Neuroprotection by misoprostol against rotenone-induced neurotoxicity in rat brain

Objective: To investigate the effect of the prostaglandin E1 analogue misoprostol on oxidative stress and neurodegeration caused by subcutaneous rotenone administration in rats. Methods: Rotenone was administered in a dose of 1.5 mg/kg every other day for 2 weeks. Starting from the 1st day of rotenone injection, rats were subcutaneously treated with misoprostol at doses of 10, 100 or 1 000

Bougainvillea spectabilis flowers extract protects against the rotenone-induced toxicity

Objective To investigate the effect of two extracts of Bougainvillea spectabilis (B. spectabilis) flowers with yellow and pink/purple on brain oxidative stress and neuronal damage caused in rats by systemic rotenone injection. Methods Rotenone 1.5 mg/kg was given three times per week alone or in combination with B. spectabilis flowers extracts (25 mg or 50 mg) via the subcutaneous route for 2 weeks. Brain concentrations of the lipid peroxidation marker malondialdehyde (MDA), reduced glutathione, nitric oxide (nitrite), the pro-inflammatory cytokine interleukin-1beta (Il-1β) as well as butyrylcholinesterase, and paraoxonase-1 (PON-1) activities, were determined. Histopathology and caspase-3 immunohistochemistry were also performed. Results Rotenone resulted in significant increases of brain MDA (the product of lipid peroxidation), and nitric oxide content along with decreased brain reduced glutathione. There were also marked and significant inhibition of brain PON-1 and BChE activities and increased Il-1β in brain of rotenone-treated rats. B. spectabilis flowers extract itself resulted in brain oxidative stress increasing both lipid peroxidation and nitrite content whilst inhibiting PON-1 activity. The yellow flowers extract inhibited BChE activity and increased brain Il-1β. When given to rotenone-treated rats, B. spectabilis extracts, however, decreased lipid peroxidation while their low administered doses increased brain GSH. Brain nitrite decreased by the pink extract but showed further increase by the yellow extract. Either extract, however, caused further inhibition of PON-1 activity while the yellow extract resulted in further inhibition of BChE activity. Histopathological studies indicated that both extracts protected against brain, liver and kidney damage caused by the toxicant. Conclusions These data indicate that B. spectabilis flowers extracts exert protective effect against the toxic effects of rotenone on brain, liver and kidney. B. spectabilis flowers extracts decreased brain lipid peroxidation and prevented neuronal death due to rotenone and might thus prove the value in treatment of Parkinson's disease.

Nitric oxide synthase inhibitors protect against brain and liver damage caused by acute malathion intoxication

Objective To investigate the effect of N

Bougainvillea spectabilis flowers extract protects against the rotenone-induced toxicity

OBJECTIVE@#To investigate the effect of two extracts of Bougainvillea spectabilis (B. spectabilis) flowers with yellow and pink/purple on brain oxidative stress and neuronal damage caused in rats by systemic rotenone injection.@*METHODS@#Rotenone 1.5 mg/kg was given three times per week alone or in combination with B. spectabilis flowers extracts (25 mg or 50 mg) via the subcutaneous route for 2 weeks. Brain concentrations of the lipid peroxidation marker malondialdehyde (MDA), reduced glutathione, nitric oxide (nitrite), the pro-inflammatory cytokine interleukin-1beta (Il-1β) as well as butyrylcholinesterase, and paraoxonase-1 (PON-1) activities, were determined. Histopathology and caspase-3 immunohistochemistry were also performed.@*RESULTS@#Rotenone resulted in significant increases of brain MDA (the product of lipid peroxidation), and nitric oxide content along with decreased brain reduced glutathione. There were also marked and significant inhibition of brain PON-1 and BChE activities and increased Il-1β in brain of rotenone-treated rats. B. spectabilis flowers extract itself resulted in brain oxidative stress increasing both lipid peroxidation and nitrite content whilst inhibiting PON-1 activity. The yellow flowers extract inhibited BChE activity and increased brain Il-1β. When given to rotenone-treated rats, B. spectabilis extracts, however, decreased lipid peroxidation while their low administered doses increased brain GSH. Brain nitrite decreased by the pink extract but showed further increase by the yellow extract. Either extract, however, caused further inhibition of PON-1 activity while the yellow extract resulted in further inhibition of BChE activity. Histopathological studies indicated that both extracts protected against brain, liver and kidney damage caused by the toxicant.@*CONCLUSIONS@#These data indicate that B. spectabilis flowers extracts exert protective effect against the toxic effects of rotenone on brain, liver and kidney. B. spectabilis flowers extracts decreased brain lipid peroxidation and prevented neuronal death due to rotenone and might thus prove the value in treatment of Parkinson's disease.

Nitric oxide synthase inhibitors protect against brain and liver damage caused by acute malathion intoxication

OBJECTIVE@#To investigate the effect of N-nitro-l-arginine methyl ester (l-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, and 7-nitroindazole (7-NI), a selective neuronal NOS inhibitor, on oxidative stress and tissue damage in brain and liver and on DNA damage of peripheral blood lymphocytes in malathion intoxicated rats.@*METHODS@#Malathion (150 mg/kg) was given intraperitoneally (i.p.) along with l-NAME or 7-NI (10 or 20 mg/kg, i.p.) and rats were euthanized 4 h later. The lipid peroxidation product malondialdehyde (MDA), nitric oxide (nitrite), reduced glutathione (GSH) concentrations and paraoxonase-1 (PON-1) activity were measured in both brain and liver. Moreover, the activities of glutathione peroxidase (GPx) acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), total antioxidant capacity (TAC), glucose concentrations were determined in brain. Liver enzyme determination, Comet assay, histopathological examination of brain and liver sections and inducible nitric oxide synthase (iNOS) immunohistochemistry were also performed.@*RESULTS@#(i) Rats treated with only malathion exhibited increased nitric oxide and lipid peroxidation (malondialdehyde) accompanied with a decrease in GSH content, and PON-1 activity in brain and liver. Glutathione peroxidase activity, TAC, glucose concentrations, AChE and BChE activities were decreased in brain. There were also raised liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and increased DNA damage of peripheral blood lymphocytes (Comet assay). Malathion caused marked histopathological changes and increased the expression of iNOS in brain and liver tissues. (ii) In brain of malathion-intoxicated rats, l-NAME or 7-NI resulted in decreased nitrite and MDA contents while increasing TAC and PON1 activity. Reduced GSH and GPx activity showed an increase by l-NAME. AChE activity increased by 20 mg/kg l-NAME and 10 mg/kg 7-NI. AChE activity decreased by the higher dose of 7-NI while either dose of 7-NI resulted in decreased BChE activity. (iii) In liver of malathion-intoxicated rats, decreased MDA content was observed after l-NAME or 7-NI. Nitrite level was unchanged by l-NAME but increased after 7-NI which also resulted in decreased GSH concentration and PON1 activity. Either inhibitor resulted in decreased liver ALT activity. (iv) DNA damage of peripheral blood lymphocytes was markedly inhibited by l-NAME or 7-NI treatment. (v) iNOS expression in brain and liver decreased by l-NAME or 7-NI. (vi) More marked improvement of the histopathological alterations induced by malathion in brain and liver was observed after 7-NI compared with l-NAME.@*CONCLUSIONS@#In malathion intoxicated rats, the neuronal NOS inhibitor 7-NI and to much less extent l-NAME were able to protect the brain and liver tissue integrity along with improvement in oxidative stress parameters. The decrease in DNA damage of peripheral blood lymphocytes by NOS inhibitors also suggests the involvement of nitric oxide in this process.

Novel neuroprotective and hepatoprotective effects of citric acid in acute malathion intoxication

OBJECTIVE@#To study the effect of citric acid given alone or combined with atropine on brain oxidative stress, neuronal injury, liver damage, and DNA damage of peripheral blood lymphocytes induced in the rat by acute malathion exposure.@*METHODS@#Rats were received intraperitoneal (i.p.) injection of malathion 150 mg/kg along with citric acid (200 or 400 mg/kg, orally), atropine (1 mg/kg, i.p.) or citric acid 200 mg/kg + atropine 1 mg/kg and euthanized 4 h later.@*RESULTS@#Malathion resulted in increased lipid peroxidation (malondialdehyde) and nitric oxide concentrations accompanied with a decrease in brain reduced glutathione, glutathione peroxidase (GPx) activity, total antioxidant capacity (TAC) and glucose concentrations. Paraoxonase-1, acetylcholinesterase (AChE) and butyrylcholinesterase activities decreased in brain as well. Liver aspartate aminotransferase and alanine aminotransferase activities were raised. The comet assay showed increased DNA damage of peripheral blood lymphocytes. Histological damage and increased expression of inducible nitric oxide synthase (iNOS) were observed in brain and liver. Citric acid resulted in decreased brain lipid peroxidation and nitric oxide. Meanwhile, glutathione, GPx activity, TAC capacity and brain glucose level increased. Brain AChE increased but PON1 and butyrylcholinesterase activities decreased by citric acid. Liver enzymes, the percentage of damaged blood lymphocytes, histopathological alterations and iNOS expression in brain and liver was decreased by citric acid. Meanwhile, rats treated with atropine showed decreased brain MDA, nitrite but increased GPx activity, TAC, AChE and glucose. The drug also decreased DNA damage of peripheral blood lymphocytes, histopathological alterations and iNOS expression in brain and liver.@*CONCLUSIONS@#The study demonstrates a beneficial effect for citric acid upon brain oxidative stress, neuronal injury, liver and DNA damage due to acute malathion exposure.

Acetylcholinesterase, butyrylcholinesterase and paraoxonase 1 activities in rats treated with cannabis, tramadol or both

OBJECTIVE@#To investigate the effect of Cannabis sativa resin and/or tramadol, two commonly drugs of abuse on acetylcholinesterase and butyrylcholinesterase activities as a possible cholinergic biomarkers of neurotoxicity induced by these agents.@*METHODS@#Rats were treated with cannabis resin (5, 10 or 20 mg/kg) (equivalent to the active constituent Δ-tetrahydrocannabinol), tramadol (5, 10 and 20 mg/kg) or tramadol (10 mg/kg) combined with cannabis resin (5, 10 and 20 mg/kg) subcutaneously daily for 6 weeks. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in brain and serum. We also measured the activity of paraoxonase-1 (PON1) in serum of rats treated with these agents.@*RESULTS@#(i) AChE activity in brain increased after 10-20 mg/kg cannabis resin (by 16.3-36.5%). AChE activity in brain did not change after treatment with 5-20 mg/kg tramadol. The administration of both cannabis resin (5, 10 or 20 mg/kg) and tramadol (10 mg/kg) resulted in decreased brain AChE activity by 14.1%, 12.9% and 13.6%, respectively; (ii) BChE activity in serum was markedly and dose-dependently inhibited by cannabis resin (by 60.9-76.9%). BChE activity also decreased by 17.6-36.5% by 10-20 mg/kg tramadol and by 57.2-63.9% by the cannabis resin/tramadol combined treatment; (iii) Cannabis resin at doses of 20 mg/kg increased serum PON1 activity by 25.7%. In contrast, tramadol given at 5, 10 and 20 mg/kg resulted in a dose-dependent decrease in serum PON1 activity by 19%, 36.7%, and 46.1%, respectively. Meanwhile, treatment with cannabis resin plus tramadol resulted in 40.2%, 35.8%, 30.7% inhibition of PON1 activity compared to the saline group.@*CONCLUSIONS@#These data suggest that cannabis resin exerts different effects on AChE and BChE activities which could contribute to the memory problems and the decline in cognitive function in chronic users.

Acetylcholinesterase, butyrylcholinesterase and paraoxonase 1 activities in rats treated with cannabis, tramadol or both

Objective To investigate the effect of Cannabis sativa resin and/or tramadol, two commonly drugs of abuse on acetylcholinesterase and butyrylcholinesterase activities as a possible cholinergic biomarkers of neurotoxicity induced by these agents. Methods Rats were treated with cannabis resin (5, 10 or 20 mg/kg) (equivalent to the active constituent Δ

Novel neuroprotective and hepatoprotective effects of citric acid in acute malathion intoxication

Objective To study the effect of citric acid given alone or combined with atropine on brain oxidative stress, neuronal injury, liver damage, and DNA damage of peripheral blood lymphocytes induced in the rat by acute malathion exposure. Methods Rats were received intraperitoneal (i.p.) injection of malathion 150 mg/kg along with citric acid (200 or 400 mg/kg, orally), atropine (1 mg/kg, i.p.) or citric acid 200 mg/kg + atropine 1 mg/kg and euthanized 4 h later. Results Malathion resulted in increased lipid peroxidation (malondialdehyde) and nitric oxide concentrations accompanied with a decrease in brain reduced glutathione, glutathione peroxidase (GPx) activity, total antioxidant capacity (TAC) and glucose concentrations. Paraoxonase-1, acetylcholinesterase (AChE) and butyrylcholinesterase activities decreased in brain as well. Liver aspartate aminotransferase and alanine aminotransferase activities were raised. The comet assay showed increased DNA damage of peripheral blood lymphocytes. Histological damage and increased expression of inducible nitric oxide synthase (iNOS) were observed in brain and liver. Citric acid resulted in decreased brain lipid peroxidation and nitric oxide. Meanwhile, glutathione, GPx activity, TAC capacity and brain glucose level increased. Brain AChE increased but PON1 and butyrylcholinesterase activities decreased by citric acid. Liver enzymes, the percentage of damaged blood lymphocytes, histopathological alterations and iNOS expression in brain and liver was decreased by citric acid. Meanwhile, rats treated with atropine showed decreased brain MDA, nitrite but increased GPx activity, TAC, AChE and glucose. The drug also decreased DNA damage of peripheral blood lymphocytes, histopathological alterations and iNOS expression in brain and liver. Conclusions The study demonstrates a beneficial effect for citric acid upon brain oxidative stress, neuronal injury, liver and DNA damage due to acute malathion exposure.

Investigation of the vasodilator effect of the new synthesized compound 2-alkylthio-4-ethyl-4-methyl-4,5dihydro-lh imidazolin-5-one oxime [Oxime] on the ischaemic rat hind limb by using laser doppler flowmetry technique

The potential vasodilator effect of the novel compound 2-alkylthio-4-ethyl-4-methyl-4,5 dihydro-lH-imidazolin-5-one oxime [oxime] was investigated in a model of hind limb ischaemia induced in rats by unilateral ligation of the right femoral artery using Laser Doppler Flowmetry. The effect of oxime was compared with that of isoprenaline or L-arginine. Test drugs and oxime were injected systemically into the femoral vein or applied locally on the planter surface of the rat hind paw. Serum level of nitrite [NO[2] and nitrate [NO[3] were measured by ELISA. Immediately after operative induction of right hind limb ischaemia, blood flow ratio [Right/Left limb ratio: BFR] decreased to 0.33-0.39 in different groups. The intravenous [i.v.] administration of oxime increased BFR in a dose-dependent manner. Compared with pre-drug BFR, oxime administered at doses of 0.064, 0.128 or 0.256 mg/kg increased BFR by 78.8, 228.9 and 605.9%, respectively. Meanwhile, L-arginine given i.v. at 100 mg/kg increased BFR by 460%. Isoprenaline given i.v. at 1 micro g/kg increased BFR by 174.3%, while isoprenaline combined with oxime [0.064 mg/kg] increased BFR by 302.7%. Similarly, after topical application of oxime, BFR increased by 13.5, 161.1 and 333.3%, respectively. L-arginine given at 1000 mg/kg increased BFR by 389.7%. Isoprenaline given at 10 micro g/kg increased BFR by 131.6%, while isoprenaline administered in combination with oxime [0.064 mg/kg] increased BFR by 208.3%. The concentration of NO in serum was significantly increased after systemic or topical administration of either 0.128 and 0.256 mg/kg oxime or 100 and 1000 mg/kg L-arginine, respectively. It is concluded that systemic or topical oxime results in marked enhancement of blood flow in the rat ischaemic hind limb. This effect of oxime is likely to be mediated through the release of NO

effect of calcium channel blockers amlodipine, lacidipine and diltiazem on thermal and visceral pain in mice

The effect of the calcium channel blockers amlodipine, lacidipine and deltiazem was studied after subcutaneous [s.c.] injection in mice using the hot plate and abdominal stretching assays. In the hot-plate test of thermal pain, amlodipine [0.43 and 0.86 mg/kg], lacidipine [0.17 and 0.35 mg/kg] or deltiazem [5.2 and 10.4 mg/kg], produced a dose-related reduction in nociceptive responses. In the acetic acid-induced abdominal constrictions test of visceral pain, amlodipine, lacidipine or deltiazem at the above doses, reduced the number of abdominal constrictions dose-dependently. The inhibition of writhing response by the three drugs was reduced by co-administration of the muscarinic acetylcholine receptor antagonist atropine [1 mg/kg, s.c.], enhanced by co-administration of the alpha-1 adrenoceptor blocker prazosin [1 mg/kg, s.c.], whilst the analgesic effect of lacidipine and deltiazem was reduced by the alpha-2 adrenoceptor blocker yohimbine [5 mg/kg, s.c.]. The analgesic effect of both amlodipine and Iacidipine was unaffected, but that of deltiazem was reduced by the beta adrenoceptor antagonist propranolol [1 mg/kg, s.c.]. The non-selective opioid receptor antagonist naloxone [5 mg/kg, i.p.] enhanced the analgesic effect of amlodipine, but reduced that of deltiazem. Meanwhile, lacidipine anti-nociception was reduced by the non-selective adenosine receptor antagonist theophylline [20 mg/kg, s.c.]. These data suggest that the calcium channel antagonists amlodipine, Iacidipine or deltiazem have analgesic effects in thermal and visceral pain models in mice. Data also indicate that muscarinic acetylcholine receptors mediate at least in part the visceral analgesic effect of these drugs. The antinociceptive effect of lacidipine involves adenosine receptors. The antinociceptive effect of deltiazem involves opioid, alpha-2 and beta adrenoceptors

Effect of Ramipril, Valsartan, Candesartan and Lacidipine on inflammation and gastric ulcer in rats

The present study investigated and compared the effect of the angiotensin converting enzyme inhibitor ramipril and the angiotensin II receptor blockers valsartan and candesartan and the calcium channel blocker lacidipine on inflammation and gastric ulcer in rats. The acute inflammation was induced by intraplantar injection of carrageenan [1%] in the rat hind paw. Gastric ulcer was evoked by s.c. indomethacin [20 mg/kg]. When given s.c. 30 min prior to induction of inflammation, ramipril [0.23 and 0.45 mg/kg], valsartan [7.5 and 15 mg/kg], candesartan [0.72 and 1.44 gm/kg] failed to reduce paw oedema response. Meanwhile, lacidipine at the lower dose of 0.18 mg/kg displayed mild anti-inflammatory activity up to 1 hr, reducing paw odema by 26.7% for 1 hr post-carrageenan, while a higher dose of 0.36 mg/kg inhibited oedema formation by 33.5, 31, 23.6 and 22.3% at 1, 2, 3 and 4 hr post-carrageenan, respectively. The acute gastric mucosal lesions evoked by indomethacin in the rat were aggravated by co-administration of ramipril 0.23 and 0.45 mg/kg, valsartan 7.5 and 15 mg/kg, lacidipne 0.18 and 0.36 mg/kg and candesartan 0.72 mg/kg, but reduced by candesartan 1.44 mg/kg. Findings in the present study do not favor an anti-inflammatory activity for ramipril, valsartan and candesartan, but indicates an antioedema effect for lacidipine at the doses employed. These agents are likely to adversely affect gastric mucosal integrity and enhance the indomethacin-induced gastric injury

Effect of hypoglycaemia induced by different agents on thermal nociception in mice

Peripheral neuropathy is a well-recognized complication of diabetes mellitus and achieving glycaemic control is presumed to be important in reducing its severity and progression. Meanwhile, the effect of hypoglycaemia on pain perception is less well studied. The current study compared the effects of four classes of oral hypoglycemics namely the sulfonylureas "glimepiride and glibenclamide", the biguanide "metformin", and the meglitinide analogue "repaglinide", besides the insulin sensitizer "rosiglitazone", in addition to insulin, sucrose and alloxan, on thermal pain using the hot-plate test in mice. Drugs were given 30 min prior to testing and blood glucose level determination. Alloxan was given 2hr before the assay. Glimepiride and glibenclamide [in two dose levels each] produced a reduction in nociceptive responses increasing hot-plate latency by 45.5-68.6% and by 18.1-12.8%, respectively, compared with pre-drug basal values. Hot-plate latency was increased by 66.2-32.8% following metformin. Rosiglitazone and repaglinide resulted in 26.7-39% and 50.1-43.1% increase in hot-plate latency, respectively. Insulin administered subcutaneously at 3 IU/kg decreased the nociceptive response by 19.5%, while a higher dose of 12 IU/kg caused 5.7% decrease in pain threshold. Hot-plate latency was also increased by oral [by 31.3-22.8%] or i.p. [by 50.1-37%] administration of 5% and 10% sucrose, respectively. Pain threshold decreased by 39.2% by alloxan [120 mg/kg, i.p.] and by 18.7% after both alloxan and glibenclamide [2.5 mg/kg, i.p.]. In case of glimepiride, insulin or alloxan treatment, correlation analysis showed relationship between the hot-plate latency and blood glucose level; R = 0.52, 0.51 and 0.72, respectively. It is concluded that within a certain range, reduction in blood glucose level impairs the perception of a thermal noxious stimulus

In vivo effect of cinnarizine on acute hepatic damage in mice

This study aimed to investigate the effect of cinnarizine, a drug used for the treatment of motion sickness and which has direct anti-dopaminergic features [Dopamine Dl and D2 receptor blockade], on the acute hepatic injury in mice. Hepatotoxicity was induced by CCI4 orally [0.28 ml/100 g given twice with one week apart]. Cinnarizine at three dose levels [5, 10 or 20 mg/kg] or silymarin [22 mg/kg] were given orally daily for 14 days. starting at the time of administration of CCI4. Liver damage was assessed by determining liver serum enzyme activities and by hepatic histopathology. Cinnarizine decreased the increases in serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP] and also prevented the development of hepatic necrosis caused by CCI4. The effect of cinnarizine was a dose-dependent one. Cinnarizine administered at 10 or 20 mg/kg caused significant reduction in the elevated plasma ALT by 32.7, 34.3%, AST by 18.8, 34.7% and ALP by 32.8, 42.9%, respectively. In comparison, the elevated serum ALT, AST and ALP levels were decreased by 42.1%, 37.9% and 43.4% of controls, respectively by 22 mg/kg of silymarin. Histopathologic examination of the livers of CCI4-treated mice administered cinnarizine at 20 mg/kg showed marked restoration of the normal architecture of the liver tissue with minimal fibrosis. It is concluded that administration of cinnarizine in a model of liver injury induced by CCI4 results in less liver damage

Effect of Trimebutine on hepatic injury caused by carbon tetrachloride in the rat

We investigated the effects of trimebutine, a peripheral opiate agonist, used in therapy of irritable bowel syndrome on the development of hepatic injury in rats treated with carbon tetrachloride. When administred s.c., at 30, 60 and 120 mg/kg, the drug increased the degree of hepatic damage caused by CCL[4] in a dose-dependent manner as reflected by serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP] and liver histopathology determined 14 days after drug administration. The effect was dose-dependant one, being most evident after administration of 60 and 120 mg/kg dose of the drug. Thus, compared with the CCl[4][control group, serum ALT increased by 28.9, 47.2%, AST by 16.2, 24.8% and ALP by 28.8, 47.2% after the administration of trimebutine at 60 and 120 mg/kg, respectively. When silymarin was combined with 120 mg/kg of trimebutine, the activities of ALT and AST were comparable with those seen after the administration of silymarin alone, suggesting a protective effect for silymarin against the increases in tranaminases by trimebutine. Histopathologic examination of the liver of rats treated with CCl[4] + trimebutine at a dose of 120 mg/kg showed massive inflammatory cellular infiltrate, fatty change and vacuolar degeneration. These changes were less marked in rats treated with CCl[4] + silymarin + 120 mg/kg trimebutine. It is concluded that the opiate agonist trimebutine aggrevates hepatocellular injury caused by CCl[4] in rats, which can be lessened by coadminisration of silymarin. We suggest monitoring of hepatic functions in patients on long term use of this drug, especially in those with already known hepatic dysfunction such as steatosis or HCV infected individuals. The administration of silymarin in patients on long-term use of trimebutine is advisable

experimental studies of the anti-inflammatory and gastric effects of ribavirin in rats

In the present study we examined effects of the broad-spectrum antiviral agent ribavirin on inflammation and gastric integrity in rats. Ribavirin 30120 mg/kg. i.p., administered 30 min beforehand, had no significant effect on carrageenan induced oedema, meanwhile a higher dose of 240 mg/kg significantly inhibited the formalin-induced paw oedema for 2 h. Injection of ribavirin in rats treated with indomethacin, rofecoxib or meloxican caused a further decrease in paw volume of carrageenan injected rats by 21.7, 23.6 and 71.2% at 4 h., respectively. It is suggested that ribavirin administered via systemic route possesses anti-inflammatory properties. Ribavirin 30-120 mg/kg, s.c, reduced the number and severity of gastric lesions caused by indomethacin [20 mg/kg, i.p.] in a dose-dependent manner. In urethane-anaesthetised rats, the drug inhibited gastric acid secretion induced by distention or distension plus histamine stimulation. The drug increases the anti-inflammatory action of NSAIDs, while reducing their gastric side effects

Investigation of the effect of unfractionated and low molecular weight heparins on inflammation and gastrointestinal mucosal injury in rats

The aim of the present work was to investigate the effect of unfractionated heparin [UFH; 1000-4000 IU/kg] in addition to three already marketed low molecular weight heparin [LMWH] preparations [nadroparin [1500-3000 anti-Xa IU/kg], tinzaparin [1500-3000 anti-Xa IU/kg], enoxaparin [300-600 anti-Xa IU/kg] on acute inflammation and on gastrointestinal mucosal integrity in rats. Acute inflammation was induced by intraplantar injection of carrageenan into rat hindpaw. Gastrointestinal mucosal injury was evoked by subcutaneous injection of indomethacin [20 mg/kg]. The results showed that: [1] Different heparin preparations given s.c., 30 mm prior to carrageenan injection exerted variable effects on the carrageenan oedema response. Oedema was not significantly changed after conventional UFH, but decreased after tinzaparin and nadroparin, the lower doses being more effective in reducing inflammation. Oedema was unchanged after enoxaparin at 600 IU/kg, but the lower dose of 300 IU/kg reduced oedema formation by 21.6% 1 h post-carrageenan.; [2] No significant change was noted in the number and severity of gastric mucosal lesions in rats treated with UFH. A significant decrease in number and severity of gastric mucosal lesions was noted in rats treated with the lower doses of either tinzaparin or enoxaparin compared with either the indomethacin control group or with the UFH [2000 IU/kg]-treated group. It is concluded that heparin preparations exert complex effects on acute [carrageenan-induced] inflammation and might have beneficial effects on gastric mucosal lesions caused by Indomethacin

Studies on the effect of the opioid receptor agonist "trimebutine" on inflammation, pain and gastric ulceration in rats

The effects of trimebutine, a peripheral opiate agonist, were investigated on the development of paw oedema by carrageenan, on visceral nociception caused by i.p. injection of acetic acid, on gastric mucosal injury induced by indomethacin and on gastric acid secretion in rats. I.p administration of trimebutine at 30, 60 or 120 mg/kg, at 30-min pretreatment, decreased paw oedema caused by carrageenan injection by 18.2-21.6%, 27.3%- 22.8% and 33.6%- 29.3%, respectively, with maximal inhibition being observed at 1-2 hr post-carrageenan. In addition, trimebutine in doses of 30, 60 or 120 mg/kg [i.p.] 30 mm after carrageenan challenge inhibited the paw oedema response by -21.2, -17%, 22.3, -21.2% and -33.1, -30% at 3 and 4 hr post-carrageenan, respectively. Trimebutine [60 mg/kg] co-administered with meloxicam [3.8 mg/kg], indomethacin [18 mg/kg] or dexamethasone [0.2 mg/kg] resulted in an additive effect. Abdominal writhes induced by i.p. injection of acetic acid were effectively inhibited by trimebutine. The drug enhanced the development of lesions by indomethacin in a dose-dependent manner. In anaesthetised rats, trimebutine caused dose-dependent inhibition of gastric acid secretion. Results indicate that trimebutine possesses anti-inflammatory properties in addition to its visceral analgesic effects. The drug likely exacerbates gastric mucosal lesions by non-steroidal anti inflammatory drugs and consequently their concurrent administration is not advisable

Comparison of the anti-inflammatory, analgesic and gastric effects of vinpocetine and piracetam in rats

The nootropic agents vinpocetine and piracetam are widely used in the treatment of memory and neurodegenerative disorders. The current study compared the effects of the two drugs in experimental models of inflammation and on the development of gastric mucosal damage evoked by indomethacin in rats. In paw oedema caused by subplantar injection of carrageenan, vinpocetine, given s.c., at doses of 0.45-1.8 mg/kg, produced only a slight decrease in paw volume. By contrast, piracetam administered s.c., at 75 mg/kg, significantly inhibited the oedema response, but at a higher dose 300 mg/kg produced a sustained dose-related increases in paw volume. In the hot-plate test of thermal pain, vinpocetine, but not piracetam, produced a dose-related reduction in nociceptive responses. Gastric mucosal lesions induced by s.c. indomethacin [20 mg/kg] were inhibited by vinpocetine [0.45-1.8 mg/kg, s.c.], but increased after piracetam [75-300 mg/kg, s.c.] in a dose-dependent manner. It is concluded that the nootropic drugs exert different effects on inflammation and gastric mucosal integrity in rats

Effect of the new anti-ischaemic drug "trimetazidine" on hepatic injury caused by carbon tetrachloride in rats

The effects of trimetazidine, a novel anti-ischaemic agent, on the development of hepatic injury induced in rats with carbon tetrachloride, were investigated. Hepatotoxicity was induced by CCl[4] orally [0.2 ml/kg followed by 0.1 ml/kg after one week]. Trimetazidine at three dose levels [3.6, 7.2 and 14.4 mg/kg], silymarin [25 mg/kg] and combination of trimetazidine [7.2 mg/kg] and silymarin [25 mg/kg] were administered orally daily for 15 days, starting at time of administration of CCL. The daily administration of trimetazidine conferred significant protection against the hepatotoxic effects of CCL, in rats. It decreased the increases in serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP] and also prevented the development of hepatic necrosis caused by CCL as determined 15 days after drug administration. Thus, compared with the CCL control group, serum ALT decreased by 35.1, 49.5 and 57%, AST by 28.2, 31.6 and 36% and ALP by 32, 39.7 and 40.6%, after the administration of trimetazidine at 3.6, 7.2 and 14.4 mg/kg, respectively. Silymarin administered alone, at the dose of 25 mg/kg reduced serum ALT by 30%, AST by 29.1% and ALP by 38.4% compared to CCL control. When silymarin was combined with 7.2 mg/kg of trimetazidine, the activities of ALT, AST and ALP were markedly decreased by 47.2%, 47.2% and 50.6%, respectively, compared with the CCl[4]control, indicating a beneficial additive effect. Histopathologic examination of the liver of rats treated with CCl[4] + trimetazidine showed less fibrosis compared with the CCl[4] -control group. Co-treatment with silymarin and trimetazidine, on the other hand resulted in marked histologic protection. It is concluded that the anti-ischaemic agent trimetazidine lessened hepatocellular injury caused by CCl[4], in rats, and had additive effect with silymarin. It was suggested, therefore, that trimetazidine alone or in combination with silymarin might have a place in the therapy of chronic liver diseases