Tyrphostin AG126 modulates Toll-like receptor (TLR) activation-induced functions in microglia by protein tyrosine kinase (PTK) -dependent and -independent mechanisms

TL;DRAbstract

Tyrphostins comprise a class of synthetic protein tyrosine kinase (PTK) inhibitors structurally derived from tyrosine and aimed at the specific prevention of substrate phosphorylation. The tyrphostin AG126 revealed anti-inflammatory properties in numerous animal disease models, including septic shock induced by lipopolysaccharide (LPS) of gram-negative bacteria and bacterial meningitis induced by gram-positive cell walls. We now show beneficial effects in another CNS complication, in experimental autoimmune encephalomyelitis (EAE) as a model of multiple sclerosis, where AG126 treatment ameliorated clinical signs and myelin damage. At a cellular level, AG126 affected several functions of microglia, the CNS macrophages, as triggered by the activation of Toll-like receptors (TLR s). These innate immune receptors can sense microbial structures as well as factors generated by tissue injuries. For the first time, the present work addressed molecular targets and mechanisms of AG126 action, wi

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