thrombinactivated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures dual roles of mitogenactivated protein kinase signaling pathways this study evaluated the role of thrombinactivated microglia in the neurodegeneration of mesencephalic cultures immunocytochemical and biochemical evidence indicated that in cocultures consisting of rat cortical microglia and mesencephalic neurons thrombin led to nonselective loss of mesencephalic neurons accompanying neurodegeneration microglial activation was obvious evidenced by expression of tumor necrosis factor tnfalpha interleukin il6 il1beta inducible nitric oxide synthase inos and cyclooxygenase2 cox2 and by increasing production of tnfalpha and nitric oxide no in mesencephalic neurons treated with conditioned media cm taken from thrombinactivated microglia the number of dopaminergic neurons was significantly attenuated the neurotoxicity of the cm was diminished when it was derived from microglia cotreated with thrombin and either an extracellular signalregulated kinase 12 erk12 pathway inhibitor pd98059 or a p38mitogenactivated protein kinase p38mapk inhibitor sb203580 moreover jun nterminal kinase jnk and p38mapk were activated in mesencephalic neurons treated with cm of thrombinactivated microglia inhibition of jnk and p38mapk rescued the dopaminergic neurons collectively these results indicate that thrombinactivated microglia induce neurodegeneration in cultured mesencephalic neurons and that the mapks actively participate in both microglial activation and neurodegeneration the present data carefully suggest that microglial activation triggered by thrombin may be involved in the neuropathological processes of dopaminergic neuronal cell death that occur in parkinsons disease