The oxidative neurotoxicity of clioquinol.
Clioquinol is a metal chelator that may attenuate beta-amyloid deposition and mitigate the progression of Alzheimer's disease. Its prior use as a systemic antibiotic was associated with a neurodegenerative syndrome, subacute myelo-optico-neuropathy (SMON), although a mechanistic link has not been precisely defined. While testing clioquinol in murine cortical cultures, it was observed to have a pro-oxidant effect. Exposure to 1-3 microM for 24 h increased malondialdehyde, and resulted in death of approximately 40% of neurons; a higher concentration (30 microM) was paradoxically less toxic. Both malondialdehyde production and cell death were attenuated by concomitant treatment with the antioxidants ascorbic acid and Trolox C, or with the lipid-soluble metal chelator 1,10-phenanthroline. In contrast, injury was increased in cultures prepared from mice lacking heme oxygenase-2, which protects against non-heme mediated oxidative injury to neurons. Addition of vitamin B12 to the culture medium was not cytoprotective. These results suggest that therapeutically relevant concentrations of clioquinol are toxic to cultured neurons by an oxidative mechanism that is unrelated to vitamin B12 deficiency. In vivo evaluation of the pro-oxidant effect of clioquinol seems warranted prior to further clinical trials.
Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Thompson Building Room 239, Philadelphia, PA 19107, USA.
Luna
L
Benvenisti-Zarom
Jing
J
Chen
Raymond F
RF
Regan
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000633:toxicity*; D007464:Clioquinol / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors; D006454:Hemoglobins / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008858:Microscopy, Phase-Contrast; D009474:Neurons / Q000187:drug effects*; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D010618:Phenanthrolines / Q000633:toxicity; D014805:Vitamin B 12 / Q000494:pharmacology
D000975:Antioxidants; D002614:Chelating Agents; D006454:Hemoglobins; D016877:Oxidants; D010618:Phenanthrolines; D008315:Malondialdehyde; D007464:Clioquinol; D007770:L-Lactate Dehydrogenase; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D014805:Vitamin B 12; C025205:1,10-phenanthroline