Effect of silymarin, melatonin, and N-acetylcysteine on bleomycin-induced lung injury in rats

Pulmonary fibrosis is the end stage of a heterogeneous group of disorders of known and unknown etiology. One of the clinically important causative agents in pulmonary fibrosis is bleomycin [BLM]. Silymarin is an old herbal remedy known to protect a cell membrane against xenobiotic injury principally due to its antioxidant potential. Melatonin, which is the chief secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. The antioxidant, N-acetylcysteine [NAC], has shown beneficial effects in diseases in which reactive oxygen species appear to be involved. The aim of the present study was to assess and compare the protective effect of orally administered silymarin, melatonin, or N-acetylcysteine on lung injury induced in rat model by endotracheal instillation of BLM. Fifty six animals were divided into: group I [control group] [n=24] which were equally subdivided into IA [vehicle and intratracheal saline]; IB [silymarin and intratracheal saline]; IC [melatonin and intratracheal saline]; ID [NAC and intratracheal saline]. Group II [treatment group] [n=32]: which were equally subdivided into IIA [vehicle and intratracheal BLM]; IIB [silymarin and intratracheal BLM]; IIC [melatonin and intratracheal BLM]; IID [NAC and intratracheal BLM]. silymarin was taken in a dose of 50 mg/kg/day suspended in 2% gum acacia mucilage. Melatonin was administered in a dose of 10 mg/kg/day. NAC was given in a dose of 486.6 mg/kg/ day. Treatments were administered orally for 14 days after the day of BLM or saline instillation. Animals received endotracheally a single dose of BLM hydrochloride [5 mg/kg body weight] to produce pulmonary fibrosis. Bronchoalveolar lavage fluid [BALF] was used to measure total protein concentration, lactate dehydrogenase [LDH] activity, and total glutathione levels. Lung tissue homogenates were used to measure myeloperoxidase [MPO] activity, lipid peroxide [LPO] content, and total lung collagen. The body weight of rats not exposed to BLM increased with time. Rats in group IIA failed to gain weight during the first week; thereafter weight gain paralleled that observed in rats not exposed to BLM. A similar but less marked trend was noticed for treated rats. Bleomycin produced a significant increase in lung weight. Treatment with silymarin, melatonin, or NAC decreased lung weight but statistical significance was not reached. The lung hydroxyproline levels were increased in BLM-instilled rats [group IIA] but significantly deceased on treatment with silymarin, melatonin, or NAC. The total cell count and neutrophil cell count in BALF were significantly increased in BLM-exposed rat group. On the contrary of melatonin and NAC, treatment with silymarin significantly decreased these elevated cell counts. The elevated protein concentration in BALF due to the effect of BLM instillation was not reduced by treatment with any of the drugs used. Treatment with silymarin, melatonin, or NAC significantly attenuated the increased LDH activity following BLM instillation. Bleomycin was shown to reduce glutathione levels in the lung. Treatment with silymarin, melatonin, or NAC resulted in a significant increase of glutathione in BALF. Silymarin, but not melatonin or NAC significantly attenuated the increase in lung MPO activity following BLM instillation. The lipid peroxide content in the lung was significantly increased in BLM instilled rats. Treatment with silymarin, melatonin, or NAC attenuated this elevated peroxidation. We conclude that treatment with silymarin inhibit lung fibrotic progression induced by BLM. The decreased neutrophil recruitment to the lung, attenuation of cell damage and the antioxidant properties of silymarin may be involved in its protective mechanism against pulmonary fibrosis. Melatonin also exerts protection against BLM- induced pulmonary fibrosis, probably by suppressing oxidative stress. Treatment with oral NAC is partially effective against lung fibrosis which may be due to replenishment of lung glutathione or reduction of damage to lung structure in the early stage of the disease

modulatory effects of some drugs with potential influence on oxidative cell damage on experimental ulcerative colitis

Ulcerative colitis is a chronic inflammatory bowel disease [IBD] where reactive oxygen species [ROS] are produced in excess. There are comparatively low tissue levels of endogenous antioxidants in the colonic mucosa. Oxidative stress occurred in IBD may therefore easily overwhelm the endogenous defenses that regulate ROS production. Our aim was to assess the ability of vitamins C, deferoxamine [Dfx] and amlodipine [Amlo] to inhibit colonic inflammation in dextran sulphate sodium [DSS]-induced colitis in rats. We used thirty mature male albino rats assigned to Group I: normal control. Group II: received DSS+0.5 ml 0.9% normal saline daily. Group III: received DSS+vitamin C 100 mg/kg b.w./day. Group IV: received DSS+amlodipine 3 mg/kg/day. Group V: received DDS+Dfx 300 micro mol/kg/day. Acute colitis was induced by 3% DSS in drinking water for 7 days. Vitamin C, amlodipine, and deferoxamine were administered orally for 7 days before and a further 7 days during treatment with DSS. Rats without colitis received regular drinking water. On day 14 of drug treatment, colons were excised and opened longitudinally. Gross colonic mucosal injury were observed and scored. Colonic wet/dry weight ratios were calculated as an indirect index of the inflammatory reaction. Colonic myeloperoxidase [MPO] activity, glutathione [GSH] and Thiobarbituric acid-reactive substances were measured. The results of the present study showed that pretreatment of the rats with vitamin C, Amlo and Dfx reduced the gross mucosal injury developed after induction of colitis. These drugs prevented the increase in MPO activity produced in these cases of inflammation. Pretreatment of animals with vitamin C, Amlo or Dfx prevented the depletion of colonic GSH caused by DSS-induced colonic injury. All of the tested drugs were found also to decrease the enhanced lipid per oxidation observed in this model of DSS-induced colitis in rats. It can be concluded that pretreatment with vitamin C, amlodipine and deferoxamine can inhibit the inflammatory process in DSS-induced colitis in rats through their antioxidant properties

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

"Epirubicin cardiotoxicity" the underlying mechanism behind the possible protection by lacidipine versus natural antioxidants

The current study probes the utility of two adjuvant regimens, vitamin E and vitamin C combination or lacidipine in hope to minimize or abort epirubicin cardiotoxic potential. The study was conducted on 40 albino rats, divided into 4 equal groups: one received 0.4 mg/kg epirubicin, the second and third received either epirubicin with vitamin E and vitamin C, 100 mg/kg and 1000 mg/kg respectively, or epirubicin with lacidipine 3 mg/kg, the fourth group served as control. Cardiotoxic profile was assessed biochemically [serum cardiac enzymes] and histopathologicaljy while the oxidative stress was assessed by determining the tissue level of glutathione, superoxide dismutase [SOD] and malondialdehyde [MDA]. The results have demonstrated that both regimens, whether vitamin E and vitamin C or lacidipine, significantly suppressed the increase in serum cardiac enzymes, and tissue MDA, and significantly elevated the decreased tissue glutathione and SOD induced by epirubicin. it can be concluded that vitamin E and vitamin C combination or lacidipine are good candidates as adjuvant therapy that can be utilized to reduce epirubicin cardiotoxic potential and they are worthy for clinical evaluation