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

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