Free radical mediated release of histamine from rat mast cells induced by drugs of abuse

Inflammation Research -     

Measles virus-specific antibody levels in individuals in Argentina who received a one-dose vaccine

In spite of active measles virus (MV) vaccination strategies, reemergence continues to occur, impairing global eradication programs. The immune status against measles was evaluated in 350 vaccinated healthy Argentine children and teenagers who received a single dose of the MV Schwarz strain Lirugen vaccine (Aventis Pasteur). Sera were assessed for immunoglobulin G (IgG) antibodies by a commercial enzyme immunoassay (EIA) (Enzygnost; Behring), an in-house EIA, and neutralization EIA. Results obtained with these methods showed a marked decline in IgG level with increasing age. At 1 to 4 years of age, 84% of children had IgG antibodies above 200 mIU/ml, conventionally accepted as protective levels, whereas only 32% of older children and teenagers had antibody levels exceeding 200 mIU/ml. Moreover, the MV IgG content in the teenage group was significantly lower than the IgG antibody level of the group of younger children (P < 0.0001). In contrast, screening for IgG antibody levels to inactivated tetanus vaccine showed that, on average, 80% of this population was fully protected and that this high level of protection remained through the teenage years. This study suggests that within this population a considerable proportion of individuals had low measles antibody levels that may be insufficient to protect against reinfections or clinical disease.     

Protective effects of relaxin in ischemia/reperfusion-induced intestinal injury due to splanchnic artery occlusion

1. Splanchnic artery occlusion (SAO) followed by reperfusion causes endothelial injury and inflammation which contribute to the pathophysiology of shock. We investigated the effects of relaxin (RLX), known to afford protection against the deleterious effects of cardiac ischemia/reperfusion, given to rats subjected to splanchnic artery occlusion and reperfusion (SAO/R)-induced splanchnic injury. 2. RLX (30 ng kg(-1), 15 min. before reperfusion) significantly reduced the drop of blood pressure and high mortality rate caused by SAO/R. RLX also reduced histopathological changes, leukocyte infiltration (myeloperoxidase) and expression of endothelial cell adhesion molecules in the ileum. RLX counteracted free radical-mediated tissue injury, as judged by significant decrease in the tissue levels of peroxidation and nitration products (malondialdehyde, nitrotyrosine), DNA damage markers (8-hydroxy-2'-deoxyguanosine, poly-ADP-ribosylated DNA) and consumption of tissue antioxidant enzymes (superoxide dismutase). As a result, RLX led to a reduction of ileal cell apoptosis (caspase 3, terminal deoxynucleotidyltransferase-mediated UTP end labeling). The effects of RLX appear specific, as inactivated RLX substituted for the bioactive hormone had no effects. 3. In conclusion, these results show that RLX exerts a clear-cut protective effect in SAO/R-induced splanchnic injury, likely due to endothelial protection, decreased leukocyte recruitment and hindrance of free radical-mediated tissue injury leading to cell death, lethal complications and high mortality rate. Thus, RLX could be used therapeutically in intestinal ischemia.     

Intravenous self-administration of amphetamine is increased in a rat model of depression

Affective disorders and substance abuse frequently coexist, yet few previous studies have examined drug self-administration using animal models of depression. The olfactory-bulbectomized rat is a well-established model that exhibits a high degree of neurochemical similarity to depression. Olfactory bulbectomy (OBX) increases dopamine receptor densities in the ventral striatum, which may increase the reinforcing effects of drugs of abuse. Experiments were designed to test the hypotheses that acquisition and stable self-administration of amphetamine would be increased in bulbectomized rats. In the first experiment, rats underwent bilateral OBX or sham surgery and intravenous jugular catheters were implanted 12-14 days later. Acquisition was examined using a standard operant paradigm involving a nose-poke response for a very low dose of D-amphetamine sulfate (12 microg/infusion, IV). A separate group of rats received coinfusions of sulpiride. In a second experiment designed to minimize differences in acquisition and examine stable self-administration, lever pressing for a low (0.10 mg/kg, IV) or high (0.25 mg/kg, IV) dose of D-amphetamine sulfate was measured in rats pretrained to lever press for food. Bulbectomized rats acquired the self-administration of very low dose amphetamine faster than sham-operated rats and this effect was reversed by sulpiride coinfusion. Stable self-administration of the low dose of amphetamine was also markedly increased in bulbectomized rats. The findings reveal the utility of the OBX model for studying the neurobiological basis of depression and drug abuse comorbidity and support the hypothesis that neurochemical abnormalities associated with depression may enhance the addictive properties of some drugs of abuse.     

Methylprednisolone acts on peripheral blood mononuclear cells and endothelium in inhibiting migration phenomena in patients with multiple sclerosis

BACKGROUND: Intravenous methylprednisolone hemisuccinate is administered to patients with multiple sclerosis (MS) during exacerbations to improve the rate of recovery. Corticosteroids could be beneficial in MS exacerbations also by decreasing transmigration of peripheral blood mononuclear cells (PBMNCs) through the blood-brain barrier. OBJECTIVES: To evaluate how in vivo intravenous methylprednisolone treatment in patients with MS could influence transmigration of PBMNCs in an in vitro model; to perform transmigration experiments through a methylprednisolone-treated endothelium with PBMNCs from untreated healthy control subjects to evaluate putative selective effects of corticosteroids on endothelium; concomitantly, to quantify the concentration of matrix metalloproteinases 2 and 9 in supernatants of PBMNCs and in serum samples from methylprednisolone-treated patients with MS; to evaluate monokine induced by interferon-gamma release in the supernatants of human umbilical vein endothelial cells treated with interferon-gamma alone or interferon-gamma and methylprednisolone; and to perform gene expression studies of matrix metalloproteinases 2 and 9 in human umbilical vein endothelial cells and PBMNCs from methylprednisolone-treated patients with MS. PATIENTS: Eight patients with MS in exacerbation were studied before and 3 and 24 hours after intravenous methylprednisolone treatment, 1 g. RESULTS: The absolute number of transmigrated PBMNCs from methylprednisolone-treated patients with MS significantly (P<.01) decreased at 3 hours and increased again at 24 hours, reaching values higher than those before treatment onset. Methylprednisolone was also able to significantly (P<.03) reduce the number of PBMNCs from healthy controls migrating through interferon-gamma-stimulated or unstimulated endothelium. In vitro methylprednisolone treatment decreased monokine induced by interferon-gamma production in human umbilical vein endothelial cells. CONCLUSIONS: Methylprednisolone may be able to decrease transmigration of PBMNCs through the blood-brain barrier, exerting its inhibitory effects on PBMNCs and endothelium. A "rebound" of transmigration at 24 hours suggests that a single infusion is not optimal for achieving a persistent reduction in transmigration.     

The fate of dolichol in rat cells and tissues

Dolichol (D) levels increase dramatically in older tissue. A better understanding of the fate of cell D and exchange between tissues could be essential for understanding the mechanism of the abnormal accumulation. The fate of red blood cell D was investigated by the use of phenylhydrazine-induced hyperhaemolysis. The effect of atrophy on D tissue levels was studied in the perineal muscles of castrated rats. Influence of D transportation between tissues on the levels of D was studied by the use of age-mismatched heterotopic transplantation of D-rich-hearts from older (22 months old) donor rats in younger (3 months old) D-poor syngenic recipients. Increased red blood cell destruction by splenic macrophages did not cause accumulation but rather a significant depletion of the D content of the spleen. The shrinkage of tissues by endocrine or disuse atrophy did not affect the D content of muscle, where D concentration increased. No significant net redistribution of D was observed from the transplanted older heart to liver and tissues of younger recipients. In conclusion, phagocytosis appears to be the only process resulting in the disposal of tissue D.     

A role for superoxide in gentamicin-mediated nephropathy in rats

Gentamicin is an antibiotic effective against Gram-negative infection, whose clinical use is limited by its nephrotoxicity. Oxygen free radicals are considered to be important mediators of gentamicin-mediated nephrotoxicity, but the exact nature of the radical in question is not known with certainty. We have investigated the potential role of superoxide in gentamicin-induced renal toxicity by using M40403, a low molecular weight synthetic manganese containing superoxide dismutase mimetic, which selectively removes superoxide. Administration of gentamicin at 100 mg/kg, s.c. for 5 days to rats induced a marked renal failure, characterised by a significant decrease in creatinine clearance and increased plasma creatinine levels, fractional excretion of sodium, lithium, urine gamma glutamyl transferase (gamma GT) and daily urine volume. A significant increase in kidney myeloperoxidase activity and lipid peroxidation was also observed in gentamicin-treated rats. M40403 (10 mg/kg, i.p. for 5 days) attenuated all these parameters of damage. Immunohistochemical localisation demonstrated nitrotyrosine formation and poly(ADP-ribose) synthetase (PARS) activation in the proximal tubule of gentamicin-treated rats. Renal histology examination confirmed tubular necrosis. M40403 significantly prevented gentamicin-induced nitrotyrosine formation, poly(ADP-ribose) synthetase activation and tubular necrosis. These results confirm our hypothesis that superoxide anions play an important role in gentamicin-mediated nephropathy and support the possible clinical use of low molecular weight synthetic superoxide dismutase mimetics in those conditions that are associated with over production of superoxide.     

Definition of platelet-derived histamine-releasing factor and histaminergic receptors modulating platelet aggregation.

Endogenous and exogenous free radical scavengers significantly decrease mast cell histamine release induced by coincubation with resting, activated platelets or with platelet-derived supernatant. Histamine and pyridylethylamine dose-dependently enhance platelet aggregation; the effect is potentiated by ranitidine and blocked by mepyramine. Histamine increases also cytosolic calcium concentration in platelets stimulated with thrombin, and binding sites for [3H]-mepyramine are present on platelet membranes.