title: The neuroprotection exerted by memantine, minocycline and lithium, against neurotoxicity of CSF from patients with amyotrophic lateral sclerosis, is antagonized by riluzole.
abstract: In a recent study we found that cerebrospinal fluids (CSFs) from amyotrophic lateral sclerosis (ALS) patients caused 20-30% loss of cell viability in primary cultures of rat embryo motor cortex neurons. We also found that the antioxidant resveratrol protected against such damaging effects and that, surprisingly, riluzole antagonized its protecting effects. Here we have extended this study to the interactions of riluzole with 3 other recognized neuroprotective agents, namely memantine, minocycline and lithium. We found: (1) by itself riluzole exerted neurotoxic effects at concentrations of 3-30 µM; this cell damage was similar to that elicited by 30 µM glutamate and a 10% dilution of ALS/CSF; (2) memantine (0.1-30 µM), minocycline (0.03-1 µM) and lithium (1-80 µg/ml) afforded 10-30% protection against ALS/CSF-elicited neurotoxicity, and (3) at 1-10 µM, riluzole antagonized the protection afforded by the 3 agents. These results strongly support the view that at the riluzole concentrations reached in the brain of patients, the neurotoxic effects of this drug could be masking the potential neuroprotective actions of new compounds being tested in clinical trials. Therefore, in the light of the present results, the inclusion of a group of patients free of riluzole treatment may be mandatory in future clinical trials performed in ALS patients with novel neuroprotective compounds.
authors.affiliation: Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Yáñez
authors.forename: Jorge
authors.initials: J
authors.lastname: Matías-Guiu
authors.forename: Juan-Alberto
authors.initials: JA
authors.lastname: Arranz-Tagarro
authors.forename: Lucía
authors.initials: L
authors.lastname: Galán
authors.forename: Dolores
authors.initials: D
authors.lastname: Viña
authors.forename: Ulises
authors.initials: U
authors.lastname: Gómez-Pinedo
authors.forename: Alvaro
authors.initials: A
authors.lastname: Vela
authors.forename: Antonio
authors.initials: A
authors.lastname: Guerrero
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martínez-Vila
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008559:Memantine / Q000494:pharmacology; D008911:Minocycline / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D019782:Riluzole / Q000633:toxicity*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D019782:Riluzole; D008094:Lithium; D008911:Minocycline; D008559:Memantine