The role of 5-HT7 receptors on isoproterenol-induced myocardial infarction in rats with high-fat diet exacerbated coronary endothelial dysfunction.

The presence of 5-HT7r's in both human and rat cardiovascular and immune tissues and their contribution to inflammatory conditions prompted us to hypothesize that these receptors contribute in acute myocardial infarction (MI) with underlying chronic endothelial dysfunction. We investigated the role of 5-HT7 receptors on heart tissue that damaged by isoproterenol (ISO)-induced MI in rats with high-fat diet (HFD). In vitro and in vivo effects of 5-HT7r agonist (LP44) and antagonist (SB269970) have been investigated on the H9C2 cell line and rats, respectively. For in vivo analyses, rats were fed with HFD for 8 weeks and after this period ISO-induced MI model has been applied to rat. To investigate the role of 5-HT7r's, two different doses of LP44 and SB269970 were evaluated and compared with standard hypolipidemic agent, atorvastatin. In vitro studies showed that LP44 has protective and proliferative effects on rat cardiomyocytes. Also in in vivo studies stimulating 5-HT7r's by LP44 improved blood lipid profile (decreased total cholesterol, low-density lipoprotein-C, and triglyceride, increased high-density lipoprotein), decreased cardiac damage markers (creatine kinase and troponin-I), and corrected inflammatory status (tumor necrosis factor-α, interleukin-6). Our results showed significant improvement in LP44 administered rats in terms of histopathologic analyses. In damaged tissues, 5-HT7 mRNA expression increased and agonist administration decreased this elevation significantly. We determined for the first time that 5-HT7r's are overexpressed in ISO-induced MI of rats with underlying HFD-induced endothelial dysfunction. Restoration of this overexpression by LP44, a 5-HT7r agonist, ameliorated heart tissue in physiopathologic, enzymatic, and molecular level, showing the cardiac role of these receptors and suggesting them as future potential therapeutic targets.

Ebselen has lithium-like effects on central 5-HT2A receptor function.

BACKGROUND AND PURPOSE: Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in Gq -protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here, we investigated both ebselen and lithium in models of the 5-HT2A receptor, a Gq -protein coupled receptor involved in lithium's actions. EXPERIMENTAL APPROACH: 5-HT2A receptor function was assessed in mice by measuring the behavioural (head-twitches, ear scratches) and molecular (cortical immediate early gene [IEG] mRNA; Arc, c-fos, Egr2) responses to 5-HT2A receptor agonists. Ebselen and lithium were administered either acutely or repeatedly prior to assessment of 5-HT2A receptor function. Because lithium and 5-HT2A receptor antagonists augment the action of selective serotonin reuptake inhibitors (SSRIs), ebselen was tested for this activity by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments. KEY RESULTS: Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT2A receptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen enhanced the increase in extracellular 5-HT induced by citalopram, and also increased regional brain 5-HT synthesis. CONCLUSIONS AND IMPLICATIONS: Our data demonstrated lithium-mimetic effects of ebselen in different experimental models of 5-HT2A receptor function, probably mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorders, including as an antidepressant augmenting agent.

THE EFFECTS OF VARIOUS DOSES OF PREDNISOLONE ADMINISTRATION ON SERUM VASPIN LEVELS IN RATS.

AIM: The aim of this study was to investigate the dose-dependent effects of prednisolone administration on serum vaspin levels and correlate this with changes in the BMI and lipogenesis in rats. MATERIALS AND METHODS: Twenty-four albino Wistar male rats weighing between 190-240 g were divided into four groups, three experimental (5 mg/kg, 10 mg/kg, and 20 mg/kg prednisolone) and one control. The prednisolone groups were given once-daily doses for 30 days, orally. In addition, the rats were weighed, and their height and waist circumferences were measured once a week. At the end of 30 days, vaspin and glucose levels were measured from blood samples. RESULTS: In the prednisolone groups, the vaspin levels significantly increased when compared with the control group. The control group has a serum vaspin level of 155 ± 20.99 pg/mL and this level has been increased by prednisolone administration in a dose dependent manner. In the prednisolone groups, especially the 10 mg/kg and 20 mg/kg groups, the glucose levels increased in a dose dependent fashion. CONCLUSION: Prednisolone administration significantly increased serum glucose and vaspin levels in a dose dependent manner, indicating that the increase in the serum vaspin levels could be related to the increase in the serum glucose concentration. Vaspin can be a molecule that is released in response to increased glucose and can be a rebound defense mechanism to modulate the blood glucose concentration. We suggest vaspin as a potential target for the treatment and diagnosis of diabetes mellitus and other metabolic disorders.

The protective effects of carvacrol and thymol against paracetamol-induced toxicity on human hepatocellular carcinoma cell lines (HepG2).

Acetaminophen (APAP) overdose could induce liver damage and lead to acute liver failure. The treatment of APAP overdoses could be improved by new therapeutic strategies. Thymus spp., which has many beneficial effects and has been used in folk medicine, is one such potential strategy. In the present study, the hepatoprotective activity of the main constituents of Thymus spp., carvacrol and thymol, were evaluated in light of APAP-induced hepatotoxicity. We hoped to understand the hepatoprotective mechanism of these agents on the antioxidant system and pro-inflammatory cytokines in vitro. Dose-dependent effects of thymol and carvacrol (25, 50, and 100 µM) were tested on cultured HepG2 cells. N-Acetylcysteine (NAC) was tested as positive control. We showed that APAP inhibited HepG2 cell growth by inducing inflammation and oxidative stress. Incubating APAP-exposed HepG2 cells with carvacrol and thymol for 24 h ameliorated this inflammation and oxidative stress. We also evaluated alanine transaminase and lactate dehydrogenase levels of HepG2 cells. We found that thymol and carvacrol protected against APAP-induced toxicity in HepG2 cells by increasing antioxidant activity and reducing pro-inflammatory cytokines, such as tumor necrosis factor α and interleukin 1ß. Taking together high-dose thymol and carvacrol treatment has an effect close to NAC treatment in APAP toxicity, but thymol has better treatment effect than carvacrol.

Effects of amlodipine on ischaemia/reperfusion injury in the rat testis.

The aim of this study was to examine the effects of amlodipine (AML) in rat testicular torsion/detorsion damage. In this study, rats were divided into eight groups: (i) sham; (ii) testicular ischaemia, 2 h of ischaemia; (iii) testicular ischaemia/reperfusion (I/R), 2 h of ischaemia followed by 2 h of reperfusion; (iv) ischaemia + AML (5 mg kg(-1)) administered 30 min before ischaemia; (v) ischaemia + AML (10 mg kg(-1)) administered 30 min before ischaemia; (vi) and (vii) I/R + AML (5 mg kg(-1)) and I/R + AML (10 mg kg(-1)) administered 1.5 h after the induction of ischaemia, respectively, and at the end of a 2-h ischaemia period and a 2-h reperfusion period applied; and (viii) sham + AML (10 mg kg(-1)). Significant decreases in levels of superoxide dismutase and glutathione were observed in ischaemia and reperfusion groups when compared with healthy controls. These antioxidant levels increased in AML groups while malondialdehyde levels significantly decreased. While increases in tumour necrosis factor-alpha and transforming growth factor-beta levels were found in the torsion and detorsion groups, significant decreases in the levels of these inflammatory cytokines were observed in the treatment groups. These results demonstrate that AML significantly produced protective effects on testis tissue damage that occurs in the torsion/detorsion model via biochemical, histopathological and molecular pathways.

Comparative study on effects of nebulized and oral salbutamol on a cecal ligation and puncture-induced sepsis model in rats.

AIM: The present study aimed to compare the effects of different routes of salbutamol administration (oral and nebulized) at different doses in a cecal ligation and puncture-induced (CLP-induced) sepsis model of rats. METHODS: Rats were separated into 8 groups: 1) sham, 2) sham+4 mg/kg oral salbutamol, 3) sham+6 min 2 mg/ml nebulized salbutamol, 4) CLP, 5) CLP+2 mg/kg oral salbutamol, 6) CLP+4 mg/kg oral salbutamol, 7) CLP+3 min 2 mg/ml nebulized salbutamol, 8) CLP+6 min 2 mg/ml nebulized salbutamol. Subsequently, sepsis was induced by CLP through 16 h. RESULTS: CLP-induced sepsis increased serum cytokine levels (TNF-α, IL-1ß, and IL-6), increased tissue oxidative stress (8-Isoprosraglandin F2α), decreased antioxidant parameters (SOD, GSH), and increased lung injury by inflammatory cell accumulation. CONCLUSION: This study showed for the first time that oral administration of salbutamol exerted protective effects on CLP-induced sepsis and related lung injury in rats. We conclude that despite the greater side effects of oral salbutamol, it should be considered for administration in oral form due to its systemic effectiveness during septic conditions in emergency settings.

Agomelatine: an antidepressant with new potent hepatoprotective effects on paracetamol-induced liver damage in rats.

Paracetamol was shown to induce hepatotoxicity or more severe fatal acute hepatic damage. Agomelatine, commonly known as melatonin receptor agonist, is a new antidepressant, which resynchronizes circadian rhythms with subjective and objective improvements in sleep quality and architecture, as melatonin does. In the present study, it was aimed to evaluate the hepatoprotective activity of agomelatine on paracetamol-induced hepatotoxicity and to understand the relationship between the hepatoprotective mechanism of agomelatine and antioxidant system and proinflammatory cytokines. A total of 42 rats were divided into 7 groups as each composed of 6 rats: (1) intact, (2) 40 mg/kg agomelatine, (3) 140 mg/kg N-acetylcysteine (NAC), (4) 2 g/kg paracetamol, (5) 2 g/kg paracetamol + 140 mg/kg NAC, (6) 2 g/kg paracetamol + 20 mg/kg agomelatine, and (7) 2 g/kg paracetamol + 40 mg/kg agomelatine groups. Paracetamol-induced hepatotoxicity was applied and liver and blood samples were analyzed histopathologically and biochemically. There were statistically significant increases in the activities of aspartate aminotransferase, alanine aminotransferase, levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) and 8-iso-prostane, and decreases in the activity of superoxide dismutase and level of glutathione in the group treated with paracetamol. Administration of agomelatine and NAC separately reversed these changes significantly. In conclusion, agomelatine administration protects liver cells from paracetamol-induced hepatotoxicity via antioxidant activity and reduced proinflammatory cytokines, such as TNF-α and IL-6.

Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study.

Sepsis is a systemic inflammatory response to infection and a major cause of morbidity and mortality. Sildenafil (SLD) is a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase PDE5. We aimed to investigate the protective effects of sildenafil on caecal ligation and puncture (CLP)-induced sepsis in rats. Four groups of rats were used, each composed of 10 rats: (i) 10 mg/kg SLD-treated CLP group; (ii) 20 mg/kg SLD-treated CLP group; (iii) CLP group; and (iv) sham-operated control group. A CLP polymicrobial sepsis model was applied to the rats. All groups were killed 16 h later, and lung, kidney and blood samples were analysed histopathologically and biochemically. Sildenafil increased glutathione (GSH) and decreased the activation of myeloperoxidase (MPO) and of lipid peroxidase (LPO) and levels of superoxide dismutase (SOD) in the septic rats. We observed a significant decrease in LPO and MPO and a decrease in SOD activity in the sildenafil-treated CLP rats compared with the sham group. In addition, 20 mg/kg sildenafil treatment in the sham-operated rats improved the biochemical status of lungs and kidneys. Histopathological analysis revealed significant differences in inflammation scores between the sepsis group and the other groups, except the CLP + sildenafil 10 mg/kg group. The CLP + sildenafil 20 mg/kg group had the lowest inflammation score. Sildenafil treatment decreased the serum tumour necrosis factor (TNF)-α level when compared to the CLP group. Our results indicate that sildenafil is a highly protective agent in preventing lung and kidney damage caused by CLP-induced sepsis via maintenance of the oxidant-anti-oxidant status and decrease in the level of TNF-α.

Relation of adrenergic receptors, which have roles in gastroprotective and anti-inflammatory effect of adrenal gland hormones, with cyclooxygenase enzyme levels in rats.

BACKGROUND AND AIMS: COX-2 enzyme inhibition is responsible for the anti-inflammatory effects of NSAIDs, COX-1 for their effects upon the gastrointestinal system (GIS), along with other side effects. We investigated the relationship between COX levels and those adrenergic receptors known to play a role in gastroprotection and anti-inflammatory activity. METHOD: The effects of adrenaline and prednisolone on gastric COX-1 and COX-2 levels in both intact and adrenalectomized rats treated with doxazosin, yohimbine, propranolol, and metoprolol were determined. RESULTS: We found that adrenaline increases COX-1 levels in the gastric tissue of both intact and adrenalectomized rats by stimulating alpha-2 receptors. Adrenaline decreases COX-2 levels by stimulating beta-2 adrenergic receptors. Prednisolone inhibits both COX-1 and COX-2 in the gastric tissue of intact rats. In adrenalectomized rats, prednisolone increases gastric COX-1 by stimulating alpha-2 receptors, and decreases COX-2 levels by stimulating beta-2 receptors. CONCLUSION: Prednisolone cannot bind to a adrenergic receptors in the presence of adrenaline (intact rats) but, in its absence (adrenalectomy), binds to alpha-2 receptors, and stimulates them more effectively than adrenaline, suggesting a direct relationship between alpha-2 adrenergic receptors and COX-1 levels, whereas beta-2 receptors are directly related to COX-2 levels.

Nimesulide is a selective COX-2 inhibitory, atypical non-steroidal anti-inflammatory drug.

In this review it is shown that nimesulide, a selective cyclooxigenase-2 (COX-2) inhibitor, is different from other selective COX-2 inhibitors and classical non-steroidal anti-inflammatory drugs (NSAIDs). The anti-inflammatory effect mechanism of nimesulide (inhibition of inflammatory mediators) is similar to other classic NSAIDs, but the protective effect of nimesulide on classic NSAID-induced ulcers elucidates the difference between nimesulide and these other drugs. It is known that the selective COX-2 inhibitor nimesulide prevents NSAID-induced ulcers, while celecoxib and rofecoxib, which are more selective to COX-2, failed to prevent these ulcers. Nimesulide produces gastro-protective effects via a completely different mechanism. In addition, while selective COX-2 inhibitors increase the risk for cardiovascular diseases, nimesulide does not exert significant cardiotoxicity. This data suggests that gastrointestinal side effects of classic NSAIDs cannot be related to the COX-1 inhibition alone and also suggest that nimesulide is an atypical NSAID, which is different from both non-selective and selective COX-2 inhibitors.

Indirect role of beta2-adrenergic receptors in the mechanism of anti-inflammatory action of NSAIDS.

In this study we investigated both intact and adrenalectomized rats to determine whether or not the anti-inflammatory effects of indomethacin, diclofenac sodium, ibuprofen, nimesulide, tenoxicam and aspirin (IDINTA) are related to adrenal gland hormones in carrageenan-induced inflammation model of rats. Also, we investigated the anti-inflammatory action mechanism of hormones (adrenalin, cortisol) which perform a role in the anti-inflammatory effect of IDINTAon the adrenergic receptors. he results show that IDINTA produces significant anti-inflammatory effects in intact rats (ID(50): 9.82, 10.81, 95.21, 75.23, 8.21 and 61.84 mg/kg), but insignificant effects in adrenalectomized rats (ID(50): 152.97, 188.17, 1275.0, 433.67, 188.16 and 1028.17 mg/kg). In addition, adrenalin and prednisolone caused anti-inflammatory effect rates of 78.3% and 95.7% respectively in adrenalectomized rats. The anti-inflammatory effects of adrenalin and prednisolone did not change when prazosin (alpha(1)-receptor blocker), yohimbine (alpha(2)a2-receptor blocker) and phenoxybenzamine (alpha(2)- and alpha(2)-receptor blocker) were given to rat groups; however, in adrenalectomized rats administered with propranolol (a non-selective blocker of beta(1) and beta(2)-receptors) the anti-inflammatory effect of adrenalin was lost, and that of prednisolone decreased to 36.2%. It was also found that metoprolol (a selective blocker of beta(1)-receptors) did not alter the anti-inflammatory effects of the drugs. As a result, it was shown that anti-inflammatory effects of IDINTA are related to adrenalin and cortisol (corticosterone in rats). It was also determined for the first time that adrenalin (totally) and prednisolone (partially) triggered anti-inflammatory effects via the beta(2)-receptors but not via the alpha(1), alpha(2) and beta(1)-receptors.

Gastroprotective and antioxidant effects of amiodarone on indomethacin-induced gastric ulcers in rats.

Reactive oxygen species (ROS) have been implicated in the etiology of indomethacin-induced gastric mucosal damage. This study investigated amiodarone's protective effects against oxidative gastric mucosal damage induced by indomethacin. Amiodarone is a widely used antiarrhythmic agent. We have investigated alterations in the glutathione level, and the activities of antioxidative enzymes [superoxide dismutase, catalase, glutathione s-transferase glutathione reductase and myeloperoxidase], as markers for ulceration process following oral administration of amiodarone and ranitidine in rats with indomethacin-induced ulcers. In the present study we found that 1) amiodarone, lansoprazole and ranitidine reduced the development of indomethacin-induced gastric damages, at a greater magnitude for amiodarone and lansoprazole than for ranitidine; 2) amiodarone and ranitidine alleviated increases in the activities of catalase and glutathione s-transferase enzymes resulting from ulcers; 3) amiodarone and ranitidine ameliorated depressions in the glutathione level and the activities of superoxide dismutase and glutathione reductase enzymes caused by indomethacin administration; and 4) all doses of amiodarone amplified the myeloperoxidase activity resulting from indomethacin-induced gastric ulcers. The results indicate that the gastroprotective activity of amiodarone, which may be linked to its intrinsic antioxidant properties, cannot be attributed to its effect on myeloperoxidase activity.