ag-556 and Multiple-Sclerosis

Tyrosine kinase blockers from the AG 126/AG-556 tyrphostin family are shown to inhibit the lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNFalpha), nitric oxide (NO), and prostaglandin E2 (PGE2) in primary rat astrocytes cultures. The tyrphostin AG-556 which was previously shown to be effective against sepsis in mice and dogs also show excellent efficacy in inhibiting experimental autoimmune encephalomyelitis (EAE) in mice. AG-556 does not block the activation of JNK/SAPK and of p38/HOG and therefore seems to act at a target down stream to these kinases which is activated in stress or at a target on an obligatory parallel pathway. These findings together with previous results showing inhibition of sepsis in mice and dogs suggest that protein tyrosine kinase (PTK) blockers of the AG-556 family may be considered in the management of human autoimmune disorders such as multiple sclerosis (MS).

Topics: Animals; Astrocytes; Calcium-Calmodulin-Dependent Protein Kinases; Cells, Cultured; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Female; Immunosuppressive Agents; JNK Mitogen-Activated Protein Kinases; Lymphocyte Activation; MAP Kinase Kinase 4; Mice; Mice, Inbred Strains; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Multiple Sclerosis; Nitric Oxide; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinases; Rats; Specific Pathogen-Free Organisms; Tumor Necrosis Factor-alpha; Tyrosine; Tyrphostins