1. The effect of high dilutions of two homeopathic drugs Lung histamine (Lung his) and Apis mellifica (Apis mel) used for the treatment of allergic diseases has been assessed on in vitro human basophil degranulation. Experiments were conducted blind. 2. Basophil degranulation induced by 1.66 X 10(-9) M anti-IgE antibody was significantly inhibited in the presence of 5 Lung his (5th centesimal dilution of Lung his) and 15 Lung his (15th centesimal dilution of Lung his) by 28.8% and 28.6% respectively and by 65.8% in the presence of 9 Apis mel (9th centesimal dilution of Apis mel). Basophil degranulation induced by 1.66 X 10(-16) to 1.66 X 10(-18) M anti-IgE antibody was also inhibited by high dilutions of Lung his and Apis mel with an inhibition of nearly 100% with 18 Lung his (18th centesimal dilution of Lung his) and 10 Apis mel (10th centesimal dilution of Apis mel). An alternance of inhibition, inactivity and stimulation was observed when basophils were incubated in the presence of serial dilutions of Lung his and Apis mel. 3. The investigation of the clinical efficacy of high dilutions of Lung his and Apis mel should be envisaged in allergic diseases in parallel with in vitro and ex vivo biological assays.
This work describes a study of the effects of combined oral contraceptives (OCs) on lipid biosynthesis in platelets of female rats and women. A highly significant hypercoagulability due solely to increased activity of platelet factor 3 can be observed in women using combined OCs. The phospholipidic nature of factor 3 has been demonstrated. Phospholipids are implicated in the aggregation of platelets because they are the essential constituents of the platelet membranes and the precursors of prostaglandins. Platelets actively synthesize their own lipids, and combined OCs modify serum lipid metabolism. In each experiment, a control group of rats weighing 180-200 g received .5 ml/g body weight of olive oil once daily for 4 days. 3 groups of experimental rats received .5 ml of olive oil containing 10 mcg of ethinyl estradiol (EE) and 250 mcg of lynestrenol or 10 mcg of EE alone or 250 mcg of lynestrenol alone per 100 g of body weight. The doses were the equivalent of 1/2 that required to block ovulation in adult female rats. Platelets were studied on the 5th day. In another experiment a group of rats was given a triple dose of EE and lynestrenol on the 1st study day. Platelets were studied on days 1, 3, 5, and 8. Lipid biosynthesis was studied by incorporation of carbon 14 labelled acetate and mevalonate precursors. Radioactivity was measured for the lipids as a whole and for different lipid fractions separated by chromatography. Incorporation of carbon 14 labelled acetate was augmented by 44.6% in animals receiving EE and lynestrenol and by 43% in animals receiving EE alone, but was not modified in animals receiving lynestrenol alone. In animals receiving a triple dose of hormones, incorporation was maximal on the 3rd day, diminished on the 5th day, and normal after 8 days. The EE component thus appears to be responsible for modifications in platelet lipid metabolism during OC use. The response appears after a latency period and seems to be irreversible, since the duration of life of platelets is 4-5 days. The increased synthesis occurs mainly in cholesterol and its precursors lanosterol and dihydrolanosterol. Supplemental in vitro experiments suggested that lanosterol was responsible for the increased platelet activity. 17 nonsmoking women aged 32 years on average who took no medications were compared to 18 women aged 30 years on average who took OCs with estrogen doses of 30-40 mcg for at least 6 months. As in the rat studies, lipid biosynthesis was analyzed by incorporation of carbon 14 labelled acetate or mevalonate in the platelets. Compared to control women, the women on OCs showed an augmentation of 37% in incorporation of mevalonate and 28% of acetate. The labelled acetate showed a higher incorporation at the level of each of the lipid fractions. Mevalonate showed the highest augmentation in the lanosterol fraction. 43% of the women taking OCs showed an increased platelet sensitivity to thrombine. The increased sensitivity was correlated with increased lanosterol synthesis, but the relation was only observed in women taking OCs. The phenomenon is of interest because of its possible relationship to the increased risk of thromboembolic accidents in women taking OCs.
We previously reported that some N-methyl-d-aspartate (NMDA)-receptor antagonists enhanced histamine neuron activity in rodents. Here, we have investigated the effects of memantine, an NMDA-receptor antagonist used for the treatment of Alzheimer9s disease, on histaminergic neurotransmission. In vitro, memantine antagonized native NMDA receptors with a micromolar potency but had no effect at recombinant human histamine receptors. In vivo, a single administration of memantine increased histamine neuron activity, as shown by the 60% increase of tele-methylhistamine (t-MeHA) levels observed in the brain of mice. This increase occurred with an ED50 of 0.3 ± 0.1 mg/kg, similar to that found on inhibition of ex vivo [3H]dizocilpine maleate (MK-801) binding (1.8 ± 1.3 mg/kg). Two days after pretreatment of mice with memantine at 5 mg/kg twice daily for 5 days, t-MeHA levels were enhanced by 50 ± 7% (p < 0.001), indicating a long-lasting activation of histamine neurons. Quantitative polymerase chain reaction analysis was used to explore genes involved in this persistent effect. H3 receptor mRNAs were strongly increased, but the density of H3 receptor binding sites was increased solely in hypothalamus (by 141 ± 24%). Up-regulations of brain-derived neurotrophic factor and NMDA-receptor 1 subunit mRNAs were also found but were restricted to hippocampus. mRNA expression of α7-nicotinic receptors remained unchanged in any region. Considering the well established cognitive effects of histamine neurons, the increase in brain t-MeHA levels after single or repeated administration of therapeutic doses of memantine suggests that the drug exerts its beneficial effects on cognitive deficits of Alzheimer9s disease, at least partly, by activating histamine neurons.
Abstract Genetic factors are known to contribute to Late Onset Alzheimer’s disease (LOAD) but their contribution to pathophysiology, specially to prodomic phases accessible to therapeutic approaches are far to be understood. To translate genetic risk of Alzheimer’s disease (AD) into mechanistic insight, we generated transgenic mouse lines that express a ∼195 kbp human BAC that includes only BIN1 , a gene associated to LOAD. This model gives a modest BIN1 overexpression, dependent of the number of BAC copies. At 6 months of age, we detected impaired entorhinal cortex (EC)-hippocampal pathways with specific impairments in EC-dentate gyrus synaptic long-term potentiation, dendritic spines of granular cells and recognition episodic memory. Structural changes were quantified using MRI. Their whole-brain functional impact were analyzed using resting state fMRI with a hypoconnectivity centered on entorhinal cortex. These early phenotype defects independent of any changes in A-beta can be instrumental in the search for new AD drug targets.
