Glutamate increases toxicity of inorganic lead in GT1-7 neurons: partial protection induced by flunarizine

Recent studies point to an interaction between the glutamatergic neurotransmitter system and inorganic lead (Pb) neurotoxicity. Pb (1-100 microM) evoked cytotoxicity over the period of 72 h in mouse hypothalamic GT1-7 neurons. Glutamate (0.1 or 1 mM) on its own did not have any effect on cell viabil...

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Bibliographic Details
Published in:Archives of toxicology 2003-12, Vol.77 (12), p.663-671
Main Authors: LOIKKANEN, Jarkko, NAARALA, Jonne, VÄHÄKANGAS, Kirsi H, SAVOLAINEN, Kai M
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biological and medical sciences
Calcium Channel Blockers - pharmacology
Calcium Channels - metabolism
Cell Death - drug effects
Cell Survival - drug effects
Cells, Cultured
Chemical and industrial products toxicology. Toxic occupational diseases
chemoprotection
Dose-Response Relationship, Drug
Environmental Pollutants - toxicity
flunarizine
Flunarizine - pharmacology
Glutamic Acid - metabolism
Glutathione - metabolism
Hypothalamus - cytology
Hypothalamus - metabolism
Lead - toxicity
Medical sciences
Metals and various inorganic compounds
Mice
Neurons - drug effects
Neurons - metabolism
Oxidative Stress - drug effects
Proteins
Reactive Oxygen Species - metabolism
Receptors, Glutamate - metabolism
Toxicology
Verapamil - pharmacology
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Summary:Recent studies point to an interaction between the glutamatergic neurotransmitter system and inorganic lead (Pb) neurotoxicity. Pb (1-100 microM) evoked cytotoxicity over the period of 72 h in mouse hypothalamic GT1-7 neurons. Glutamate (0.1 or 1 mM) on its own did not have any effect on cell viability. However, 1 mM glutamate clearly increased Pb-induced cell death at 48 and 72 h. Although flunarizine (0.1-10 microM), an antagonist of L- and T-type voltage-sensitive calcium channels (VSCCs), partially protected from the cytotoxicity induced by co-exposure to Pb (10 or 100 micro M) and glutamate (1 mM), it had no protective effect on cytotoxicity induced by Pb alone. The flunarizine-induced protection was dependent on time and observed only at 48 h. Neither verapamil, an antagonist of L-type VSCCs, nor DIDS, an inhibitor of anion exchange, at non-toxic concentrations (0.1-10 microM) had any effect on cytotoxicity induced by Pb alone or together with glutamate at any studied time point. Co-exposure to Pb and glutamate also resulted in more prominent production of reactive oxygen species (ROS) than either of the compounds alone. Interestingly, we observed an increase in intracellular glutathione (GSH) levels in cells exposed to micromolar concentrations of Pb. Glutamate decreased the levels of intracellular GSH and also partially reduced the Pb-induced increase in GSH levels. These results suggest that the interaction of glutamate and Pb results in increased neuronal cell death via mechanisms that involve an increase in ROS production, a decrease in intracellular GSH defense against oxidative stress and probably T-type VSCCs.
ISSN:0340-5761
1432-0738
DOI:10.1007/s00204-003-0498-z