ag-490 and Nerve-Degeneration

The present study shows that JAK2-STAT3 inflammatory signaling mediates thrombin-stimulated microglia activation. In rat primary microglia, thrombin rapidly activated JAK2 and induced phosphorylation of STAT3. In addition, thrombin increased transcription of the inflammation-associated genes tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), production of TNF-alpha, NO and induced neurodegeneration of dopaminergic neurons in mesencephalic cultures. AG490, a JAK inhibitor, markedly reduced activation of JAK2 and STAT3 in thrombin-treated microglia. AG490 also inhibited thrombin-induced transcription and expression of TNF-alpha, iNOS and/or NO release, moreover rescued dopaminergic neurons. These results suggest that JAK2-STAT3 signaling pathway plays a critical role in mediating thrombin-induced activation of microglia and degeneration of dopaminergic neurons.

Topics: Animals; Animals, Newborn; CD11b Antigen; Cells, Cultured; Coculture Techniques; Dopamine; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Janus Kinase 2; Mesencephalon; Microglia; Nerve Degeneration; Neurons; Nitric Oxide; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Thrombin; Time Factors; Tumor Necrosis Factor-alpha; Tyrphostins