RESUMEN
The current study aimed to evaluate the role of cannabinoid receptors in the regulation of gastric acid secretion and oxidative stress in gastric mucosa. To fulfill this aim, gastric acid secretion stimulated with histamine (5 mg/kg, subcutaneous [SC]), 2-deoxy- d-glucose (D-G) (200 mg/kg, intravenous) or -carbachol (4 µg/kg, SC) in the 4-hour pylorus-ligated rats. The CB1R agonist ( N-arachidonoyl dopamine, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and carbachol but not in histamine, reduced pepsin content, and increased mucin secretion. Furthermore, it decreased malondialdehyde (MDA) and nitric oxide (NO) contents with an increase in glutathione (GSH) and paraoxonase 1 (PON-1). Meanwhile, CB2R antagonist (AM630, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and reduced MDA and NO contents with an increase in GSH and PON-1. Meanwhile, CB1R antagonist rimonabant or CB2R agonist GW 405833 had no effect on stimulated gastric acid secretion. Therefore, both CB1R agonist and CB2R antagonist may exert antisecretory and antioxidant potential in the stomach.
Asunto(s)
Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Ácido Gástrico/metabolismo , Mucosa Gástrica/efectos de los fármacos , Animales , Mucosa Gástrica/metabolismo , Histamina , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Cannabinoides/efectos de los fármacosRESUMEN
OBJECTIVE: The aim of the present study was to investigate the effect of the serotonin selective reuptake inhibitors (SSRIs) fluoxetine and sertraline and the tricyclic drug imipramine on oxidative stress in the brain and liver caused by thioacetamide in rats. MATERIALS AND METHODS: Drugs were administered orally once daily at doses of 10 and 20 mg/kg for two weeks prior to intraperitoneal injection of thioacetamide (300 mg/kg). Rats were euthanized 24 h after thioacetamide. Reduced glutathione (GSH), malondialdehyde (MDA) and nitric oxide were measured in brain and liver. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were measured in serum and histopathological evaluation of liver injury was performed. RESULTS: The administration of thioacetamide increased MDA by 151.8% and 161.2%, increased nitric oxide by 57.2% and 63.9% and decreased GSH by -40.6% and -67% in the brain and liver, respectively. Thioacetamide markedly increased serum ALT, AST and ALP by 277.8, 80.8 and 121%, respectively. In the brain, MDA was decreased in rats treated with fluoxetine or sertraline. The level of GSH increased by fluoxetine and by the higher dose of sertraline. Nitric oxide in brain was unchanged by fluoxetine, but increased after sertraline at 20 mg/kg. Brain MDA was increased by imipramine, which also decreased brain nitrite level. In the liver, fluoxetine or sertraline treatment increased GSH and nitrite levels. MDA was also increased by either drug. The drugs markedly decreased ALT, but increased ALP in serum. Meanwhile, imipramine decreased liver nitric oxide levels (at the lower dose only -32.9%), markedly increased hepatic GSH, but did not change MDA level. Serum ALT decreased by imipramine (but AST and ALP showed no change). Histopathological and histochemical examinations indicated that thioacetamide-induced liver injury was not decreased after treatment with the antidepressant drugs. CONCLUSIONS: In thioacetamide-treated rats, pretreatment with the SSRIs drugs fluoxetine and sertraline is associated with decreased lipid peroxidation in brain; liver peroxidation, however, is increased. Imipramine displayed opposite effects. The thioacetamide-induced hepatic damage was not reduced by fluoxetine, sertraline or imipramine.
Asunto(s)
Antidepresivos/farmacología , Estrés Oxidativo/efectos de los fármacos , Tioacetamida/farmacología , Alanina Transaminasa/metabolismo , Fosfatasa Alcalina/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Femenino , Fluoxetina/farmacología , Glutatión/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Malondialdehído/metabolismo , Óxido Nítrico/metabolismo , Ratas , Ratas Sprague-Dawley , Sertralina/farmacologíaRESUMEN
This study aimed to investigate the effect of cerebrolysin on oxidative stress in the brain and liver during systemic inflammation. Rats were intraperitoneally challenged with a single subseptic dose of lipopolysaccharide (LPS; 300 µg/kg) without or with cerebrolysin at doses of 21.5, 43 or 86 mg/kg. After 4 h, rats were euthanized and the brain and liver tissues were subjected to biochemical and histopathological analyses. Cerebrolysin revealed inhibitory effects on the elevation of lipid peroxidation and nitric oxide induced by LPS. In contrast, the decrease in reduced glutathione level and paraoxonase activity induced by LPS was attenuated by an injection of cerebrolysin in a dose-dependent manner. Moreover, cerebrolysin reduced LPS-induced activation of brain NF-κB and reversed LPS-induced decline of brain butyrylcholinesterase and acetylcholinesterase activities in a dose-dependent manner. Histopathological analyses revealed that neuronal damage and liver necrosis induced by LPS were ameliorated by cerebrolysin dose-dependently. Cerebrolysin treatment dose-dependently attenuated LPS-induced expressions in cyclooxygenase 2, inducible nitric oxide synthase, and caspase-3 in the cortex or striatum as well as the liver. These results suggest that cerebrolysin treatment might have beneficial therapeutic effects in cerebral inflammation. Cerebrolysin might also prove of value in liver disease and this possibility requires further exploration.
Asunto(s)
Aminoácidos/farmacología , Encéfalo/efectos de los fármacos , Lipopolisacáridos/toxicidad , Hígado/efectos de los fármacos , Animales , Encéfalo/enzimología , Encéfalo/patología , Caspasa 3/análisis , Ciclooxigenasa 2/análisis , Femenino , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Óxido Nítrico Sintasa de Tipo II/análisis , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: The dipeptide aspartame (N-L-alpha-aspartyl-Lphenylalanine, 1-methyl ester; alpha-APM) is one of the most widely used artificial sweeteners. The present study aimed to investigate the effect of repeated administration of aspartame in the working memory version of Morris water maze test, on oxidative stress and brain monoamines in brain of mice. MATERIALS AND METHODS: Aspartame (0.625, 1.875 or 5.625 mg/kg) was administered once daily subcutaneously for 2 weeks and mice were examined four times a week for their ability to locate a submerged plate. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide levels (the concentrations of nitrite/nitrate) and glucose were determined in brain. RESULTS: Only at the highest dose of 5.625 mg/kg, did aspartame significantly impaired water maze performance. The mean time taken to find the escape platform (latency) over 2 weeks was significantly delayed by aspartame 5.625 mg/kg, compared with the saline-treated control group. Significant differences occurred only on the first trial to find the escape platform. Significant increase in brain MDA by 16.5% and nitric oxide by 16.2% and a decrease in GSH by 25.1% and glucose by 22.5% occurred after treatment with aspartame at 1.875 mg/kg. Aspartame administered at 5.625 mg/kg significantly increased brain MDA by 43.8%, nitric oxide by 18.6% and decreased GSH by 32.7% and glucose by 25.8%. Aspartame caused dose-dependent inhibition of brain serotonin, noradrenaline and dopamine. CONCLUSIONS: These findings suggest impaired memory performance and increased brain oxidative stress by repeated aspartame administration. The impaired memory performance is likely to involve increased oxidative stress as well as decreased brain glucose availability.
Asunto(s)
Aspartame/toxicidad , Encéfalo/efectos de los fármacos , Memoria/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Encéfalo/metabolismo , Masculino , Malondialdehído/análisis , Ratones , Óxido Nítrico/análisis , Fenilalanina/metabolismoRESUMEN
The potential vasodilator effect of the novel compound 2-alkylthio-4-ethyl-4-methyl-4,5 dihydro-1H-imidazolin-5-one oxime (oxime) was investigated in a model of lower 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 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 lower 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 to 178.8, 328.9 and 705.9 %, respectively. Meanwhile, L-arginine given i.v. at 100 mg/kg increased BFR to 560 %. Isoprenaline given i.v. at 1 microg/kg increased BFR to 274.3 %, while isoprenaline combined with oxime (0.064 mg/kg) increased BFR to 402.7 %. Similarly, after topical application of oxime, BFR increased to 113.5, 261.1 and 433.3 %, respectively. L-arginine given at 1000 mg/kg increased BFR to 389.7 %. Isoprenaline given at 10 microg/kg increased BFR to 231.6 %, while isoprenaline administered in combination with oxime (0.064 mg/kg) increased BFR to 308.3 %. 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 1,000 mg/kg L-arginine, respectively. It is concluded that systemic or topical oxime results in marked enhancement of blood flow in the rat ischaemic lower limb. This effect of oxime is likely to be mediated through the release of NO.
Asunto(s)
Extremidades/irrigación sanguínea , Isquemia/tratamiento farmacológico , Oximas/uso terapéutico , Vasodilatadores/uso terapéutico , Animales , Arginina/farmacología , Isquemia/fisiopatología , Isoproterenol/farmacología , Flujometría por Láser-Doppler , Masculino , Oximas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Vinpocetine is a widely used drug for the treatment of cerebrovascular and memory disorders. This study aimed to investigate the effect of vinpocetine on the acute hepatic injury caused in the rat by the administration of CCl4 in vivo. Vinpocetine (2.1, 4.2, 8.4 mg/kg) or silymarin (30 mg/kg) was given once daily orally simultaneously with CCl4 and for 15 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. Stained sections were subjected to morphometric evaluation using computerized image analyzer. The results showed that vinpocetine administered to CCl4-treated rats decreased the elevated alanine aminotransferase (ALT) by 49.3, 58.1 and 63.6%, aspartate aminotransferase (AST) by 10.5, 22.6 and 27.2% and alkaline phosphatase (ALP) by 52.5, 59.6 and 64.9%, respectively, and in a dose-dependent manner. Meanwhile, silymarin reduced elevated ALT, AST and ALP levels by 53.1, 26.9 and 66%, respectively. Histological examination of liver specimens revealed a marked reduction in liver cell necrosis in vinpocetine and silymarin-treated rats compared with vehicle-treated CCl4-treated rats. Quantitative analysis of the area of damage showed 85.3% reduction in the area of damage after silymarin and 72.2, 78.9 and 82.6% reduction after vinpocetine treatment at 2.1, 4.2, 8.4 mg/kg, respectively. It is concluded that administration of vinpocetine in a model of CCl4-induced liver injury in rats reduced liver damage. The reduction obtained by 4.2 mg/kg of vinpocetine was similar to that obtained by 30 mg/kg silymarin. Therefore, it is suggested that vinpocetine might be a good pharmacological agent in the treatment of liver disease besides its neuroprotective effects.