally, effects of these drugs on capillary vascular permeability were examined in the hyaluronidase test and were compared with that of indomethacin (nonselective COX inhibitor). The results of the study demonstrated that rofecoxib, celecoxib, nimesulide, indomethacin at a dose of 10 mg kg(-1) reduced the volume of paw edema by 40.6% (p < 0.05), 21.6% (p < 0.05), 20.3% (p < 0.05), 64.0% (p < 0.05), respectively. Anti-proliferative effect of rofecoxib was of 29%, while those of celecoxib and nimesulide were of 13.5 and 21.2%, respectively. Indomethacin had an anti-proliferative effect of 44.2%. When the drugs were given at a dose of 25 mg kg(-1) rofecoxib, celecoxib, nimesulide reduced carrageenan-induced paw edema by 50.6% (p < 0.004), 27.9% (p < 0.004) and 33.0% (p < 0.004), respectively. Positive control, indomethacin, reduced the paw edema by 86.1% (p < 0.004). As a result, indomethacin, rofecoxib, celecoxib, nimesulide significantly inhibited both acute and chronic inflammation. While indomethacin, celecoxib, nimesulide significantly reduced capillary vascular permeability, the effect of rofecoxib was insignificant. We could not clarify this observation. Further studies are required to enlighten this effect of rofecoxib.     

Effect of cyclooxygenase inhibitors in postoperative ileus: an experimental study

The aim of our study was to investigate the effect of various cyclooxygenase (COX) inhibitors (namely, indomethacin [a nonselective COX inhibitor], nimesulide [a partially selective COX inhibitor] and celecoxib [a highly selective COX inhibitor]) on postoperative ileus in rats. Equianalgesic doses of the three drugs were determined previously by formalin-induced hyperalgesia. Three comparative doses of the drugs were taken. After overnight fasting, a standardized laparotomy was performed on the rats. Bowel motility was determined by the charcoal meal test. The distance traveled by the charcoal meal was expressed as a percentage of the total length of the small intestine. The animals were pretreated intraperitoneally with either indomethacin (2.5, 5.0 and 10 mg/kg), nimesulide (10.0, 20.0 and 40 mg/kg), celecoxib (10.0, 20.0 and 40 mg/kg) or vehicle 1 h prior to the experiment. The lowest doses at which an increase in postoperative bowel motility occurred were 10 mg/kg of indomethacin and 20 mg/kg for both nimesulide and celecoxib. For equianalgesic doses it was noted that celecoxib was more effective than nimesulide or indomethacin in increasing postoperative bowel motility (52.15 +/- 1.08, 55.11 +/- 0.87 and 60.65 +/- 1.22 at the highest doses of indomethacin, nimesulide and celecoxib, respectively).     

Four-week administration of nimesulide, a cyclooxygenase-2 inhibitor, improves endothelial dysfunction in the hindlimb vasculature of streptozotocin-induced diabetic rats

The aim of this study was to examine the effect of chronic administration of nimesulide, a cyclooxygenase-2 inhibitor, on endothelial dysfunction in streptozotocin-induced diabetic rats. Three groups of Sprague-Dawley rats (300–350 g, n = 6) were used. The first group served as normoglycemic control and the second and third groups were rendered diabetic by an intraperitoneal injection of streptozotocin (60 mg/kg). The third group received the selective COX-2 inhibitor, nimesulide (20 mg/kg/day), orally by gavage for 4 weeks while the second group received only drinking water and served as diabetic control. At the end of the treatment period, the rats were anesthetized with urethane (1.2 g/kg) and mean arterial pressure, heart rate and hindlimb blood flow were monitored. This was followed by the injection of acetylcholine (endothelium-dependent vasodilator, 0.1–0.8 μg/kg) and sodium nitroprusside (endothelium-independent vasodilator 1–4 μg/kg). Mean arterial pressure was significantly reduced and hindlimb vascular conductance was not significantly affected in the control diabetic group when compared to the normoglycemic control group. Nimesulide treatment did not cause any significant change in any of the measured hemodynamic parameters. Acetylcholine and sodium nitroprusside induced dose-dependent increases in hindlimb vascular conductance in control normoglycemic rats which were attenuated in diabetic control rats. Nimesulide reversed the attenuation of acetylcholine-induced increase in hindlimb vascular conductance. In conclusion, chronic administration of the selective COX-2 inhibitor, nimesulide improved endothelial dysfunction in the hindlimb vasculature of streptozotocin induced diabetic rats. This suggests that COX-2 products might be involved in the pathogenesis of endothelial dysfunction in streptozotocin-induced diabetic rats.     

Effect of nimesulide, rofecoxib and celecoxib on gastric tissue glutathione level in rats with indomethacin-induced gastric ulcerations

Glutathione (GSH) is a tripeptide and a superoxide radical scavenger and it protects thiol protein groups required for maintaining the integrity of cell against oxidation. GSH is present in the stomach at high concentrations and plays an important role in maintaining the integrity of the gastric mucosa. We investigated whether oral administration of nimesulide, rofecoxib and celecoxib, selective COX-2 inhibitors, changed GSH level in the gastric tissue of indomethacin-treated rats. Thirty albino Wistar rats were used in this study. Animals were randomly assigned to five groups as follows: control group received only distilled water (group I). Nimesulide at a dose of 100 mg/kg (group II), rofecoxib at a dose of 25 mg/kg (group III) and celecoxib at a dose of 100 mg/kg (group IV) were intragastrically administered 5 min before indomethacin (25 mg/kg) treatment. Equal volume of distilled water was given to the indomethacin-administered group (group V). Indomethacin was administered intragastrically. Gastric tissue mean GSH level was significantly higher in nimesulide-given rats than in rofecoxib- and celecoxib-treated groups, there was not any significant difference between the nimesulide and control groups. Our study showed that although nimesulide prevented the indomethacin-induced gastric ulcers completely, rofecoxib and celecoxib did not prevent the indomethacin-induced ulcer formation. In conclusion, we propose that nimesulide exerts a prophylactic effect on the indomethacin-induced gastric ulcers by enhancing gastric GSH level.     

Intestinal effects of nonselective and selective cyclooxygenase inhibitors in the rat

It is now widely recognized that nonsteroidal anti-inflammatory drugs (NSAIDs) may cause extensive damage to the intestine. The pathogenesis of NSAID-induced intestinal injury, however, is still controversial and both local irritant actions and cyclooxygenase (COX) inhibition have been proposed as underlying mechanisms. In this study we investigated further on NSAID-induced intestinal damage by using nonselective (indomethacin and ibuprofen), COX-1 selective (SC-560) or COX-2 selective (celecoxib) inhibitors. NSAIDs were administered orally to conscious rats and small intestinal injury was evaluated 24 h afterwards in terms of macroscopic and microscopic alterations, myeloperoxidase activity, lipid peroxidation, number of enterobacteria in the mucosa and epithelial mucin content. Oral administration of indomethacin (20 mg/kg) induced macroscopic and microscopic damage to the small intestine, increased translocation of enterobacteria from lumen into the mucosa, myeloperoxidase activity and lipid peroxidation. Ibuprofen (120 mg/kg), SC-560 (20 mg/kg), celecoxib (60 mg/kg) or the combination of SC-560 plus celecoxib did not cause any intestinal injury nor modified the number of bacteria in mucosal homogenates. SC-560 significantly increased both myeloperoxidase activity and lipid peroxidation, whereas celecoxib significantly reduced myeloperoxidase levels, while leaving unaltered lipid peroxidation. Finally, all NSAIDs, mostly indomethacin, increased neutral mucins and decreased acidic mucins in the intestinal goblet cells. These results indicate that inhibition of cyclooxygenase, although variably influencing mucosal integrity homeostasis, is not sufficient to initiate acute intestinal damage in rats. Moreover, topical mucosal injury induced by the NSAID molecule seems to be a critical factor in the development of intestinal injury.     

Protective effect of nimesulide against hepatic ischemia/reperfusion injury in rats: Effects on oxidant/antioxidants,DNA mutation and COX-1/COX-2 levels

BackgroundNimesulide is a pharmacological agent and selective COX-2 inhibitor. It has anti-inflammatory, analgesic and antipyretic properties. The purpose of this study was to investigate the effect of nimesulide on oxidant/antioxidant, DNA mutation and COX-1/COX-2 activities in rat liver tissue with induced ischemia/reperfusion (I/R).MethodsBefore the experiment, rats were divided into four groups; liver ischemia/reperfusion (LIR), 50 mg/kg nimesulide + liver ischemia/reperfusion (NLIR50), 100 mg/kg nimesulide + liver ischemia/reperfusion (NLIR100) and a control group to be given a sham operation (SG). Malondialdehyde (MDA), total glutathione (GSH) levels and myeloperoxidase (MPO), COX-1/COX-2 enzyme activities and DNA damage product level results from liver tissues and serum AST and ALT levels were determined. The data obtained were compared with the results from the liver ischemia/reperfusion and sham operation groups.ResultsMDA levels, MPO and COX-2 activities and products of DNA injury were significantly lower in the groups given nimesulide, and particularly the NLIR100 group, compared to the LIR group (p < 0.05), while tGSH levels were significantly higher (p < 0.05). There was no significant difference between the NLIR50 and NLIR100 groups and the LIR group in terms of COX-1 levels (p > 0.05). AST and ALT levels were significantly lower in the other groups compared to the LIR group (p < 0.05).ConclusionsNimesulide at 100 mg/kg prevented oxidative liver damage induced with I/R significantly better than at a dose of 50 mg/kg. These experimental findings indicate that nimesulide may be useful in the treatment of hepatic I/R damage.     

Tanshinone congeners improve memory impairments induced by scopolamine on passive avoidance tasks in mice

Tanshinones are a group of diterpenoids found in the roots of Salvia miltiorrhiza Bunge which has been used to treat cardiac disease. In the present study, we investigated the effect of the tanshinone congeners, tanshinone I, tanshinone IIA, cryptotanshinone, and 15, 16-dihydrotanshinone I, on learning and memory impairments induced by scopolamine (1 mg/kg, i.p.), a muscarinic antagonist, using passive avoidance tasks in mice. Tacrine was used as a positive control. Tanshinone I (2 or 4 mg/kg, p.o.), tanshinone IIA (10 or 20 mg/kg, p.o.), cryptotanshinone (10 mg/kg, p.o.), and 15, 16-dihydrotanshinone I (2 or 4 mg/kg, p.o.) significantly reversed scopolamine-induced cognitive impairments (P<0.05). Tanshinone I (2 mg/kg, p.o.) and tanshinone IIA (10 or 20 mg/kg, p.o.) were also reversed diazepam-induced cognitive dysfunctions (P<0.05). In addition, cryptotanshinone and 15, 16-dihydrotanshinone I were found to have an inhibitory effect on acetylcholinesterase in vitro with IC(50) values 82 and 25 microM, respectively. Furthermore, cryptotanshinone inhibited acetylcholinesterase activity for 3 h and 15, 16-dihydrotanshinone I for 6 h in an ex-vivo study. These results suggest that tanshinone congeners may be useful for the treatment of cognitive impairment and that their beneficial effects are mediated, in part, by cholinergic signaling enhancement.     

Neuroprotective effect of Manasamitra vatakam against aluminium induced cognitive impairment and oxidative damage in the cortex and hippocampus of rat brain

Manasamitra vatakam (MMV) has long been used as a traditional medicine in India for the treatment of psychosomatic diseases, anxiety neurosis, and stress. The present study was designed to examine the neuroprotective effect of MMV against aluminum (Al)-induced memory impairment and oxidative damage in rats. Neurotoxicity was induced by the administration of Al [100?mg/kg body weight (b.w.) per oral (p.o.)/day] to Wistar albino rats for 90 days. Al administration induced neurotoxicity as well as oxidative stress by affecting the active avoidance and memory impairment, as well as altering antioxidants, such as HSP70 protein, superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase, and acetylcholinesterase. It was observed that the administration of MMV (100?mg/kg b.w./p.o./day) along with AlCl(3) improves memory performance and antioxidant activity against Al-induced neurotoxicity in rats. In conclusion, these data suggest that MMV can prevent brain damage from Al-induced neurotoxicity in rats and thus can be used as a neuroprotective agent.