anisomycin and Fever

The present study aimed to examine the proteins involved in the methamphetamine (MA)-induced nigrostriatal dopaminergic toxicity. Infusion of anisomycin into striatum and substantia nigra both abolished the MA-induced striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) depletions, indicating a critical role of local protein synthesis in determining such dopaminergic toxicity. Moreover, local protein synthesis blockade reversed this neurotoxicity via a temperature-independent mechanism. We then employed a proteomic approach, two-dimensional gel electrophoresis (2-DE) in conjunction with mass spectrometry analysis, to identify the protein candidates associated with the MA-induced neurotoxicity. In striatal samples, 2-DE analysis revealed that the intensities of nine protein spots were altered by MA treatment. Mass spectrometry analysis allowed us to identify five proteins, including an up-regulated protein, alpha-synuclein, and four down-regulated proteins, ATPase, F-actin capping protein beta subunit, ubiquitin carboxy-terminal hydrolase/PGP 9.5, and peroxidase. MA-altered expression levels of alpha-synuclein and ubiquitin carboxy-terminal hydrolase/PGP 9.5 in striata were confirmed by western blotting analysis. Taken together, these results suggest that local up-regulation of alpha-synuclein and down-regulation of ubiquitin carboxy-terminal hydrolase/PGP 9.5 could be linked to the MA-induced dopaminergic terminal toxicity.

Topics: 3,4-Dihydroxyphenylacetic Acid; alpha-Synuclein; Animals; Anisomycin; Blotting, Western; Corpus Striatum; Dopamine; Electrophoresis, Gel, Two-Dimensional; Fever; Male; Mass Spectrometry; Methamphetamine; Mice; Mice, Inbred Strains; Nerve Tissue Proteins; Neurotoxins; Protein Synthesis Inhibitors; Substantia Nigra; Synucleins; Ubiquitin; Ubiquitin Thiolesterase

Rabbits were injected intravenously with 10 to 100 ng of staphylococcal enterotoxin A (SEA) per kg, and colonic temperatures were monitored. The febrile responses were compared with circulating levels of interferon (IFN), tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-2, and IL-6 just before the injection of SEA. Both colonic temperatures and circulating levels of IFN, TNF, and IL-2 started to rise at 1 to 2 h and reached their peak levels at 3 to 5 h after SEA injection. Both the fever and the increased circulating levels of IFN, TNF, and IL-2 produced by SEA were decreased by pretreatment with indomethacin (a cyclo-oxygenase inhibitor) (15 mg/kg, intraperitoneally), anisomycin (a protein synthesis inhibitor) (15 mg/kg, subcutaneously), or dexamethasone (an effective anti-inflammatory and immunosuppressive agent) (4 mg/kg, intravenously) in rabbits. Rabbits were injected intravenously with 30 ng of SEA per kg on four consecutive days, and colonic temperatures were monitored. Compared to rabbits that received the single injection of SEA, rabbits that received four consecutive injections of SEA showed a lesser increase in circulating levels of IFN, TNF, and IL-2 as well as colonic temperatures in response to an intravenous dose of SEA (30 ng/kg). The data suggest that the prevention of the febrile response elicited by SEA by indomethacin, anisomycin, or dexamethasone is due to prevention by these compounds of the increase in the circulating levels of IFN, TNF, and IL-2. The pyrogenic hyporesponsiveness to repeated injection of SEA is associated with decreased production of these circulating cytokines.

Topics: Animals; Anisomycin; Anti-Inflammatory Agents; Body Temperature; Dexamethasone; Enterotoxins; Fever; Immunosuppressive Agents; Indomethacin; Injections, Intravenous; Interferon Inducers; Interferons; Interleukin-1; Interleukin-2; Interleukin-6; Male; Rabbits; Staphylococcus aureus; Tumor Necrosis Factor-alpha

The effect of macrophage inflammatory protein-1 beta (MIP-1 beta) on body temperature, following its injection into the anterior hypothalamic pre-optic area (AH/POA), was examined by a radiotelemetry system in the freely moving rat. The purpose of this study was to examine the action of an inhibitor of protein synthesis, anisomycin, on the pyrexia which follows intrahypothalamic injection of MIP-1 beta. The micro-injection of 10 to 20 pg MIP-1 beta into the AH/POA induced a dose-dependent monophasic increase in body temperature, whereas a higher dose of 25 pg of the cytokine caused a biphasic febrile response. When MIP-1 beta was heated at 70 degrees C for 30 min prior to its administration, the pyrogenic response was abolished. Pretreatment of the micro-injection site in the AH/POA with 10 micrograms anisomycin did not alter the febrile response to 25 pg MIP-1 beta given at the same site in the AH/POA. When 10 mg/kg anisomycin was administered subcutaneously, the febrile response to 25 pg MIP-1 beta injected in the AH/POA was significantly suppressed. The present results suggest that fever caused by MIP-1 beta within the cells of the AH/POA may not require the synthesis of a new protein factor; however, the de novo synthesis of a protein outside of the AH/POA presumably plays a functional role, at least in part, in the intense fever produced by this cytokine in the hypothalamus.

Topics: Animals; Anisomycin; Body Temperature; Chemokine CCL4; Dose-Response Relationship, Drug; Fever; Growth Inhibitors; Hypothalamus; Hypothalamus, Anterior; Macrophage Inflammatory Proteins; Male; Microinjections; Monokines; Nerve Tissue Proteins; Preoptic Area; Protein Denaturation; Protein Synthesis Inhibitors; Rats; Rats, Wistar

1. Anisomycin (15 mg/kg) was administered s.c. to cats at ambient temperatures of 5 degrees C, 20 degrees C and 38 degrees C. It produced biphasic effects on body temperature at 5 degrees C and 20 degrees C, an initial fall in temperature followed by a rise in body temperature, and a rise in body temperature of long latency at 38 degrees C. 2. Anisomycin (15 mg/kg) attenuated the hyperthermic responses to centrally injected PGE2 (1 microgram) at all ambient temperatures studied and also completely abolished the hyperthermic response to arachidonic acid (100 ng i.c.v.) at 20 degrees C. 3. Shigella dysenteriae (100 ng i.c.v.) raised the body temperature of cats by increasing heat production and reducing heat loss at 5 degrees C and 20 degrees C, and by increasing heat conservation at 38 degrees C. Anisomycin (15 mg/kg s.c.) pretreatment did not affect the temperature responses to the pyrogen at 20 degrees C and 38 degrees C, but did reduce the responses to Shigella dysenteriae (100 ng and 1 microgram i.c.v.) at 5 degrees C. 4. Anisomycin (15 mg/kg s.c.) was administered to cats, 90 min after the injection of Shigella dysenteriae (100 ng i.c.v.), at 20 degrees C at the onset of hyperthermia in control experiments. Under these conditions, no hyperthermia was observed over a 2 h period following anisomycin injection. 5. It is concluded that anisomycin interferes with pyrogen induced fever by acting at a site after PGE2 in the pathway to fever.

Topics: Animals; Anisomycin; Antigens, Bacterial; Arachidonic Acid; Arachidonic Acids; Body Temperature Regulation; Cats; Dinoprostone; Female; Fever; Injections, Intraventricular; O Antigens; Prostaglandins E; Protein Synthesis Inhibitors; Pyrogens; Pyrrolidines; Shigella dysenteriae

In rabbits the third cerebral ventricle was perfused using a push-pull cannula. Prostaglandin E2 concentration in the perfusate was measured by radioimmunoassay. Prostaglandin concentration rose during fever induced by an intraventricular injection of endogenous pyrogen. Both fever and the increased prostaglandin concentration were suppressed by the intraventricular injection of 100 micrograms of the protein synthesis inhibitor, anisomycin. A possible interpretation of the findings is that anisomycin inhibits the formation of phospholipase A2. If this is true, the implication is that phospholipase A2 has a rapid turnover in brain.

Topics: Animals; Anisomycin; Brain; Dinoprostone; Fever; Injections, Intraventricular; Interleukin-1; Male; Nerve Tissue Proteins; Phospholipases A; Phospholipases A2; Prostaglandins E; Proteins; Rabbits

1. The protein synthesis inhibitor, anisomycin, was given into the cerebral ventricles of rabbits as a priming dose followed by a continuous infusion. Doses of 100, 200 and 300 microgram followed by infusions at 100, 200 and 300 microgram/hr inhibited the incorporation of [14C] leucine into hypothalamic protein by over 90%. 2. Injection and infusion of anisomycin (300 microgram) suppressed the febrile response to leucocyte (endogenous) pyrogen given into the ventricles (I.C.V.) or I.V. 3. Dialysis experiments showed that anisomycin did not combine irreversibly with leucocyte pyrogen. 4. Anisomycin did not interfere with thermoregulation in a cold environment. 5. It is concluded that pyrogenesis may involve a step which is dependent on synthesis of hypothalamic protein with a rapid turnover.

Topics: Animals; Anisomycin; Body Temperature Regulation; Depression, Chemical; Fever; Hypothalamus; Nerve Tissue Proteins; Pyrogens; Pyrrolidines; Rabbits