Archives of Toxicology

, Volume 77, Issue 12, pp 663–671 | Cite as

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

  • Jarkko Loikkanen
  • Jonne Naarala
  • Kirsi H. Vähäkangas
  • Kai M. Savolainen
Inorganic Compounds

Abstract

Recent studies point to an interaction between the glutamatergic neurotransmitter system and inorganic lead (Pb) neurotoxicity. Pb (1–100 µM) 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 µM), 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 µM) 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 µM) 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.

Keywords

Lead Glutamate Reactive oxygen species Glutathione Calcium channels Neurons 

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Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Jarkko Loikkanen
    • 1
  • Jonne Naarala
    • 2
  • Kirsi H. Vähäkangas
    • 1
  • Kai M. Savolainen
    • 3
  1. 1.Department of Pharmacology and ToxicologyUniversity of KuopioKuopioFinland
  2. 2.Department of Environmental SciencesUniversity of KuopioKuopioFinland
  3. 3.Department of Industrial Hygiene and ToxicologyFinnish Institute of Occupational HealthHelsinkiFinland

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