Toxic effects of apomorphine on rat cultured neurons and glial C6 cells, and protection with antioxidants

Many catechol derivatives are currently used as drugs, even if they produce reactive oxygen species that may cause tissue damage. Among them, apomorph ine, a potent dopamine agonist, displays efficient anti-parkinsonian proper ties, but the consequences of its oxidant and toxic properties have been po orly investigated on in vitro models. In the present work, we investigated apomorphine cytotoxicity by incubating cultures of rat glioma C6 cells and primary cultures of neurons with different concentrations of the drug. Apom orphine-promoted cell death was proportional to its concentration and was t ime-dependent. The ED50 of apomorphine on C6 cell death after 48 hr was abo ut 200 muM. The cytotoxic effects induced by apomorphine were correlated to its autoxidation, which leads to the formation of reactive oxygen species, semiquinones, quinones, and a melanin-like pigment. C6 cells that underwen t treatment with 400 muM apomorphine for 6 hr displayed features of necrosi s, including loss of membrane integrity, degeneration of mitochondria, and DNA fragmentation. Thiols, such as cysteine, N-acetyl-L-cysteine, and gluta thione, significantly protected cultured neurons and C6 cells against apomo rphine-induced cytotoxicity. Thiols also inhibited apomorphine autoxidation . These data strongly suggest that apomorphine cytotoxicity towards neurons and C6 cells results from an intracellular oxidative stress. (C) 2000 Else vier Science Inc. All rights reserved.