ABSTRACT
There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.
Subject(s)
Drug Evaluation, Preclinical/methods , Neuroprotective Agents/therapeutic use , Oligodendrocyte Precursor Cells/drug effects , Remyelination , Animals , Cell Differentiation , Cell Proliferation , Clinical Trials as Topic , Mice , Myelin Sheath/drug effects , Oligodendrocyte Precursor Cells/metabolismABSTRACT
OBJECTIVE: to evaluate whether oral supplementation with zinc or zinc/arginine increases the antibody response to influenza vaccine or modulates the lymphocyte phenotype in elderly subjects. DESIGN: a randomized controlled trial with two supplemented groups and one control group. SETTING: a community nursing home. PARTICIPANTS: 384 subjects aged 64-100 (mean age 82 years) examined in three separate studies. INTERVENTION: oral supplementation with zinc (400 mg/day) or zinc plus arginine (4 g/day) for 60 days starting 15 days before influenza vaccination. The control groups received vaccine only. MEASUREMENTS: haematological and nutritional indices, antibody titre against influenza viral antigens, lymphocyte phenotype. RESULTS: supplementation with zinc or zinc plus arginine increased zinc plasma concentrations restoring the age-related impairment in zinc concentrations to values found in younger people. The antibody titre against influenza viral antigens was not increased in zinc or zinc/arginine supplemented groups in comparison with subjects receiving vaccine alone. The number of CD3, CD4 or CD8 lymphocytes was not affected by zinc or zinc/arginine supplementation. CONCLUSION: prolonged supplementation with zinc or zinc/arginine restores zinc plasma concentrations but is ineffective in inducing or ameliorating the antibody response after influenza vaccination in elderly subjects.
Subject(s)
Antibodies, Viral/immunology , Arginine/pharmacology , Dietary Supplements , Influenza Vaccines/immunology , Lymphocyte Subsets/drug effects , Zinc/pharmacology , Aged , Aged, 80 and over , Antibodies, Viral/blood , Arginine/administration & dosage , Arginine/blood , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Female , Hematology , Humans , Immunophenotyping , Lymphocyte Subsets/immunology , Male , Middle Aged , Nutritional Status , Vaccination , Zinc/administration & dosage , Zinc/bloodABSTRACT
We studied the ultrastructural morphology and function of platelets collected by apheresis procedure with discontinuous flow using the Surge Pump Technique. The platelet concentrates obtained by this technique are free of erythrocyte and lymphocyte contamination. The platelet morphology as well as the platelet aggregation induced by ADP, adrenaline and collagen of platelet concentrates were similar to those observed in PRP before the apheresis. The response to the hypotonic shock of platelet concentrates was also normal, indicating membrane integrity and good platelet metabolism. These results show that platelet concentrates obtained by the Surge Pump Technique maintain their haemostatic effects and may be infused in thrombocitopenic patients, reducing the risk of alloimmunization related to the presence of erythrocytes and lymphocytes.
