possible protective effect of exroxisome proliferator-activated receptors-gamma [PPAR-gamma]-agonist in middle cerebral artery occlusion-induced focal cerebral ischemia in rats

Focal cerebral ischemia [st, oke] is a leading cause of death and disability among adult population. Many pathological events including inflammation and oxidative stress during the acute period contribute to the secondary neuronal death. Peroxisome prohferator-activated receptors [PPARs] are ligand-activated transcription factors known to upstream to many inflammatory and antioxidant genes. The present study was carried out to evaluate the physiological role of PPAR-gamma and possible neuroprotective effects of its agonist, rosiglitazone, in experimentally induced focal cerebral ischemia in rats. The current study was conducted on 30 male albino rats [180-220 gm], they were divided into 3 groups: Group 1: included 10 normal healthy control rats that were sham operated. Group 2: included 10 rats that were subjected to middle cerebral artery occlusion [MCAO] induced focal cerebral ischemia for 2 h followed by reperfusion for 22 h. Group 3: included 10 rats that were pretreated with rosiglitazone 3mg/kg body weight orally for 7 days followed by MCAO induced focal cerebral ischemia. The following parameters were assessed in all rats of the studied groups: Serum levels of both tumor necrosis-alpha [TNF-alpha] and interleukin-6 [IL-6] and cerebral cortex tissue levels of glutathione reductase [GR], reduced glutathi one [GSH] and glutathi one peroxidase [GPx] The present study revealed that the induced focal cerebral ischemia in rats of group2 was associated with a statistical sign ifi cant increase in serum levels of both TNF-alpha and IL-6 as compared to normal controls. Pretreatment of rats with rosiglitazone in group3 resulted in a statistical significant reduction of the TNF-alpha and IL-6 levels as compared to group2 [This reflects that the ischemic neuronal injury is associated with massive inflammatory processes that lead to brain damage]. And treatment with rosiglitazone could have an anti-inflammatory neuroprotective role. Considering the brain tissue levels of GR, GSH and GPx, which are tissue oxidant defense mechanisms, the present study showed that focal cerebral ischemia in rats of group2 led to a statistical signfi cant reduction in their levels as compared to control group indicating that cerebral ischemia and reperfusion are responsible for oxidative stress by generation of free radicals which culminate to serious damaging effect and overproduction of free radicals takes the upper hand and predominates the detoxication and scavenging capacity of cellular antioxidant enzymes. Treatment of rats with rosiglitazone before induction of focal cerebral ischemia led to a statistical significant increase in the brain tissue levels of defense antioxidant enzymes as GR and GPx as well as GSH assuming its potential neuroprotective role which could be due to its ability to increase the natural defense mechanisms in case of ischemic oxidative stress. PPAR-gamma agonist [rosiglitzone] could be the drug of use in stroke therapy due to its potential to influence multiple molecular mechanisms by its ability to minimize both the inflammation and oxidative stress and at the same time promotes the antioxidant defense mechanisms and protein chaperones

comparative study of the effect of peroxisome proliferator activated receptor gamma agonist and angiotensin converting enzyme inhibitor on experimental pancreatitis in rats

There is accumulating evidence that peroxisome proliferators-activated receptor gamma [PPARgamma] plays important roles in the processes of fat metabolism, adipocyte differentiation, tumorigenesis, inflammation, and a variety of immune processes. Thiazolidinediones [TZDs], including rosiglitazone, are high-affinity ligands for [PPAR-gamma] and are used as insulin-sensitizing drugs. They inhibit chernokines [interleukin-8] in epithelial cells, leading to the suggestion of their use in inflammation. Angiotensin-converting enzyme [ACE] inhibitors are commonly prescribed to reduce the risk of myocardial infarction and cardiovascular death. They also modulate proinflammatory signals and reduce macrophage accumulation. Thus, they may have beneficial action in various inflammatory conditions. The present study aimed to investigate the possible anti-inflammatory effects of [PPAR] gamma agonist [rosiglitazone] and ACE inhibitor [lisinopril] in cerulein-induced chronic pancreatitis [CP] in rats. Also to compare between their actions, separately or in combination, in CP. Fifty male albino rats weighing from 150-200 gm were included in this study. Rats were divided into two main groups. Group 1, [10 rats] served as a control group, they were received 1 ml physiological saline [0.9%], by intraperitoneal [i.p.] injections six hourly, three times a week for three weeks. Group II: cerulein-induced CP group [40 rats] injected with cerulein i.p. in a dose of 50 microg/kg.b.wt. six hourly, three times a week for three weeks. Rats were further subdivided into A, B, C, and D, each often rats. Group- A received 1ml of 2% gum acacia daily orally for two weeks starting from the third week of cerulein administration. Groups B and C treated with rosiglitazone in a dose of 3 mg/kg.b.wt. or lisinopril in a dose of 2.5 mg/kg.b.wt orally daily for the same previous duration. Group-D, treated with both drugs for the same previous doses and duration. I.p. injection of cerulein produced significant increases in serum levels of amylase, tumor necrosis factor-alpha [TNF-alpha] and transforming growth factor-beta 1 [TGF- beta1] with elevations of pancreatic tissue content of hydroxyproline [HPO] and myeloperoxidase [MPO] activity. Rosiglitazone and lisinopril produced improvement of CP manifested by the significant decreases in the previous measured parameters, but rosiglitazone, provided a better effect. Combined administration of rosiglitazone and lisinopril, produced marked and superior ant-inflammatory and antifibrotic actions. I.p. injection of cerulein is a reliable method for induction of CP resembles the human CP. RAS proved to be incriminated in the pathogenesis of CP as evidenced by the effective therapeutic effect of lisinopril in cerulein-induced CP. Rosiglitazone, provided a better effect than lisinopril, reflecting the important role of PPARgamma in CP. The combination of both drugs proved to be superior in alleviated chronic pancreatitis which may be due to the synergistic anti-inflammatory, anti-oxidant and antifibrotic effects of these drugs

possible cytoprotectiye effect of vitamins C and E and L-carnitine on monosodium glutamate induced oxidative stress in the rat

Monosodium glutamate [MSG] consumption has increased throughout the world as flavoring agent in cooking. However, consumption of a highly palatable diet has been shown to cause endothelial dysfunction, cardiovascular disease and various age-related degenerative disease processes long before development of any significant obesity. The major purpose of the present study was to investigate the effects of MSG on glucose metabolism, lipid profile and oxidative stress. A secondary purpose was to determine the possible protective effect of vitamin C, vitamin E and L-carnitine [LC], separately or in combination in MSG inducing oxidative stress in the rat. Sixty male albino rats weighing from 100-150 g were included in this study. Rats were divided into two main groups. Group 1, [10 rats] served as a control group for group II, and were received 1 ml of physiological saline [0.9%], daily subcutaneously [s.c.] for eight weeks. Group II: MSG -induced oxidative stress [50 rats] injected s.c. MSG in a dose of 200 mg/kg.b.wt. daily for eight weeks. Rats were further subdivided into A, B, C, D and E, each of ten rats. Group- A, received 1 ml of 2% gum acacia daily orally for eight weeks starting from the first day of MSG administration. Groups B, C, D treated with orally daily vitamin C in a dose of 100 mg/kg.b.wt. or vitamin E in a dose of 10 mg/kg.b.wt. or L-carnitine in a dose of 200 mg/kg.b.wt for the same previous duration. Group-E, received vitamins C, E and LC in the same previous doses and durations. S.C. injections of MSG produced significant increases in body weight, serum levels of glucose, insulin, leptin, total cholesterol, LDL-cholesterol and triglycerides, while HDL- cholesterol and Apo A 1 were significantly decreased. There were insignificant changes in serum iron, ferrritin and total iron binding capacity [TIBC] The levels of glutathione and the activities of both catalase and superoxide dismutase [SOD] in heart, liver and kidney were significantly decreased. In addition, there were significant decreases in both basal arid insulin stimulated glucose uptake by the soleus muscle and fatty tissue of the rat. Intake of vit. C or vit. E or LC, reduced the abnormalities in body weight, glucose metabolism, lipid profile and antioxidant enzymes. Also, they procducd a significant increase in both basal and insulin stimulated glucose uptake by the soleus muscle and fatty tissue of the rat. Still vit. C revealed better effects as compared to the corresponding groups. The combination of vit. C and E and LC was found to be the best as shown by the correction of glucose metabolism, lipid profile and highest levels of antioxidant enzymes as compared to the corresponding groups. MSG enhanced food intake. Overfeeding induced metabolic disorders associated with oxidative stress. The present study provides evidence that combination of antioxidant vitamins C and E with LC combat metabolic disorders and oxidative stress induced by MSG. Thus, sufficient dietary intake of these vitamins with LC is beneficial in combating MSG adverse effects

possible role of peroxisome proliferator-activated receptors agonists in the vascular reactivity and myocardial changes induced by long-term blockade of nitric oxide synthesis in the rat

Peroxisome proliferator-activated receptors [PPARs] are a family of ligand-activated nuclear transcription factors. PPAR alpha and gamma are the most extensively key modulators of lipid and glucose homeostasis. They are predominantly expressed in adipose tissues, some non adipose tissues including heart, kidney, spleen, and all relevant cells of the vasculature: endothelial cells, smooth muscle cells, and macrophages. The vascular distribution suggests their involvement in the control of cardiovascular function. The present experimental work was designed to study the effects of fenofibrate and rosiglitazone treatment on blood pressure, antioxidant enzymes, vascular reactivity and cardiac hypertrophy in N[G]-nitro-L-arginine methyl ester [L-NAME] induced hypertension in rats. Fifty male albino rats weighing from 150-200 g were included in this study. Rats were divided into two main groups. Group 1, [10 rats] served as a control group for group II, and was received 1 ml of physiological saline [0.9%], orally for seven weeks.Group II: hypertensive group [40 rats] was given daily L-NAME in a dose of 40 mg/kg orally for seven weeks. Rats were further subdivided into A, B, C, and D, each of ten rats. Group- A, received 1ml of 2% gum acacia daily orally for six weeks, starting one week after L-NAME administration.Groups B,C and D treated with daily fenofibrate [30 mg / kg.b.wt. orally] and rosiglitazone [3 mg / kg.b.wt.], alone or together for six weeks. Blood pressure, serum tumor necrosis factor- alpha [TNF- alpha], body weight [BW] and heart weight [HW] were measured. Malondialdehyde [MDA] and reduced glutathione [GSH] were estimated in cardiac tissues. Thoracic aorta was isolated and the aortic rings were allowed to achieve maximal tension by cumulative addition of phenylephrine [PE] [10[-9]-10[-5] M] to the bath solution. Fenofibrate and rosiglitazone, alone or together produced significant decreases in blood pressure and TNF- alpha. Higher oxidative stress accompanying hypertension was significantly reduced by fenofibrate and rosiglitazone treatment. The results showed that both drugs significantly attenuated the augmented contractile response to PE in hypertensive rats. In addition, they inhibited the cardiac hypertrophy [reduction in HW/BW ratio]. These data suggest that PPAR alpha and gamma activation contribute to normal regulation of blood pressure and exert protective actions in hypertension via inhibition of generation of free radicals

Evidence for anti-inflammatory activity of captopril

Captopril is an inhibitor of angiotensin-converting enzyme [ACE] that is largely used in the treatment of cardiovascular diseases. Several previous studies have demonstrated that exhibits a wide variety of biological activities, including an anti-inflammatory action. The present study was investigated the efficacy of captopril on inflammation, in two rat models, carrageenan- induced paw edema and trinitrobenzene sulphonic acid [TNBS]-induced colonic inflammation. In treatment groups, the rats were treated with captopril [0.1,0.5 and 1 mg/kg/day, intraperitoneally]. The drug was given 5 min after induction of paw edema or colitis and the treatment was continued daily for 3 days. Daily measurement of paw edema was done. Three days after the induction of colitis, all rats were decapitated. The distal colon was isolated and the mucosal lesions were scored at macroscopical levels. Malondialdehyde [MDA], glutathione [GSH] levels and myeloperoxidase [MPO] activity were assessed in tissue samples. Tumor necrosis factor- alpha [TNF- alpha] was measured in the serum. Captopril treatment was found to be beneficial in all parameters in dose dependent manner. In conclusion, sulphydryl ACE inhibitor, captopril seems to be effective in both models of inflammation at least at the doses tested in this study

possible beneficial effects of HMG-CoA- reductase inhibition and renin-angiotensin system blockade on experimental atherosclerotic mice

Hypertension and dyslipidemia are often present in the same patient, their treatment frequently involves both statins and renin-angiotensin system[RAS] inhibitors. The present study aimed at clarifying the potentially additive effects of a combined treatment, 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA]-reductase inhibitors [statins] and RAS blockade. We hypothesised that the adjunction of simvastatin with losartan or ramipril might achieve synergistic effects on experimental atherosclerosis through prevention of atherosclerotic plaque progression and achieve plaque stabilization.The study was conducted on forty two male albino mice, divided into 7 groups, each of 6 mice. One served as a normal control group. The other 6 groups were fed a high-fat diet for 12 weeks and divided into either placebo [control +], simvastatin [SIM], ramipril [RAM], losartan [LOS] or RAM+SIM and LOS+SIM. RAS-blockade, but not SIM, reduced systolic blood pressure. SIM alone or in combined therapy, lowered systemic cholesterol levels and lipoprotein fractions. Additive effects of the adjunction were observed on interleukin [IL]-6 and IL-10. These results indicate that a combined treatment with RAS-blockade and statins may have additive effects on systemic cardiovascular risk markers

Effect of some hypolipidemic drugs on glycemic control, lipid profile and some oxidative indiced in experimental hyperlpidemic diabetic rats

Diabetic patients, especially those with type-2 diabetes, are at a higher risk of developing cardiovascular disease. The specific pattern of diabetic dyslipidaemia, hyperglycemia, hyperinsulinemia, increased oxidative stress and inflammatory cytokines are co-operative factors for increasing cardiovascular morbidity and mortality in these patients. The present study was conducted to investigate the impact of different antidyslipidemic agents on these risk factors in a rat model of diabetic dyslipidaemia with hyperinsulinemia. A total of 70 rats were involved in the study; 10 of which served as a normal control group. The remaining rats were lipid-fed and streptozotocin [STZ]-injected, and were randomly assigned to no treatment [control group] or to 2-month treatment with pravastatin, fenofibrate, cholestyramine, nicotinic acid or fish oil. The lipid-fed STZ-injected rats developed high fasting serum glucose and glycated hemoglobin [HbAlc] levels together with hyperinsulinemia. They also acquired the characteristic pattern of diabetic dyslipidemia, i.e. increased levels of low density lipoprotein-cholesterol [LDL-C] and triglycerides [TG], and decreased high density lipoprotein-cholesterol [HDL-C] level. This was associated with increased markers of oxidative stress and inflammation "increased serum levels of malondialdehyde [MDA] and tumor necrosis factor-alpha [TNF-c_ together with decreased concentration of reduced glutathione and superoxide dismutase [SOD] activity in liver and kidney' Both pravastatin and fenofibrate significantly decreased serum cholesterol, LDL-C and TG, and increased serum HDL-C. However, only fenofibrate could normalize serum levels of HDL-C and TG. Cholestyramine significantly decreased serum levels of total cholesterol and LDL-C but increased the serum level of TG. Nicotinic acid produced significant decreases in serum TG and LDL-C levels and a significant increase in serum HDL-C level. Fish oil only significantly decreased the serum TG level. Fenofibrate and fish oil produced significant decreases in serum glucose, HbAJc and serum insulin levels. Pravastatin only decreased serum insulin level significantly. Cholestyramine did not affect the glycemic control, Nicotinic acid, on the other hand, produced significant increases in serum glucose, HbAlc and serum insulin levels. .Pravastatin, fenofibrate and fish oil decreased the oxidative stress and serum level of TNF-a. On the other hand, cholestyramine and nicotinic acid did not significantly change any of the studied oxidative and inflammatory parameters. Major outcome clinical studies are required to compare the effect of the most promising agents, pravastatin, fenofibrte, fish oil and/or their possible combinations on the overall mortality and morbidity in diabetic dyslipidemic patients

possible protective effect of some drugs on hepatic ischemia / reperfusion injury

This work aimed to clarify the possible protective effect of verapamil, allopurinol, dimethyl sulfoxide [DMSO], N-acetylcysteine [NAC], pentoxifylline [PTX] on hepatic injury induced by acute ischemia, followed by reperfusion in normal rats and rats sensitized to oxidative injury by depletion of endogenous glutathione. 84 male rats were randomized into seven groups. One served as a control group and the other groups were treated either with vehicle or with one of the previously mentioned drugs prior to induction of ischemia. The present study showed that ischemia/reperfusion [IR] significantly decreased hepatic glutathione [GSH] in both normal and GSH-depleted rat groups. All the tested drugs significantly prevented this reduction in both groups. Ischemia/reperfusion injury significantly increased hepatic malonyldialdehyde [MDA] level only in GSH-depleted rats. Hepatic myeloperoxidase [MPO] activity was significantly increased both in normal and GSH-depleted rats subjected to ischemia/reperfusion injury. Pretreatment with PTX significantly prevented this increase in hepatic MPO activity. Other tested drugs could not exert any protective effect

Evaluation of the hepatoprotective effect of some drugs in paracetamol-induced liver cell toxicity in the rat

This study aimed to clarify the hepatocellular injury induced by paracetamol and the possible hepatoprotective effect of fructose, cocktail of fructose, cyclosporin A and trifluoperazine, Nigella sativa oil, vitamin C and vitamin E