Journal
CURRENT NEUROPHARMACOLOGY
Volume 7, Issue 1, Pages 60-64Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/157015909787602788
Keywords
Fumaric acid; immunomodulation; multiple sclerosis; neuroprotective effects; phase II study
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Fumaric acid is an intermediate product of the citric acid cycle that is a source of intracellular energy in the form of adenosine triphosphate (ATP). It is generated by oxidation of adenylsuccinate by the enzyme succinate dehydrogenase and is then converted to maleate by the enzyme fumarase. At present, fumaric acid esters (FAE) are licensed for the treatment of psoriasis. Several lines of evidence have demonstrated immunomodulatory effects for FAE. Clinical studies in psoriasis showed a reduction of peripheral CD4(+)- and CD8(+)- T-lymphocytes due to the ability of FAE to induce apoptosis. In vitro studies with the ester dimethyl fumarate (DMF) described an inhibitory effect on nuclear factor kappa B (NF-kappa B)-dependent transcription of tumor necrosis factor-alpha (TNF-alpha) induced genes in human endothelial cells. Animal studies using a model of central nervous system demyelination, MOG-induced experimental autoimmune encephalomyelitis (EAE), revealed a reduction of microglia and macrophages in inflamed lesions. A phase II clinical study in relapsing-remitting multiple sclerosis (RRMS) patients with a modified fumaric acid ester, BG-12, showed as proof of principle a significant reduction in the number of gadolinium enhancing lesions after 24 weeks of treatment as compared to placebo. Further phase III studies have now started to explore the long-term efficacy of FAE.
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