Involvement of p38 mitogen-activated protein kinase activation in bromocriptine-induced apoptosis in rat pituitary GH3 cells

Bromocriptine, a dopamine D-2 receptor agonist, is a therapeutic agent for patients with prolactinoma and hyperprolactinemia. In this study we demonst rated that bromocriptine induced activation of p38 mitogen-activated protei n (MAP) kinase, with concomitant induction of apoptosis in rat pituitary ad enoma cell line GH3 cells. Treatment of GH3 cells for 48 h with bromocripti ne increased the p38 MAP kinase activity up to 3- to 5-fold and simultaneou sly increased the number of apoptotic cells. Inclusion in the medium of SB2 12090 or SB203580, specific p38 MAP kinase inhibitors, completely abolished the bromocriptine-induced activation of p38 MAP kinase and significantly r educed the number of apoptotic cells. The bromocriptine-induced p38 MAP kin ase activation was not prevented by S(-)-eticropride hydrochloride, a speci fic D-2 receptor antagonist. Treatment with either epidermal growth factor (EGF) or thyrotropin-releasing hormone (TRH), which stimulates p44/42 MAP k inase, rescued cells from the bromocriptine-induced apoptosis, with concomi tant inhibition of the bromocriptine-induced p38 MAP kinase activation. The se results suggest that bromocriptine induces apoptosis in association with p38 MAP kinase activation, and that the p44/42 MAP kinase signaling throug h EGF and TRH receptors has an opposing effect on p38 MAP kinase activation as well as on apoptosis induced with bromocriptine in GH3 cells.