ABSTRACT
The entorhinal cortex lesion paradigm is a widely accepted and efficient method to provoke reactive synaptogenesis and terminal remodeling in the adult CNS. This approach has been used successfully to contrast the profile of reactivity from various proteins associated with Alzheimer's disease pathophysiology in wild-type and apolipoprotein E (apoE)-deficient (APOE ko) mice. Results indicate that the production of the beta-amyloid 1-40 peptide (A beta 40) is increased in response to neuronal injury, with a timing that is different between wild-type and APOE ko animals. Moreover, we report that baseline levels of the A beta 40 peptide are significantly higher in the APOE ko mice. The expression of the apolipoprotein E receptor type 2 (apoER2) is also modulated by the deafferentation process in the hippocampus, but only in APOE ko mice. These results provide novel insights as to the molecular mechanisms responsible for the poor plastic response reported in apoE4-expressing and apoE deficient mice in response to hippocampal injury.
Subject(s)
Amyloid beta-Peptides/metabolism , Apolipoproteins E/physiology , Brain Injuries/pathology , Gene Expression Regulation/physiology , Hippocampus/metabolism , Peptide Fragments/metabolism , Receptors, Lipoprotein/metabolism , Animals , Apolipoproteins E/deficiency , Brain Injuries/etiology , Electrolysis/adverse effects , Enzyme-Linked Immunosorbent Assay/methods , Functional Laterality/physiology , Hippocampus/injuries , LDL-Receptor Related Proteins , Mice , Mice, Inbred C57BL , Mice, Knockout , Time FactorsABSTRACT
Cysteinyl leukotrienes are potent inflammatory molecules playing a major role in asthma. The involvement of these mediators in hypersensitivity in mice is not well known. This study aimed at elucidating their implication by using MK-571, a cysLT(1)receptor antagonist. Mice were sensitized with a suspension of ovalbumin (8 microg) adsorbed to alum (2 mg) and were challenged with an aerosolized ovalbumin solution (0.5%). Inflammatory cell infiltration in the bronchoalveolar lavage (mostly eosinophils) following antigen challenge was inhibited by dexamethasone (0.1, 1 and 5 mg kg(-1)s.c.) and MK-571 (1, 10, 100 mg kg(-1)i.v.) in a dose-dependent manner. Maximal inhibition was 95% with 5 mg kg(-1)dexamethasone and 90% with 100 mg kg(-1)MK-571. When injected together they showed an additive inhibitory effect on eosinophil infiltration. Bronchial hyperreactivity, measured by the increased pulmonary insufflation pressure to carbachol injections, was also inhibited dose-dependently by MK-571. The EC(50)values for carbachol were of 22.39+/-1.12 microg kg(-1)in sensitized and challenged animals that did not receive MK-571 and increased to 43.65+/-1.10, 50.12+/-1.15 and 83.18+/-1.16 microg kg(-1)in animals treated with 1, 10 and 100 mg kg(-1)MK-571 respectively. Lung microvascular leakage (as measured by Evans blue extravasation) induced by antigen bronchoprovocation was reduced by 22% after treatment with 10 mg kg(-1)MK-571. All these inhibitory effects of MK-571 suggest a role for leukotriene D(4)in this animal model of allergic asthma.
Subject(s)
Asthma/drug therapy , Leukotriene Antagonists , Leukotriene D4/antagonists & inhibitors , Membrane Proteins , Propionates/pharmacology , Quinolines/pharmacology , Receptors, Leukotriene , Animals , Asthma/immunology , Asthma/physiopathology , Bronchial Hyperreactivity/drug therapy , Bronchial Hyperreactivity/physiopathology , Bronchial Provocation Tests , Bronchoalveolar Lavage Fluid/chemistry , Capillary Permeability/drug effects , Dexamethasone/pharmacology , Disease Models, Animal , Drug Therapy, Combination , Leukotriene D4/physiology , Male , Mice , Mice, Inbred BALB C , Ovalbumin/immunology , Propionates/therapeutic use , Pulmonary Eosinophilia/drug therapy , Quinolines/therapeutic useABSTRACT
OBJECTIVE AND DESIGN: This study evaluated the complement activation in guinea pigs that were given an intravenous injection of Sephadex and its correlation with markers of the development of inflammation. MATERIALS AND METHODS: Dunkin Hartley guinea pigs (250-300 g) were used. Whole blood was collected by heart puncture in a sodium citrate solution (0.315 g/ml) for complement measurements. Complement activation was measured using a colorimetric haemolytic assay. Bronchoalveolar lavages (BAL) were performed to monitor cell infiltration and inflammation was monitored by measurements of eosinophil peroxidase (EPO), histamine, beta-glucuronidase, albumin and total proteins in the BAL fluid. TREATMENT: Guinea pigs were pre-treated with aprotinin (40000 IKU/kg) 30 min before they were given an intravenous injection of Sephadex beads (24 mg/kg). Carboxymethyl (CM)-Sephadex (24 mg/kg) was administered alone. RESULTS: Sephadex beads activated the complement system in vitro (14.12+/-2.29 U/ml) and in vivo (9.95+/-0.08 U/ml) reaching a peak 6 h after the injection. This activation was accompanied by other characteristic features of inflammation such as leukocyte infiltration and activation. Both CM-Sephadex and aprotinin reduced the blood complement activation and eosinophil infiltration/activation observed. CONCLUSIONS: Our results strongly suggest that complement is involved in the cascade of events leading to the inflammatory state observed in guinea pig following the intravenous injection of Sephadex beads.
