Ebselen, a redox regulator containing a selenium atom, induces neurofilament M expression in cultured rat pheochromocytoma PC12 cells via activation of mitogen‐activated protein kinase

We found that ebselen [2‐phenyl‐1,2‐benzisoselenazol‐3(2H)‐one] caused phosphorylation of mitogen‐activated protein kinase (MAPK), followed by expression of neurofilament‐M, a neuron‐specific protein, in cultured PC12 rat pheochromocytoma cells. The ebselen‐induced MAPK activation was suppressed by U0126, an inhibitor of MAPK kinase (MEK1/2), but not by K252a, a selective inhibitor of Trk family tyrosine kinases; AG1478, an antagonist of epidermal growth factor receptor (EGFR); pertussis toxin, an inhibitor of Gi/o; or GP antagonist‐2A, an inhibitor of Gq. Furthermore, we observed that N ‐acetyl‐ L ‐cysteine, an inhibitor of tyrosine kinases, suppressed ebselen‐induced MAPK activation and buthionine sulfoximine, an activator of protein tyrosine phosphatases, enhanced the effect, indicating that ebselen activated MEK1/2 through one or more tyrosine kinases. Based on these results, we propose that ebselen stimulated intracellular tyrosine kinase activity, thus activating a MAPK cascade (tyrosine kinase–MEK1/2–ERK1/2) in PC12 cells and that this activation resulted in their neuronal differentiation. © 2007 Wiley‐Liss, Inc.