Thymoquinone ameliorates amikacin induced oxidative damage in rat brain tissue.

We investigated the potential neuroprotective effects of thymoquinone (TQ) on amikacin (AK) induced oxidative damage in rat brain. We used 21 male rats divided randomly into three equal groups. The control group was injected intraperitoneally (i.p.) with 0.5 ml 0.9% aqueous NaCl and given 1 ml 0.9% aqueous NaCl orally. The AK group was administered 1.2 g/kg aqueous AK i.p. as a single dose on the day 3 of the study. The AK + TQ group was given a single 1.2 g/kg dose of AK i.p. on the day 3 of the study plus 40 mg/kg/day TQ by oral gavage daily. Treatment with TQ increased serum ferritin and decreased serum calcium levels significantly. TQ also decreased NADPH oxidase-2, NADPH oxidase-4, and caspase-3 levels. Decreased malondialdehyde (MDA) levels and increased superoxide dismutase (SOD) and catalase (CAT) activities were detected in the AK + TQ group compared to the AK group. TQ administration inhibited lipid peroxide formation and blocked oxidative reactions, which reduced the MDA level and increased SOD and CAT activities induced by AK. Oxidative damage caused by AK was ameliorated by TQ treatment owing to its antioxidative and anti-apoptotic effects. TQ may be a potential therapeutic agent for reducing the severity of AK induced oxidative damage to the brain.

Effects of cannabinoid receptor 2 synthetic agonist, AM1241, on bleomycin induced pulmonary fibrosis.

Bleomycin (BLM) is a chemotherapeutic agent that can cause pulmonary fibrosis. Little is known about the possible protective role of the CB2 receptor agonist, AM1241. We investigated the effects of CB2 receptor activation by AM1241 on BLM induced lung fibrosis in a rat model. BLM was administered via the trachea. Adult female Wistar rats were divided into five groups: saline (control group), BLM (BLM group), CB2 agonist (AM1241) + BLM (BLMA group), CB2 antagonist (AM630) and CB2 agonist (AM1241) + BLM (BLMA + A group), and vehicle (dimethylsulfoxide) + BLM (BLM + vehicle group). Hydroxyproline, collagen type 1, total protein, glutathione (GSH), malondialdehyde (MDA), interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels were measured in lung fibrosis and control tissue using standard methods. We investigated the histopathology of lung tissue to determine the extent of fibrosis. We found significantly higher levels of hydroxyproline, TNF-α, IL-6 and total protein in the BLM group compared to the BLMA group. The level of GSH also was higher in the BLMA group compared to the BLM group. Inflammation and fibrotic changes were significantly reduced in the BLMA group. Our findings suggest that CB2 receptor activation provided protection against BLM induced pulmonary fibrosis by suppressing oxidative stress and increasing cytokines.

The exogenous administration of CB2 specific agonist, GW405833, inhibits inflammation by reducing cytokine production and oxidative stress.

The present study aimed to investigate the role of cannabinoid 2 (CB2) receptors in a rat model of acute inflammation. Therefore, the potential of anti-inflammatory effects of CB2 receptor agonist (GW405833), CB2 receptor antagonist (AM630), and diclofenac, were investigated in carrageenan induced paw oedema in rats: as were assessed by measuring paw oedema; myeloperoxidase (MPO) activity in paw tissue; malondialdehyde (MDA) concentration; glutathione (GSH) level in paw tissue for oxidant/antioxidant balance; cytokine (interleukin-1ß, IL-1ß; tumour necrosis factor-α, TNF-α) levels in serum; histopathology of paw tissue for inflammatory cell accumulations. The results showed that GW405833 or diclofenac significantly reduced carrageenan-induced paw oedema. GW405833 also inhibited the increase of MPO activity, the recruitment of total leukocytes and neutrophils, and MDA concentration during carrageenan-induced acute inflammation, along with reversed nearly to the normal levels the increased of TNF-α, and IL-1ß in serum. AM630 did not affect inflammation alone however clearly reversed the effects of agonist when co-administered. The mechanism of GW405833's suppression of inflammation is supported by these results, which are achieved by the inhibition of neutrophil migration, which regulates the reduction of oxidative stress, TNF-α and IL-1ß levels. Finally, the activation of CB2 receptor, by selective agonist, has a major role in peripheral inflammation, and in the near future, targeting the peripheral cannabinoid system as a promising alternative to treat inflammation diseases may be considered a novel pharmacologic approach.

Risperidone-Induced Renal Damage and Metabolic Side Effects: The Protective Effect of Resveratrol.

OBJECTIVE: The aim of the study was to investigate the possible protective qualities of resveratrol (RSV) against the side effects of risperidone (RIS) in an experimental model in rat kidneys with histologic and biochemical assessments. MATERIALS AND METHODS: Experimental procedures were performed on 35 female Sprague Dawley rats. Rats were randomly divided into five groups: control, untreated rats (n = 7) were in group 1; group 2 was given 2 mg/kg/day RIS (n = 7); group 3 was treated with 2 mg/kg/day RIS and 20 mg/kg/day RSV (n = 7); group 4 was treated with 2 mg/kg/day RIS and 40 mg/kg/day RSV (n = 7); and group 5 was treated with 2 mg/kg/day RIS and 80 mg/kg/day RSV (n = 7). All treatments were administered for two weeks by gavage. On treatment day 15, kidney tissues were removed for analysis. RESULTS: The results showed that RSV treatment reduced weight gain induced by RIS. In addition, RSV increased the total antioxidant status (TAS) and decreased serum creatinine (Cr), blood urea nitrogen (BUN), oxidative stress index (OSI), and total oxidant status (TOS) levels significantly (p < 0.05). CONCLUSION: This study revealed that treatment with RSV might protect kidney tissues against the side effects of RIS. RSV could be an effective course of therapy to enhance therapeutic efficacy.

Effect of Caffeic Acid Phenethyl Ester on Vascular Damage Caused by Consumption of High Fructose Corn Syrup in Rats.

Fructose corn syrup is cheap sweetener and prolongs the shelf life of products, but fructose intake causes hyperinsulinemia, hypertriglyceridemia, and hypertension. All of them are referred to as metabolic syndrome and they are risk factors for cardiovascular diseases. Hence, the harmful effects of increased fructose intake on health and their prevention should take greater consideration. Caffeic Acid Phenethyl Ester (CAPE) has beneficial effects on metabolic syndrome and vascular function which is important in the prevention of cardiovascular disease. However, there are no known studies about the effect of CAPE on fructose-induced vascular dysfunction. In this study, we examined the effect of CAPE on vascular dysfunction due to high fructose corn syrup (HFCS). HFCS (6 weeks, 30% fed with drinking water) caused vascular dysfunction, but treatment with CAPE (50 micromol/kg i.p. for the last two weeks) effectively restored this problem. Additionally, hypertension in HFCS-fed rats was also decreased in CAPE supplemented rats. CAPE supplements lowered HFCS consumption-induced raise in blood glucose, homocysteine, and cholesterol levels. The aorta tissue endothelial nitric oxide synthase (eNOS) production was decreased in rats given HFCS and in contrast CAPE supplementation efficiently increased its production. The presented results showed that HFCS-induced cardiovascular abnormalities could be prevented by CAPE treatment.

Effects of captopril and angiotensin II receptor blockers (AT1, AT2) on myocardial ischemia-reperfusion induced infarct size.

The renin-angiotensin system (RAS) plays a major role in regulating the cardiovascular system, and disorders of the RAS contribute largely to the cardiac pathophysiology, including myocardial ischemia-reperfusion (MI/R) injury. Two subtypes of angiotensin II (Ang II) receptors have been defined on the basis of their differential pharmacological properties. The current study was undertaken to address the question as to whether the inhibition of the angiotensin converting enzyme (ACE) by captopril and the AT1 and AT2 receptor blockers losartan and PD123319 modulate MI/R-induced infarct size in an in vivo rat model. To produce necrosis, a branch of the descending left coronary artery was occluded for 30 min followed by two hours of reperfusion. ECG changes, blood pressure, and heart rate were measured during the experiment. Captopril (3 mg/kg), losartan (2 mg/kg), and PD123319 (20 µg/kg/min) were given in an IV 10 min before ischemia and were continued during the ischemic period. The infarcted area was measured by TTC staining. The volume of infarct and the risk zone was determined by planimetry. Compared to the control group (55.62±4.00%) both captopril and losartan significantly reduced the myocardial infarct size (30.50±3.26% and 37.75±4.44%), whereas neither PD123319 nor PD123319+losartan affected the infarct size volume (46.50±3.72% and 54.62±2.43%). Our data indicates that captopril and losartan exert cardioprotective activity after an MI/R injury. Also, infarct size reduction by losartan was halted by a blockade of the AT2 receptor. Therefore, the activation of AT2 receptors may be potentially protective and appear to oppose the effects mediated by the AT1 receptors.

Effects of misoprostol on cisplatin-induced renal damage in rats.

Cisplatin (CP) is a potent anticancer drug. However, it has side effects on kidney such as nephrotoxicity. Abnormal production of reactive oxygen species (ROS) has been accused in the etiology of CP-induced nephrotoxicity. Several ROS scavengers have been reported to prevent nephrotoxicity after CP administration. In this study, we used prostaglandin E1 (PGE1) analogues misoprostol (MP) to reduce this damage. MP has gained considerable interest as a ROS scavenger. Rats were received a single injection of CP (5 mg/kg, i.p.) with or without MP pretreatment (200 mcg/kg, orally). The renal tissue morphology was investigated by light microscopy. Trunk blood was also obtained to determine lipid peroxidation product malondialdehyde (MDA) and activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT). CP administration increased MDA production and decreased SOD and CAT levels in the kidney tissue when compared to the control group. Morphological damage in CP administrated rats was also severe in the kidney tissue. MP treatment after CP application protected the renal tissues from CP's side effect. These findings indicate that MP has beneficial effects on CP induced nephrotoxicity in rats.

Effects of aspirin and nimesulide on tissue damage in diabetic rats.

This study was designed to compare the effect of Aspirin (AS) and Nimesulide (NM) on renal failure and vascular disorder in streptozotocin (STZ)-induced diabetic rats. Rats were divided into four groups; control, diabetic rats, diabetic rats plus AS and diabetic rats plus NM, which are COX inhibitors. The renal and aorta tissues morphology were investigated by light microscopy. Trunk blood was also obtained to determine plasma lipid peroxidation product malondialdehyde (MDA) and plasma activity of antioxidant enzymes. MDA levels were increased in the diabetic rats when compared to the control group. AS and NM administration caused a significant decrease in MDA production. Morphological damage in diabetic rats was severe in the kidney and in the aorta tissue. Treatment of AS reduced these damages, but NM did not exert positive effect on these damages in diabetic rats. As a result, although both AS and NM corrected lipid peroxidation parameters such as MDA via their antioxidant properties, only AS ameliorated pathological alteration in tissues. These findings indicate that there may be another mechanism in beneficial effect of AS in diabetic rats.

Effects of pentoxifylline on amikacin-induced nephrotoxicity in rats.

The nephrotoxicity of amikacin (AK) was prevented with pentoxifylline (PTX) in a rat model. Rats were received a single injection of AK (1.2 g/kg, i.p.) with or without PTX pretreatment (25 mg/kg, orally). Renal morphology was investigated by light microscopy. Tissue samples and trunk blood were also obtained to determine renal malondialdehyde (MDA), blood urea nitrogen (BUN), and creatinine (Cr) levels. MDA production was found to be higher in AK group. PTX administration caused a significant decrease in MDA production. Morphological damage in rats given AK was severe in the kidney, whereas in rats given AK plus PTX, no histological changes occurred. It is concluded that PTX could be useful for reducing the nephrotoxic effects of AK.

Investigating the protective effect of melatonin on liver injury related to myocardial ischemia-reperfusion.

BACKGROUND: An animal model of myocardial ischemia-reperfusion (MI/R) was used to test the hypothesis that free radicals released with MI/R have hazardous effects on liver through remote organ injury. MATERIAL/METHODS: Twenty-one rats were divided into three groups: sham-treated, MI/R, and MI/R+melatonin. To produce MI/R, a branch of the left coronary artery was occluded for 30 min followed by two hours of reperfusion. Melatonin or vehicle was given 10 min before ischemia. At the end of the study, liver tissue was obtained for biochemical determination. The false discovery rate (FDR) is explained and was used for multiple comparisons of the groups' means. RESULTS: Compared with the sham group, MI/R significantly decreased glutathione (GSH) content and increased levels of nitric oxide (NO) and malondialdehyde (MDA). Melatonin administration significantly increased GSH levels and decreased the levels of NO and MDA compared with the MI/R group. CONCLUSIONS: Melatonin could prevent liver damage due to its strong antioxidant and free radical scavenger effects. Therefore, melatonin may have beneficial effects on remote organ injury such as MI/R-induced liver disorders.

Renal damage in rats induced by myocardial ischemia/reperfusion: Role of nitric oxide.

BACKGROUND: It has been demonstrated that myocardial ischemia/reperfusion (MI/R) causes renal damage. However, the mechanism underlying this damage in kidneys during revascularization of myocardium is unclear. Direct renal ischemia/reperfusion has been implicated in the induction of inducible nitric oxide synthase (iNOS) that leads to increase production of nitric oxide (NO). Recently, excessive production of NO has been found to be involved in causing renal injury by formatting peroxinitrite (ONOO(-)). The aim of this study was to investigate whether NO has a role in this damage, using aminoguanidine (AMG), a known iNOS inhibitor and an antioxidant, in rats undergoing MI/R. METHODS: Male Wistar rats were used for the experiments (n = 7 each group). In the MI/R group, the left coronary artery was occluded for 30 min and then reperfused for 120 min; the same procedure was used for the AMG group, with the additional step of AMG (200 mg/kg) administered 10 min prior to ischemia. A control group underwent sham operation. At the end of the reperfusion period, all rats were killed and their kidneys removed for biochemical determination and histopathological analysis. RESULTS: Myocardial ischemia/reperfusion in the rat kidney was accompanied by a significant increase in malondialdehyde and NO production, and a decrease in glutathione content. Administration of AMG reduced malondialdehyde and NO production and prevented depletion of glutathione content. These beneficial changes in the biochemical parameters were also associated with parallel changes in histopathological appearance. CONCLUSION: These findings suggest that MI/R plays a causal role in kidney injury and AMG exerts renal-protective effects, probably by inhibiting NO production and antioxidant activities.

Ameliorating role of caffeic acid phenethyl ester (CAPE) against isoniazid-induced oxidative damage in red blood cells.

Isoniazid (INH) still remains a first-line drug both for treatment and prophylaxis of tuberculosis, but various organs toxicity frequently develops in patients receiving this drug. We aimed to investigate possible toxic effects of INH on rat red blood cells (RBCs), and to elucidate whether Caffeic acid phenethyl ester (CAPE) prevents a possible toxic effect of INH. Experimental groups were designed as follows: control group, INH group, INH + CAPE group. Compared with the control, the INH caused a significant increase in superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels, and a decrease in glutathione peroxidase (GSH-Px) and catalase (CAT), which are recently used to monitor the development and extent of damage due to oxidative stresses. CAPE administration to INH group ameliorated above changes due to INH.

Protective effects of caffeic acid phenethyl ester (CAPE) on amikacin-induced nephrotoxicity in rats.

Amikacin (AK) has nephrotoxic side effects. AK-induced nephrotoxicity may be the consequence of oxidative stress and so anti-oxidant agents could be useful in reducing AK toxicity. Caffeic acid phenethyl ester (CAPE) was recently shown to have free radical scavenging ability and it reduces lipid peroxidation. For this purpose, the rats were distributed into three groups: (I) injected with vehicle (control); (II) injected (i.p.) with 1.2 g kg(-1) AK at a single dose; (III) injected (i.p.) with AK plus 10 micromol kg(-1) CAPE. Renal morphology was investigated by light microscopy. Tissue samples and trunk blood were also obtained to determine renal malondialdehyde (MDA), blood urea nitrogen (BUN) and creatinine (Cr) levels. MDA production was found to be higher in rats given AK than among control rats. CAPE administration before AK injection caused a significant decrease in MDA production. Morphological tubule damage in rats given AK was severe in the renal cortex, whereas in rats given AK plus CAPE, no histological changes occurred. It is concluded that CAPE could be useful for reducing the nephrotoxic effects of AK.

Effect of aminoguanidine on ischemia-reperfusion induced myocardial injury in rats.

Myocardial ischemia-reperfusion (MI/R) has been implicated in the induction of inducible nitric oxide synthase (iNOS) that leads to increase production of nitric oxide (NO). Recently, excessive production of NO has been involved in causing myocardial injury. In our in vivo model, we examined the effects of aminoguanidine (AMG), a known iNOS inhibitor, on percentage infarct size in anaesthetized rats. A total of 14 rats were equally divided into two groups (n = 7 in each group). To produce myocardial necrosis, the left main coronary artery was occluded for 30 min, followed by 120 min of reperfusion, in anesthetized rats. AMG (200 mg kg(-1)) was given intravenously 10 min before occlusion. The volume of infarct size and the risk zone were determined by planimentry of each tracing and multiplying by the slice thickness. Infarct size was normalized by expressing it as a percentage of the area at risk. Hemodynamic parameters were measured via the left carotid artery. Compared to MI/R group, whereas AMG administration elevated mean arterial blood pressure, statistically reduced the myocardial infarct size (21+/- 1 and 14+/- 4%, respectively) and infract size/risk zone (53+/- 3 and 37+/- 5%, respectively) in rat model of ischemia-reperfusion. In conclusion, this study indicates that iNOS inhibitor, AMG, show reduction in NO's side effect in I/R injury.

Ischemia-reperfusion leads to depletion of glutathione content and augmentation of malondialdehyde production in the rat heart from overproduction of oxidants: can caffeic acid phenethyl ester (CAPE) protect the heart?

During restoration of blood flow of the ischemic heart induced by coronary occlusion, free radicals cause lipid peroxidation with myocardial injury. Lipid peroxidation end-products, such as malondialdehyde (MDA), have been used to assess oxygen free radical-mediated injury of the ischemic-reperfused (I/R) myocardium in rats. This experimental study assessed the preventive effect of caffeic acid phenthyl ester (CAPE), antioxidant, on I/R-induced lipid peroxidation in the rat heart. We are also interested in the role of CAPE on glutathione (GSH) levels, an antioxidant whose levels are influenced by oxidative stress. I/R leads to the depletion of GSH which is the major intracellular nonprotein sulphydryl and plays an important role in the maintenance of cellular proteins and lipid in their functional state and acts primarily to protect these important structures against the threat of oxidation. In addition, we also examined morphologic changes in the heart by using light microscopy. The left coronary artery was occluded for 30 min and then reperfused for 120 min more before the experiment was terminated. CAPE (50 microM kg(-1)) was administered 10 min prior to ischemia and during occlusion by infusion. At the end of the reperfusion period, rats were sacrificed, and the heart was quickly removed for biochemical determination and histopathological analysis. I/R was accompanied by a significant increase in MDA production and decrease in GSH content in the rat heart. Administration of CAPE reduced MDA production and prevented depletion of GSH content. These beneficial changes in these biochemical parameters were also associated with parallel changes in histopathological appearance. These findings imply that I/R plays a causal role in heart injury due to overproduction of oxygen radicals or insufficient antioxidant and CAPE exert cardioprotective effects probably by the radical scavenging and antioxidant activities.

Myocardial ischemia/reperfusion-induced oxidative renal damage in rats: protection by caffeic acid phenethyl ester (CAPE).

Myocardial ischemia-reperfusion (MI/R) may induce renal damage. A rat model of M/IR injury was established. The left coronary artery was clamped for 30 min, constituting the ischemic period, and was then released for 120 min, thus constituting the reperfusion period. The purpose of this study was to evaluate the effects of caffeic acid phenethyl ester (CAPE), an antioxidant, on renal dysfunction in rats undergoing MI/R. CAPE (50 mumol/kg) was administered by infusion 10 min before ischemia and during occlusion. Hemodynamic changes were recorded during the different periods. At the end of the reperfusion period, rats were sacrificed, and the kidneys were quickly removed for biochemical determination and histopathological analysis. MI/R was accompanied by a significant increase in malondialdehyde (MDA) production and decrease in glutathione (GSH) content in the rat kidney. Administration of CAPE reduced MDA production and prevented depletion of GSH content. These beneficial changes in these biochemical parameters were also associated with parallel changes in histopathological appearance. These findings imply that MI/R plays a causal role in kidney injury through overproduction of oxygen radicals or insufficient antioxidant, and CAPE exerts renal-protective effects probably by its radical scavenging and antioxidant activities.