anisomycin and Body-Weight

Anisomycin is a pyrrolidine antibiotic isolated from Streptomyces griseolus. Recent studies have shown that Anisomycin as a novel immunosuppressive agent is superior to Cyclosporine A (J. Immunother. 31, 858-870, 2008). In order to make toxicological evaluation of Anisomycin, acute and four-week continuously intravenous toxicity studies were performed in mice. IC(50) value tested on peripheral lymphocytes was 25.44 ng/ml. The calculated LD(50) for Anisomycin was 119.64 mg/kg. The mice were intravenously injected through mouse tail vein with a total dose of 5, 15, 30 and 60 mg/kg/mice of Anisomycin every other day for 4 weeks. Just in the high-dose mice, death of three mice happened and body weight of the mice was significantly decreased. Statistically significant changes in organ index included increases in ratios of the spleen, liver, lung and brain to the body weight, and decrease in ratio of the thymus to the body weight. Changes in clinical biochemistry parameters included increases in the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, and decreases in the glucose (GLU) activity. The distinct inflammation appeared in the lung, liver and kidney, and the number and size of megakaryocytes in the spleen were significantly increased. Anisomycin did not induce formation of the peripheral blood micronucleus, but increased the number of micronucleated polychromatic erythrocytes in bone marrow and sperm aberrations. However, the above aberrant changes occurred only in the mice treated with the high-dose Anisomycin. These results indicate that although Anisomycin has no significant side effects at effectively therapeutic doses, its over-dosage may lead to toxicity, particularly pulmo-, nephro- and hepato-toxicity.

Topics: Animals; Anisomycin; Anti-Bacterial Agents; Body Weight; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Inhibitory Concentration 50; Injections, Intravenous; Kidney; Lethal Dose 50; Liver; Lung; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Random Allocation; Spermatozoa; Toxicity Tests, Acute

It has been proposed that p38 mitogen-activated protein kinase (MAPK) isoforms sensitive to the pyridinylimidazole compounds SB 203580 and SB 202190 may participate in the acute insulin-dependent activation of glucose transporters recruited to the plasma membrane of adipocytes and skeletal muscle. Here, we explore whether these kinases support the insulin stimulation of glucose uptake in these tissues by investigating the effects of a genetic loss in p38beta and that of the p38 MAPK inhibitor SB 203580. Glucose uptake in adipocytes and soleus muscle was stimulated by insulin by up to fourfold irrespective of whether tissues were isolated from wild-type or p38beta-null mice. Consistent with this finding, mice lacking p38beta exhibited normal glucose tolerance, insulinemia, and glycemia compared with their wild-type counterparts. Insulin-stimulated glucose uptake was not inhibited by SB 203580 when adipocytes were preincubated with the drug at a cytocrit of 50%, but intriguingly, uptake was suppressed (by 35%) when the cytocrit was reduced by one-half. Despite the activation of glucose uptake at the higher cytocrit, insulin failed to induce any detectable activation of p38 MAPK, whereas p38 signaling was robustly activated by anisomycin in a SB 203580-sensitive manner. Although insulin also failed to induce any detectable activation of p38 MAPK in muscle, insulin-dependent glucose uptake was reduced by SB 203580 (approximately 44%) in muscle of both wild-type and p38beta-null mice. Our results indicate that p38beta is not required for insulin-stimulated glucose uptake in adipocytes or muscle. Moreover, given that insulin fails to promote any significant activation of p38 MAPK in these tissues and the finding that sensitivity of glucose uptake, but not that of the kinase, to SB 203580 can be influenced by cytocrit, we suggest that p38 signaling is unlikely to participate in any putative activation of transporters recruited to the cell surface by insulin and that SB 203580 suppresses insulin-stimulated glucose transport by a mechanism unrelated to its inhibitory effect on p38 MAPK.

Topics: Adipose Tissue; Animals; Anisomycin; Biological Transport; Blood Glucose; Body Weight; Gene Deletion; Glucose; Imidazoles; Insulin; Mice; Muscle, Skeletal; Myocardium; p38 Mitogen-Activated Protein Kinases; Pyridines; Signal Transduction

Cocaine has been shown to reduce food intake and body weight in rodents and humans. The results of recent research suggest that de novo protein synthesis in the brain is associated with neuroadaptive changes in the central nervous system. The present study reports the effect of anisomycin, a protein synthesis inhibitor with limited toxicity, on the reduction in body weight resulting from repeated daily injections of cocaine (50 mg/kg) to mice from 7 inbred strains (AKR/J, BALB/cByJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J and SJL/J). Repeated cocaine administration resulted in substantial weight loss in all but the BALB strain. Anisomycin (5-30 mg/kg), administered 5 min. prior to each daily cocaine injection, significantly attenuated cocaine-induced weight loss in SJL, C3H and CBA mice. The same treatment, however, had no effect on reduction in body weight in C57, AKR and DBA mice. In BALB mice, neither cocaine, anisomycin alone, nor the coadministration of the two drugs, affected weight gain during the experiment. The results suggest that there is a genotype-specific involvement of protein synthesis associated with cocaine-induced weight loss.

Topics: Animals; Anisomycin; Body Weight; Cocaine; Genotype; Male; Mice; Mice, Inbred Strains; Species Specificity; Weight Loss