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

Do desipramine and fluoxetine ameliorate the extent of colonic damage induced by acetic acid in rats?

The present study was aimed to compare the anti-inflammatory and antioxidant effects of two antidepressant drugs; desipramine and fluoxetine, administered in two different doses, on experimentally induced colitis in rats. Two doses for each drug [10, 20 mg/kg/d] were injected intraperitoneally in forty eight adult male albino rats for 2 weeks after induction of colitis by intra-colonic administration of 2ml 3% acetic acid. Several parameters including, macroscopic [ulcer score index], microscopic [histological] and biochemical such as myeloperoxidase [MPO], reduced glutathione [GSH], tumor necrosis factor alpha [TNF-alpha] and interleukin-1 Beta [IL-1beta] were measured using standard assay procedures. The study demonstrated that both desipramine and fluoxetine significantly attenuated the extent and the severity of the macroscopic and microscopic histological signs of cell damage. Both drugs significantly reduced tissue MPO activity in a dose dependent manner. Both desipramine and fluoxetine at either dose increased significantly the GSH in colonic tissue. On the contrary, both desipramine and fluoxetine significantly reduced TNF-alpha and IL-beta in a dose dependent manner. However, desipramine at the dose of 20 mg/kg produced more decrease in the level of TNF-alpha compared to the effect of the smaller dose, and on the contrary, fluoxetine at the dose of 10 mg/kg showed more decrease in the level of IL-beta compared to the effect of the larger dose. The available data indicate that both desipramine and fluoxetine have anti-inflammatory and antioxidants effects in experimentally induced colitis in rats opening the avenue to their possible protective role in patients with inflammatory bowel disease

Role of nigella sativa oil, thymoquinone with and without pyrimethamine in freund's adjuvant arthritis in rat

Nigella sativa oil and its active principal thymoquinone have been screened for their beneficialeffects that had been attributed to their cytoprotective, antioxidant actions and to their effect on many mediators ofinflammation. Similarly, pyrimethamine [PY], which is well known for its anti-parasitic action for a long time, hasbeen reported to have immunomodulating and apoptotic activities. The aim of the present study was to investigate the effect of Nigella sativa oil [NSO] andthymoquinone [TQ] in Freund's adjuvant arthritis [AA] in rats, an immunological experimental model of arthritiseither by sole administration of each of them or by their combination with pyrimethamine. The pain response and polyarthritis index were scored. Certain biochemical markers of inflammation,namely, interleukin-6 [IL-6], leukotriene B[4][LTB[4]], Matrix metalloproteinase-9 [MMP-9] were measured.Oxidative stress indices; reduced glutathione [GSH], erythrocytic superoxide dismutase [SOD] activity andmalondialdehyde [MDA] were also assayed in the sera of studied rats. The study demonstrated secondary inflammatory reactions in adjuvant arthritic rats [AA] as compared tothe control non- arthritic group. The study also revealed significant suppression of these secondary inflammatoryreactions as guided by reduction in the mean values of both polyarthritis index and pain response score in AA-treated rats. Significant reduction in IL-6, LTB[4], MMP-9 in the serum of treated groups was observed. This wasaccompanied with a significant increase in GSH serum level together with reduction of MDA levels in the treatedgroups. SOD activity did not change with the observed protection obtained by the studied drugs. PY + TQ, then PY + NSO, TQ and lastly NSO had reduced secondary reaction to Freund's adjuvantinoculation when used in the day of inoculation up to 20 days. It can be also concluded that combination with PYenhanced the chemoprotective effects of both TQ and NSO. Further experimental and clinical trials have to bedone for further screening of such combinations

Role of the trace metals, selenium and zinc, in pilocarpine-induced epilepsy in rats

Excitotoxic brain lesions, such as epilepsy, lead to increasing destruction of neurons, in the course of few hours after the insult. The deadly cascade of events possibly involves detrimental actions by free radicals, proinflammatory cytokines and the activation of pro-apoptotic transcription factors, which finally result in neuronal destruction. Several reports suggest that the level of some trace elements play a vital role in seizure conditions to prevail. The aim of the present study was to assess the possible modulatory role of the trace elements, selenium and zinc on pilocarpine-induced epilepsy in rats.The study was carried out on 40 male albino rats, weighing 150-200 grams that were divided into the following groups each of 10 rats: Group I: control rats that received intraperitoneal [i.p.] saline, Group II: pilocarpine induced epilepsy, Group 111: selenium pretreated for 3 weeks before pilocarpine injection and Group IV: zinc pretreated for 3 weeks before pilocarpine injection. The seizure latency and severity for each rat was recorded. Twenty four hours following pilocarpine injection, rats were exsanguinated and the following parameters were determined: cerebral caspase-3 activity [as a marker of apoptosis], interleukin-lbeta [IL-ljB], reduced glutathione [GSH] and malondialdehyde [MDA] concentrations, serum neuron specific enolase[NSE] concentration [as a marker of brain injury].Intraperitoneal injection of pilocarpine in rats resulted in progression to limbic seizures with progressing behavioural scores at various time intervals [recorded every 30 minutes up to 2 hours]. Latency to forelimb clonus was 51.86 +/- 1.89 min. The results of the present study demonstrated significantly increased cerebral MDA concentration together with significant decrease in cerebral GSH concentration in non-treated pilocarpine injected rats compared to normal control rats. A significant increase in cerebral caspase-3 activity, and in cerebral 1L-1/beta as well as in serum NSE concentrations could be observed in non-treated pilocarpine-injected rats compared to normal control rats. Pretreatment with selenium or zinc reduced the severity of pilocarpine- induced seizures. In addition, both trace elements decreased the latency to attain the forelimb clonus [score 4]. A significant decrease in cerebral MDA and IL-1/beta, serum NSE concentrations could be observed in selenium and zinc-treated rats compared to non-treated pilocarpine-injected rats. A significant' increase in cerebral GSH concentration was observed in zinc-treated, but not in selenium-treated ones.The results of the present study confirm the role of the trace elements, selenium and zinc, in mitigating epilepsy. Further human studies to evaluate the role of trace elements in epilepsy are recommended. Furthermore, since antiepileptic drugs [AEDs] are reported to induce zinc and selenium deficiency,thus combining these trace elements with AEDs are worthy to be evaluated

Role of simvastatin, tetrandrine and candesartan in experimental induced liver fibrosis in rats

Liver fibrosis which insidiously and frequently develops to cirrhosis showed implications of manymitogenic and fibrogenic cytokines such as tumor necrosis factor a [TNF alpha] and transforming growth factor beta [TGF- beta] respectively. Moreover, the chemoattractant effect of reactive oxygen metabolites which recruit Kupffercells, hepatic stellate cells [HSCs]and other inflammatory cells makes more cytokine release and production ofextracellular matrix [ECM] proteins and myoflbroblast mitogens.In this study, three drugs were chosen, each of them is supposed to act by a quite differentmechanism in thioacetamide [TAA] experimental model of hepatic fibrosis in rats. Simvastatin, an example ofHMG Co A reductase inhibitor. Tetrandrine, an alkaloid with calcium channel blocking property and Candesartanas a receptor blacker for angiotensin II.This study was carried out on 40 male albino rats,8 rats served as normal controls, while in the other32 rats liver fibrosis was induced by intraperitonial TAA injection. The incidence of fibrosis or its protection wasassessed by intrasplenic pressure measurement, spleen /body weight ratio, liver hydroxyproline [HPO] contents,serum TNF alpha and TGF- beta levels, oxidative stress parameters as reduced glutathione [GSH] and malondialdehyde [MDA] levels were measured. In addition to liver transaminases and tissue inhibitor of matrix metalloproteinase [TIMP-1] activities.In the present study Six weeks administration of TAA resulted in significant rise in portal blood pressureas compared to saline control rats; associated with a significant reduction in hepatic GSH contents and asignificant increase in hepatic HPO and serum MDA concentration in TAA group as compared to all groups.Meanwhile, there were significant increases in serum levels of TNF- alpah, TGF- 01, and TIMP-lactivity in TAA ratsas compared to control group . There were also statistical significant reduction in the cytokine levels and inhibitorof metalloproteinase activities in Simvastatin, Tetrandrine and Candesartan groups as compared to TAA nontreated group.The same was the effect on liver function tests; there were significant higher serum activities of aspartateaminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALB] and y - glutamyl transferase [GGT] in TAA group as compared to saline control group. However, these serum enzymes activities showedsignificant reduction in the drug treated groups Simvastatin, Tetrandrine and Candesartan respectively. The studyfailed in detecting any significant statistical difference between the degree of protection against TAA inducedfibrosis that had been exerted by the three drugs used in the study.It was concluded that both Tetrandrine and Candesartan have marked protective effects in TAAinduced liver fibrosis by more than one mechanism .Simvastatin had a modest effect that may be by its antioxidanteffect. Clinical trials are recommended to support or disprove these results

ACE inhibitors or ATI antagonists protect against an experimental model of pulmonary fibrosis in rats?

A common side effect to cytotoxic antibiotic bleomycin [BLM] is interstitial pneumonitis with progressive pulmonary fibrosis. At the same time, some of the angiotensin renin system [RAS] inhibitors are reported to have anti-inflammatory in addition to their antihypertensive effects. This study investigated the potential anti-inflammatory effect of angiotensin converting enzyme inhibitors captopril and enalapril and angiotensin receptor blockers losartan and candesartan on experimental BLM-induced acute lung injury in rats. BLM-induced lung injury was assessed by the total white cell count, neutrophil count and interleukin-8 [IL-8] in bronchoalveolar lavage [BAL] fluid and serum level of tumor necrosis factor-alpha [TNF- alpha]. In addition, oxidative stress in lung tissue was measured by tissue contents of malondialdehyde [MDA] and reduced glutathione [GSH], enzymatic activity of superoxide dismutase [SOD] and catalase [CAT] in lung homogenate. A single intravenous dose of BLM was given on day 14[th] of the study. The four investigated RAS inhibitors [Captopril, enalapril, losartan and candesartan] were examined in two different regimens. The first regimen [a] was to start the RAS inhibitor on day 14[th] of the study with BLM and to continue for one week after BLM. In the second regimen [b], the RAS was started 2 weeks prior to BLM and continued for one week thereafter. Administration of candesartan was accompanied with significant decrease in the total white cell and neutrophil counts. Further, significantly lower counts were found when the drug was started two weeks prior to induction of BLM-lung injury [regimen b] compared to its introduction with BLM on day 14[th] [regimen a] [p<0.001]. The associated lower level of IL-8 in BAL in all RAS inhibitors groups failed to reach level of statistical significance compared to BLM control injury [p>0.05]. However, the level of TNF-alpha in serum was decreased significantly in all RAS inhibitors-treated groups. Significant higher lung tissue content of GSH with all RAS treated groups - especially with captopril, there was a significant difference between regimen a and b- compared to BLM-injury control group. There was a significant lower activation of SOD and CAT and less MDA content with all RAS inhibitors treated groups than BLM-injury control group [p<0.001]. All the investigated drugs exhibited significant anti-inflammatory and antioxidant effect especially the prophylactic regimen with captopril. Candesartan was the only drug that affects the macrophage mobility and its chemotactic activity