Assessment of the possible roles of SB-269970 versus ketanserin on carbon tetrachloride-induced liver fibrosis in rats: Oxidative stress/TGF-ß1-induced HSCs activation pathway.

BACKGROUND: In liver fibrosis, a major morbid and mortal disease, oxidative stress motivation of hepatic stellate cells (HSCs)-into myofibroblasts terminated in collagen deposition remain the key pathophysiological deal. Serotonin (5-HT) through its HSCs-expressed receptors, especially 5-HT2A and 7, shows crucial events in fibrogenesis of chronic liver diseases. Molecular hepatic oxidative stress-fibrotic roles of 5-HT2A and 7 receptors antagonists (ketanserin and SB-269970 respectively) are still a challenging issue. METHODS: Seven groups of adult male Wistar rats (n=10) were used. A carbon tetrachloride (CCl4) solution was injected intraperitoneally twice weekly for 6 weeks. On the 7th week, rats developed liver fibrosis were treated either by ketanserin (1mg/kg/day, ip) or SB-269970 (2mg/kg/day, ip) for 14days. Survival rates, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in addition to hepatic malondialdehyde (MDA) and reduced glutathione (GSH) levels, superoxide dismutase (SOD) and catalase (CAT) activities, and transforming growth factor-beta1 (TGF-ß1) and procollagen type I N-terminal propeptide (PINP) levels, beside the hepatic histopathological fibrotic changes, were evaluated. RESULTS: In CCl4-challenged rats, each therapeutic approach showed significant reductions in elevated serum ALT, and AST levels, hepatic MDA, TGF-ß1, and PINP levels, and histopathological hepatic fibrotic scores as well as significant elevations in survival rates, reduced hepatic GSH levels, and SOD, and CAT activities. Remarkably, significant ameliorative measurements were observed in SB-269970 treated group. CONCLUSION: Blockade of 5-HT2A and 7 receptors each alone could be a future reliable therapeutic approach in liver fibrosis through a reduction in oxidative stress/TGF-ß1-induced HSCs activation pathway.

Combination of coenzyme Q10 with methotrexate suppresses Freund's complete adjuvant-induced synovial inflammation with reduced hepatotoxicity in rats: Effect on oxidative stress and inflammation.

Methotrexate (MTX) is a cornerstone disease modifying anti-rheumatic drug. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Coenzyme Q10 (CoQ10) is an antioxidant and anti-inflammatory compound, possessing both anti-arthritic and hepatoprotective potential. The present study was carried out to evaluate the effect of CoQ10 (10mg/kg) alone and in combination with MTX (2mg/kg) on the progression of adjuvant-induced arthritis in rats, and to elucidate the potential properties of CoQ10 in ameliorating MTX-induced liver damage in rats. Rats were assigned to; normal, arthritic, MTX treated, CoQ10 treated or a combination of MTX and CoQ10. CoQ10 administration potentiated the antiarthritic effect of MTX. Moreover, the combination therapy was effective in attenuating the severity of MTX-induced liver damage displayed by the improvement in hepatospecific serum markers and confirmed by the histo-pathological evaluation. Additionally, it attenuated the hepatic oxidative stress and the intensity of inflammatory mediators associated with MTX administration as evident by the regulation of oxidant/anti-oxidant balance and the inhibitory effects on TNF-α and IL-6 levels. These results revealed that CoQ10 can serve as a useful adjuvant and promote the safe use of MTX in the management of arthritis, not only by potentiating the antiarthritic effect of MTX, but also by alleviating MTX-induced hepatocellular injury.

Evaluation of the antifibrotic effect of fenofibrate and rosiglitazone on bleomycin-induced pulmonary fibrosis in rats.

Idiopathic pulmonary fibrosis is the most prevalent chronic fibrosing lung disease. Peroxisome proliferator-activated receptors-gamma agonists provide potential therapy for fibrotic diseases of the lung. Peroxisome proliferator-activated receptors-alpha agonists may be helpful in the treatment of lung inflammatory diseases, however their therapeutic potential on the "fibro-proliferative" process and extracellular matrix accumulation in idiopathic pulmonary fibrosis has been less well studied. So, the present study was conducted to evaluate the anti-fibrotic effects of fenofibrate (peroxisome proliferator-activated receptors-alpha agonist) alone and in combination with rosiglitazone (peroxisome proliferator-activated receptors-gamma agonist) on lung injury induced by bleomycin administration. Oral administration of either rosiglitazone (5 mg/kg/d) or fenofibrate (100 mg/kg/d) for 14 days, attenuated the severity of bleomycin-induced lung injury and fibrosis through decreasing lung water contents, lung fibrotic grading, lung hydroxyproline contents and lung transforming growth factor-beta1 levels; with no significant difference between them. Combined low doses of rosiglitazone (1 mg/kg/d) and fenofibrate (30 mg/kg/d) provided more benefits than full separate doses of each on the deleterious effects accompanied bleomycin administration. These findings suggested the potential use of peroxisome proliferator-activated receptors-alpha ligands as anti-fibrotic agents in lung fibrosis. Additionally, the concurrent administration of fenofibrate and rosiglitazone in low doses has synergistic effect and enhanced the beneficial effects afforded by either fenofibrate or rosiglitazone.

Coenzyme Q10 enhances the anticonvulsant effect of phenytoin in pilocarpine-induced seizures in rats and ameliorates phenytoin-induced cognitive impairment and oxidative stress.

Conventional antiepileptic drugs fail to adequately control seizures and predispose to cognitive impairment and oxidative stress with chronic usage in a significant proportion of patients with epilepsy. Coenzyme Q10 (CoQ10), an antioxidant compound, exhibits a wide range of therapeutic effects that are attributed to its potent antioxidant capacity. To evaluate the neuroprotective effects of CoQ10 in rats against the observed oxidative stress during seizures induced by pilocarpine, and to study its interactions with the conventional antiepileptic drug phenytoin, two experiments were performed. Experiment 1 was conducted to test the effect of phenytoin, CoQ10, or both on seizure severity and oxidative markers in the pilocarpine model of epilepsy. Experiment 2 was conducted to test the effect of 2 weeks of chronic treatment with phenytoin, CoQ10, or both on oxidative markers and behavioral tests in rats. Overall, CoQ10 reduced the severity of pilocarpine-induced seizures and the severity of oxidative stress. Moreover, it potentiated the antiepileptic effects afforded by phenytoin treatment, with the potential safety and efficacy in ameliorating oxidative stress and cognitive impairment caused by chronic phenytoin therapy. Our findings strongly suggest that CoQ10 can be considered a safe and effective adjuvant to phenytoin therapy in epilepsy both to ameliorate seizure severity and to protect against seizure-induced oxidative damage by reducing the cognitive impairment and oxidative stress associated with chronic use of phenytoin.

The role of ATP-sensitive potassium channel blockers in ischemia-reperfusion-induced renal injury versus their effects on cardiac ischemia reperfusion in rats.

In renal ischemia reperfusion (V/R), opening of adenosine-triphosphate (ATP)-sensitive potassium (K(ATP)) channels results in massive influx of neutrophils in both renal and lung tissues. Our study was focused on the role of ATP-dependent potassium channel modulators, glimepiride and glibenclamide on I/R induced renal injury in rats. Additionally we evaluated their effects on normal heart and on ischemic reperfused heart subjected to ischemic preconditioning protection afforded by diazoxide. To test this hypothesis, we used renal I/R and cardiac I/R experiment. Renal ischemia reperfusion induced marked renal dysfunction associated with significant increase in arterial pressure, TNF-alpha levels, superoxide anion production, and myeloperoxidase activity. Treatment with glibenclamide or glimepiride, demonstrated a significant improvement in the reperfusion-induced injury in both kidney and lung. Glimepiride has no effect on superoxide anion production. However glibenclamide induced a significant improvement in these measurements as compared to glimepiride group. Before coronary artery ligation, neither diazoxide nor glimepiride pretreatment influenced significantly the electrocardiographic parameters in comparison with control group. Conversely, glibenclamide supplementation induced a significant elevation in these parameters. After left coronary artery ligation, reperfusion of the ischemic hearts caused a significant elevation in the measured electrocardiographic parameters. These elevations were significantly ameliorated by the pretreatment with diazoxide. In conclusion, the administration of glibenclamide significantly abolished the protective effects of diazoxide, while the pretreatment with glimepiride didn't abolish it. So, glimepiride offers some promise for therapy of renal I/R with minimizing the undesirable cardiac side effects.