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, apomorphine, a potent dopamine agonist, displays efficient anti-parkinsonian properties, but the consequences of its oxidant and toxic properties have been poorly 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. Apomorphine-promoted cell death was proportional to its concentration and was time-dependent. The ED(50) of apomorphine on C6 cell death after 48 hr was about 200 microM. 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 underwent treatment with 400 microM apomorphine for 6 hr displayed features of necrosis, including loss of membrane integrity, degeneration of mitochondria, and DNA fragmentation. Thiols, such as cysteine, N-acetyl-L-cysteine, and glutathione, significantly protected cultured neurons and C6 cells against apomorphine-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.
dos Santos El-Bachá
R
R
UMR 7561 CNRS-Université Henri Poincaré-Nancy 1, Laboratoire de Pharmacologie, Faculté de Médecine, B.P. 184, F-54505 Cedex, Vandoeuvre-lès-Nancy, France.
Daval
J
J
Koziel
V
V
Netter
P
P
Minn
A
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001058:Apomorphine / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D018491:Dopamine Agonists / Q000633:toxicity; D004347:Drug Interactions; D004587:Electrophoresis, Agar Gel; D009457:Neuroglia / Q000187:drug effects* / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D010084:Oxidation-Reduction / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D051381:Rats
D000975:Antioxidants; D018491:Dopamine Agonists; D020011:Protective Agents; D011506:Proteins; D004247:DNA; D001058:Apomorphine