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PubMed2003

Acute renal toxic effect of amiodarone in rats.

Amiodarone is an antiarrhythmic drug now more frequently used after a number of years in which the use had been on the decline due to a number of studies which reported side effects such as chronic toxicity, primarily in the lungs, liver and thyroid glands. Additionally, in some patients an increase in serum creatinine was noted, however the effect of amiodarone on renal function had never been closely examined. Thus, the aim of our study was to analyse the effects of amiodarone on renal function in rats. Experiments were carried out in male Wistar rats divided in two experimental groups: 1) a control group, (n=8), 2) a group that received a daily intraperitoneal injection of amiodarone (50 mg/kg body weight) for 6 days (n=5). At the end of the treatment, renal function was measured by clearance creatinine and acute clearance studies. Renal toxicity was evaluated by urinary N-acetyl-glucosamine and alkaline phosphatase. At the end of the experiment, histology studies were done. Rats treated with amiodarone had a higher serum creatinine (182%) and a lower glomerular filtration rate (53%), renal plasma flow (68%) and filtration fraction (62%) than controls. Rats treated with amiodarone also showed an increase in urinary N-acetyl-glucosamine (221%) and alkaline phosphatase (4.151%) excretion which corresponds with tubular alterations showed on electron microscopy. In conclusion our data confirm that amiodarone induces acute renal damage in the rat.

Acute Disease↗
PubMed2003

Changes in brain serotonin turnover, body and head shakes in kainic acid-treated rats.

Kainic acid induces seizures and neurotoxicity in rats, produces changes in brain serotonin (5-HT), dopamine and noradrenaline metabolites among other changes in neurotransmitters. In this work, we investigated the changes in 5-HT turnover in brain regions from 84 rats intraperitoneally injected with kainic acid and a specific behavioural change, the body and head shakes, exerted by this neurotoxin in the presence of 5-HT receptor antagonists. Kainic acid produced an increase in 5-hydroxyindoleacetic acid levels in frontal cortex (212%; 180%), striatum (177%; 116%), amygdala (202%; 337%) and hippocampus (43%; 70 %) at 2 and 24 hr as compared with controls, respectively. Serotonin turnover was increased in amygdala (157%) and frontal cortex (169%) at 2 hr; whereas 24 hr after kainic acid administration, increases were observed in amygdala (207%), and frontal cortex (178%). Kainic acid also produced an increase in the frequency of head and body shakes when administered alone or together with pargyline, a monoamine oxidase inhibitor; whereas the administration of 5-HT receptor antagonists such as ketanserin and methiothepin, decreased this behaviour 54% and 50% as compared with kainic acid alone, respectively. These results suggest an active participation of 5-HT neurotransmission on the excitotoxic action of kainic acid in the brain.

Amygdala↗
PubMed2000

Therapeutic effect of melatonin on carbon tetrachloride-induced acute liver injury in rats.

The therapeutic effect of melatonin on acute liver injury was examined in rats intoxicated with carbon tetrachloride (CCl4). Melatonin (10, 50, or 100 mg/kg body weight [BW]) was intraperitoneally administered to male Wistar rats 6 hr after intraperitoneal injection of CCl4 (1.6 g/kg BW) at which time an apparent liver injury occurred. This post-melatonin administration dose dependently prevented the progression of liver injury at 24 hr after CCl4 injection, judging from the levels of serum transaminases, indices of liver cell damage. Rats injected with CCl4 alone showed an increase in liver lipid peroxide (LPO) content and a decrease in liver reduced glutathione content at 6 and 24 hr after the injection. The post-melatonin administration dose dependently ameliorated both changes found at 24 hr after CCl4 injection. Rats injected with CCl4 alone showed an increase in liver triglyceride (TG) content and decreases in serum TG concentration and liver tryptophan 2,3-dioxygenase (TDO) activity, a marker of the inhibition of liver protein synthesis by CCl4, at 6 and 24 hr after the injection, and also a decrease in serum albumin concentration at 24 hr. The changes in serum TG, albumin concentration, liver TG content, and TDO activity found at 24 hr after CCl4 injection were not ameliorated by the post-administration of melatonin. The same administration of melatonin dose dependently reduced liver LPO content in CCl4-untreated rats. These results indicate that melatonin exerts a therapeutic effect on CCl4-induced acute liver injury in rats, possibly through its antioxidant action.

Animals↗
PubMed1991

Effects of cadmium on cocaine-induced changes in activity.

Adult male rats were exposed to a diet that contained 100 parts per million added cadmium or a control diet for 72 days before being tested in a Digiscan activity monitor. During the 1-hr test period, each animal's baseline activity levels were recorded for 20 min. Animals then received intraperitoneal injections of 0, 10, 20, or 40 mg/kg cocaine HCl, and their activity levels were recorded for the remaining 40 min of the test session. The results showed that the 10, 20, and 40 mg/kg doses of cocaine produced behavioral activation in the control-diet animals. For cadmium-treated animals, cocaine-induced behavioral changes at the 10 mg/kg dose were not observed, but increased activity was evident at the two higher doses.

Animals↗
PubMed2000

Effects of d-amphetamine and alcohol on a measure of behavioral inhibition in rats.

This study was designed to develop a version of the stop task, a putative measure of behavioral inhibition, for use in rats and to assess the effects of d-amphetamine (AMP) and alcohol (ALC). The stop task provides a quantitative index of the ability to inhibit a response that has been initiated. Rats (N = 11) were tested after intraperitoneal injections of AMP (0.125, 0.25, 0.5, 1.0 mg/kg) and ALC (250, 500, 750 mg/kg). AMP improved the ability to inhibit responses only in rats with relatively poor inhibitory performance at baseline. ALC impaired inhibition at doses that did not affect simple reaction time. The results support the sensitivity, reliability, and validity of the procedure as a measure of behavioral inhibition in rats and are highly concordant with a parallel study conducted with humans.

Animals↗
PubMed1975

Phenylpropanolamine inhibits feeding, but not drinking, induced by hypothalamic stimulation.

In rats bearing lateral hypothalamic electrodes that elicited both feeding and drinking, intraperitoneal injection of the appetite suppressant drug phenylpropanolamine (Propadrine) inhibited only feeding. This occurred whether feeding and drinking were tested simultaneously or separately. Selective inhibition of lateral hypothalamic feeding also followed injection of this drug through lateral, but not medial, hypothalamic electrode cannulas. We conclude that hypothalamically induced feeding is under some of the same pharmacological controls as spontaneous feeding, that this control may be exerted, in part, in or near the lateral hypothalamus, and that the neural systems which induce feeding and drinking during hypothalamic stimulation can be pharmacologically separated.

Animals↗
PubMed1971

The effect of neonatal administration of sex hormones on ribonucleic acid metabolism in the liver of male and female rats.

Fifteen minutes after the intraperitoneal injection of (32)P labelled phosphate, normal adult male rats show a higher incorporation of isotope into their liver nuclear RNA than do females. A single injection of testosterone into neonatal female rats causes a higher uptake of (32)P in adult life, while a single injection of oestradiol into male neonates lowers the incorporation in adult life. Gonadectomy at 4 weeks of age has only a small effect on the subsequent incorporation of (32)P into nuclear RNA either in control rats or in rats injected with sex hormones immediately after birth, showing that this effect of liver metabolism is mainly determined by the hormanal pattern at about the time of birth. The possible relevance of this sex difference in RNA metabolism to the different sex incidence of spontaneous or induced liver cancer is discussed.

Animals↗
PubMed1971

Studies on the binding and distribution of radioactively labelled 3'-methylcholanthrene in subcellular fractions of rat liver.

The subcellular distribution of either [(14)C] or [(3)H]3'-methylcholanthrene was studied in rat liver following a single intraperitoneal injection of the labelled hydrocarbon 10 hours previously.Adsorbed or non-covalently bound methylcholanthrene and its metabolic derivatives occurred in all cell fractions studied with the exception of purified cell walls. The highest specific activities (d.p.m./mg. protein) were found in washed mitochondria, microsomes and ribosome-free microsomal membranes.Covalent binding of methylcholanthrene and its metabolic derivatives to different cell fractions of rat liver occurs to a small extent and is considered not to be significant. The highest degree of binding occurs in washed mitochondria, microsomes, ribosome-free microsomal membranes and their constituent core proteins.Cell sap which contains non-covalently bound 3'-methylcholanthrene was fractionated into pH 5 enzyme and pH 5 supernatant fractions. The pH 5 enzyme fraction which possesses a high specific activity (d.p.m./mg. protein) was further fractionated with ammonium sulphate into three fractions. The 0-30% ammonium sulphate fraction had the highest specific activity.

Adsorption↗
PubMed1976

Treatment of transplanted rat tumours with double-stranded RNA(BRL 5907). II. Treatment of pleural and peritoneal growths.

Intrapleural growth of transplanted rat tumours was prevented or retarded by intrapleural administration of double-stranded RNA. A similar suppression of growth was achieved with peitoneal tumours by the intraperitoneal injection of the compound. These studies indicate the possible potential of this form of treatment of thoracic and peritoneal tumours for clinical application in the treatment of mesothelioma.

Animals↗
PubMed1996

Immunoscintigraphy of small-cell lung cancer xenografts with anti neural cell adhesion molecule monoclonal antibody, 123C3: improvement of tumour uptake by internalisation.

The efficacy of three murine monoclonal antibodies (MAbs) for immunoscintigraphy of small-cell lung cancer (SCLS) xenografts was studied in a Balb/c nu/nu mouse model. These Mabs, 123C3, 123A8 and MOC191, belong to cluster 1 of anti-SCLC MAbs and bind to the neural cell adhesion molecule (NCAM) with similar affinity. After intraperitoneal injection of these MAbs, labelled with 125I, the highest uptake in tumour tissue was obtained with MAb 123C3. Seven days after the administration of this MAb 13.9% of the injected dose per gram of tumour tissue was retained in the tumour. The corresponding tumour tissue ratios ranged from 3.97 for blood to 31.03 for colon. The imaging results and the tumour uptake were less favourable for the two other MAbs, 123A8 and MOC191 (fractions of injected dose respectively 6.7% and 9.2%), although affinity, biological activity after labelling and uptake in non-tumour tissues were very similar for all three MAbs. These results may be explained by the differences in the interaction between the MAbs and the tumour cells. Mab 123C3 is internalised into tumour cells, whereas both other anti-NCAM Mabs are not. Internalisation into NCI H69 cells was demonstrated in vitro by radioimmunoassay, confocal laser scanning microscopy and electron microscopy. The internalised fraction of MAb 123C3 was 22.3% after 24h, whereas this fraction was only 7.5% for MAb 123A8. Although the internalised radiolabeled Mabs are usually degraded and dehalogenated intracellularly, the retained radioactivity is high. Apparently, intracellular degradation of radiolabelled MAb 123C3 and subsequent secretion of radioactive iodine did not prevent the accumulation of intracellular radioactivity. In conclusion, accumulation and retention of radioactivity in the tumour tissue, due to internalisation of radiolabelled MAbs, may improve the results immunoscintigraphy.

Animals↗
PubMed1995

Lipid peroxidation accompanies cyclosporine nephrotoxicity: effects of vitamin E.

Cyclosporine A (CsA) has been demonstrated to induce renal microsomal lipid peroxidation in vitro. To examine whether CsA induces lipid peroxidation in vivo, uninephrectomized rats were gavaged with vehicle, CsA 12.5 or 25 mg/kg/day for four weeks. CsA-induced reduction in GFR and RBF was associated with a dose-related increase in renal cortical malondialdehyde (MDA) and conjugated diene, as well as a similar increase in arterial MDA. The latter was apparent within two hours of a single intraperitoneal injection of 25 mg/kg CsA and preceded the acute fall in GFR. To address whether lipid peroxidation contributed to CsA nephrotoxicity, rats were gavaged with vehicles, CsA 25 mg/kg/day or CsA plus vitamin E 25 mg/kg/day for eight weeks. Vitamin E, a lipid radical scavenger, inhibited MDA raise and reduced CsA-induced renal damage. Conversely, CsA administration to vitamin E and selenium deficient rats was accompanied by a greater increase in arterial MDA and fall in GFR. These novel findings, that CsA nephrotoxicity is associated with lipid peroxidation and that a chain-breaking antioxidant ameliorates whereas its deficiency exacerbates, indicate a role for lipid peroxidation, presumably free radical-mediated, in CsA toxicity.

Animals↗
PubMed1995

Toward novel antirejection strategies: in vivo immunosuppressive properties of CTLA4Ig.

Allograft rejection is a process that depends on T cell receptor-ligand interaction and costimulatory signals generated when accessory molecules binds to their ligands, such as CD28 to the B7 molecules. We investigated the possibility that B7 blockade in vivo by the soluble CD28 receptor homolog CTLA4Ig modulates rejection process in a rat model of kidney allograft. Lewis rats orthotopically transplanted with MHC incompatible kidney from Brown-Norway rats were given an intraperitoneal injection of CTLA4Ig (0.2 or 0.5 mg/day) or a nonspecific immunoglobulin for seven days, starting the day of transplant. While control rats rejected the graft within 10 days, all animals given CTLA4Ig had a prolonged kidney allograft survival, independently from the dose of the fusion protein employed. Actually, at the dose of 0.2 mg/day kidney grafts survived 36 to 50 days (median 44 days), while with the highest dose graft survival was 40 to 60 days (median 50 days). In all CTLA4Ig-treated rats renal grafts were well functioning as documented by serum creatinine concentrations comparable to age- and sex-matched control rats 30 days after transplant. At this time in vitro mixed lymphocyte culture (MLR) experiments showed a significant reduction of proliferation of peripheral blood lymphocytes from CTLA4Ig-treated rats when challenged with BN but not third party Wistar Furth lymphocytes. We have also shown that combining a short course of CTLA4Ig (0.2 mg/day) with a dose of cyclosporine (CsA) low enough to fail to inhibit graft rejection allowed indefinite engraftment of kidney allograft without the need of continuous immunosuppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Abatacept↗
PubMed1994

[Leu]enkephalin enhances active avoidance conditioning in rats and mice.

The effects of intraperitoneal (IP) administration of the endogenous opioid peptide, [Leu]enkephalin (LE), on avoidance conditioning in rodents were investigated. At a dose of 30 micrograms/kg (IP), LE enhanced acquisition of a one-way step-through active avoidance response when administered 2 minutes before training to Swiss Webster mice. [Leu]enkephalin produced a U-shaped dose-response function because both lower and higher doses of LE did not affect avoidance responding. [Leu]enkephalin-induced enhancement of avoidance acquisition was also observed in Sprague-Dawley rats; the intraperitoneal injection of 10 micrograms/kg LE, administered 5 minutes before training, enhanced acquisition of a jump-up one-way active avoidance response. When administered to Sprague-Dawley rats immediately after training, LE (30 micrograms/kg IP) enhanced jump-up avoidance responding at test 24 hours after peptide injection. Previously, we found LE to impair acquisition in the same tasks in both rats and mice, also at microgram doses, and also in a U-shaped manner. Thus, LE can either enhance or impair learning within the same species and the same task; these findings are in agreement with recent theoretical proposals regarding the nature of compounds, such as LE, that modulate learning and memory.

Amino Acid Sequence↗
PubMed2003

Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity.

The interaction between Fas and Fas ligand (FasL) is involved in the apoptotic death of a number of cells including lymphocytes. Forced expression of FasL in tumors can induce apoptosis of infiltrating Fas-positive T cells; accordingly, tumors can survive in the milieu of systemic immune responses. However, FasL-expressing murine lung carcinoma (A11) and melanoma (B16) cells did not develop subcutaneous tumors and FasL-expressing A11 (A11/FasL) cells produced few spontaneous lung metastatic foci in syngeneic mice. The mice that rejected A11/FasL cells were resistant to subsequent challenge of parent A11 but not irrelevant B16 cells. Vaccination of mice with UV-treated A11/FasL, but not UV-treated A11 cells, however, augmented the growth rate of A11 but not B16 tumors, both of which were subsequently inoculated. The number of lung metastatic foci of A11 cells was also increased in the mice that received UV-treated A11/FasL but not UV-treated A11 cells. Intraperitoneal injection of UV-treated A11/FasL cells resulted in the production of larger amounts of immunosuppressive TGF-beta in peritoneal exudate than that of UV-treated A11 cells. Expression of the CD80 costimulatory molecule in tissues where UV-treated A11/FasL cells were inoculated was lower than the expression at an untreated A11/FasL-injected site. Our results indicated that apoptotic FasL-expressing tumor cells could impair host immune responses against the tumors, in contrast to potent antitumor immunity generated by viable FasL-expressing tumors.

Animals↗
PubMed2000

Amelioration of established collagen induced arthritis by systemic IL-10 gene delivery.

A novel formulation of cationic liposomes containing the novel cytofectin ACHx was used for delivery of an anti-inflammatory cytokine gene, IL-10, to mice with established collagen induced arthritis. A single intraperitoneal injection of human IL-10 expression plasmid complexed with liposomes 2 to 4 days after the onset of arthritis was sufficient to give significant and prolonged amelioration of arthritis for 30 days. Preliminary experiments suggested that the therapeutic effect was IL-10 dose-dependent. The distribution of the human IL-10 DNA after injection was widespread, including the inflamed paws. Human IL-10 mRNA was also detected in the paws 24 h after injection. IL-10 protein was below the level of detection in paws and serum but was detected in some tissues up to 10 days after injection. The target cell of transfection was demonstrated to be the macrophage. These results suggest that systemic therapy with plasmid DNA complexed with cationic liposomes merits further development as an alternative method for anti-inflammatory treatment of arthritis.

Animals↗
PubMed2002

Ablation of microvessels in vivo upon dimerization of iCaspase-9.

Anti-angiogenic therapies based on targeted disruption of the tumor microvascular network have been proposed for cancer treatment. Inhibitors of the endothelial cell pro-survival pathway mediated by VEGF were shown to activate caspases and cause microvascular regression, but the efficacy of this strategy can be hindered by the engagement of redundant survival pathways. Alternatively, if direct activation of an apical pro-apoptotic caspase is sufficient to disrupt microvessels in vivo, such a strategy could potentially override upstream endothelial cell survival inputs and disrupt tumor neovascular networks. Here, we fused caspase-9 to a mutated FKBP12 domain to express an inducible caspase-9 molecule (iCaspase-9) that can be activated by a cell-permeable dimerizer drug, and transduced this construct into primary endothelial cells. We found that drug-induced dimerization of iCaspase-9 is sufficient to activate endogenous caspase-3 and trigger apoptosis even when endothelial cells are treated with the pro-survival factors VEGF or bFGF. A single intraperitoneal injection of the dimerizer drug induced apoptosis of endothelial cells expressing iCaspase-9 and elimination of human microvessels engineered in immunodeficient mice. These results demonstrate that the activation of iCaspase-9 disrupts microvessels in vivo, and suggest a novel anti-angiogenic strategy based on the expression and controlled activation of an inducible death gene in neovascular endothelial cells.

Animals↗
PubMed2006

Reconstituted influenza virus envelopes as an efficient carrier system for cellular delivery of small-interfering RNAs.

Application of RNA interference for in vivo evaluation of gene function or for therapeutic interventions has been hampered by a lack of suitable delivery methods for small interfering RNA (siRNA). Here, we present reconstituted viral envelopes (virosomes) derived from influenza virus as suitable vehicles for in vitro as well as in vivo delivery of siRNAs. Virosomes are vesicles that bear in their membrane the influenza virus spike protein hemagglutinin (HA). This protein mediates binding of native virus to and fusion with cellular target membranes. Accordingly, virosomes with membrane-incorporated HA bind to cells, are taken up by receptor-mediated endocytosis, and fuse with the endosomal membrane to release their contents into the cytoplasm. When complexed to cationic lipids, siRNA was successfully encapsulated in virosomes. Virosomes with encapsulated siRNA fused with target membranes in a pH-dependent manner and delivered the encapsulated siRNA to several cell lines in vitro. Virosome-delivered siRNA markedly downregulated the synthesis of newly induced and constitutively expressed green fluorescent protein. Moreover, intraperitoneal injection of siRNA-loaded virosomes resulted in delivery of the nucleotides to cells in the peritoneal cavity. Our results indicate that virosomes are a promising delivery device for in vivo application, especially where topical administration of siRNA, for example, to the respiratory tract is envisaged.

Animals↗
PubMed2006

Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure.

Administration of human recombinant erythropoietin (EPO) at time of acute ischemic renal injury (IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa (DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats (N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation (T0), or post-treated (6 h after the onset of reperfusion, T6) with EPO (5000 IU/kg), DPO (25 mug/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.08 +/- 0.03 mmol/l vs EPO-IRI 0.04 +/- 0.01 mmol/l, P = 0.01). Delayed administration of DPO or EPO (T6) also significantly abrogated subsequent renal dysfunction (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.06 +/- 0.01 mmol/l vs EPO-IRI 0.03 +/- 0.03 mmol/l, P = 0.01). There was also significantly decreased tissue injury (apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.

Acute Kidney Injury↗