ascorbic-acid and Spinal-Cord-Diseases

Clear therapeutic guidelines for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-α and high-dose ascorbic acid (AA) monotherapy in a large open clinical trial. However, there is a lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-α treatment in the context of HAM/TSP. Therefore, we performed the first comparative analysis of the ex vivo and in vitro molecular and cellular mechanisms of action of IFN-α and high-dose AA in HAM/TSP.. Through thymidine incorporation and quantification of Th1/Th2/Th17 cytokines, we demonstrate that high-dose AA displays differential and superior antiproliferative and immunomodulatory effects over IFN-α in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-α, induced cell death in both HAM/TSP PBMCs and HTLV-1-infected T-cell lines MT-2 and MT-4. Microarray data combined with pathway analysis of MT-2 cells revealed AA-induced regulation of genes associated with cell death, including miR-155. Since miR-155 has recently been demonstrated to up-regulate IFN-γ, this microRNA might represent a novel therapeutic target in HAM/TSP, as recently demonstrated in multiple sclerosis, another neuroinflammatory disease. On the other hand, IFN-α selectively up-regulated antiviral and immune-related genes.. In comparison to IFN-α, high-dose AA treatment has superior ex vivo and in vitro cell death-inducing, antiproliferative and immunomodulatory anti-HTLV-1 effects. Differential pathway activation by both drugs opens up avenues for targeted treatment in specific patient subsets.

Topics: Adult; Aged; Antineoplastic Agents; Ascorbic Acid; Cell Death; Cells, Cultured; Female; Gene Expression Profiling; Humans; Immunologic Factors; Interferon-alpha; Leukemia-Lymphoma, Adult T-Cell; Male; Microarray Analysis; Middle Aged; Organ Culture Techniques; Spinal Cord Diseases; Young Adult

Topics: Adult; Amino Acids; Anemia, Hemolytic; Ascorbic Acid; Cerebellar Diseases; Cyanides; Electroencephalography; Electromyography; Erythrocytes; Female; Glutathione; Humans; Leukocytes; Male; Metabolism, Inborn Errors; Muscles; Neural Conduction; Peptide Synthases; Potassium; Renal Aminoacidurias; Spinal Cord Diseases; Syndrome

We determined the respiration, respiratory control, and Pi:O ratios with different substrates in mitochondria isolated from five cases of human neuromuscular disorders (two cases of central core disease, two cases of neuropathy of Dejerine-Sottas, and one case of Kugelberg-Welander's disease) and compared them with normal human muscle. In all the myopathies studied, a severe derangement of the respiratory control with variable derangement of oxidative phosphorylation was found. This supports the idea that a group of neuromyopathies shares the same biochemical lesion as the so-called mitochondrial myopathies, forming with them a group of myopathies which may be related through a similar biochemical lesion of varying degree. Alternatively, disturbance of mitochondrial functions in a number of myopathies could be considered as a non-specific finding.

Topics: Adenosine Diphosphate; Adolescent; Adult; Ascorbic Acid; Child; Female; Glutamates; Humans; Hypertrophy; Infant; Malates; Male; Middle Aged; Mitochondria, Muscle; Motor Neurons; Muscular Atrophy; Muscular Diseases; Myotonic Dystrophy; Neuromuscular Diseases; Oxidative Phosphorylation; Oxidative Phosphorylation Coupling Factors; Oxygen Consumption; Phosphates; Spinal Cord Diseases; Succinates