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Title: Attenuation of malonate toxicity in primary mesencephalic cultures using the GABA transport blocker, NO-711.

Authors: Stokes, A H; Bernard, L P; Nicklas, W J; Zeevalk, G D

Published In J Neurosci Res, (2001 Apr 1)

Abstract: Cultured rat mesencephalic neurons were used to assess the effects of gamma-aminobutyric acid (GABA) transport blockers on toxicity caused by malonate, a reversible, competitive inhibitor of succinate dehydrogenase. Previous studies utilizing an ex vivo chick retinal preparation have shown that GABA release and cell swelling are early consequences of acute energy impairment and that GABA transport blockers attenuate this toxicity. The present results demonstrate that the nonsubstrate GABA transport blocker, NO-711 (1 nM-1 microM), dose-dependently protected cultured mesencephalic dopamine (DA) and GABA neurons from malonate-induced toxicity. Similar protection was demonstrated with nipecotic acid (1 mM) and SKF89976A (100 nM), substrate and nonsubstrate GABA transport blockers, respectively. These compounds by themselves produced no signs of toxicity, although nipecotic acid caused a long-term decrease in GABA uptake not associated with toxicity. Compounds which decrease intracellular reactive oxygen species (ROS) are protective in this model, but NO-711 did not prevent the rise in intracellular ROS induced by malonate, indicating its protective effects were downstream of ROS production. Supplementation of malonate treated cultures with the GABA(A) agonist, muscimol (10 microM), increased the toxicity toward the DA and GABA neuron populations. Antagonists at the GABA(A) and glycine receptors provided partial protection to both the GABA and DA neurons. These findings suggest that the GABA transporter, GABA(A), and/or glycine channels contribute to cell damage associated with energy impairment in this model.

PubMed ID: 11276050 Exiting the NIEHS site

MeSH Terms: Animals; Cells, Cultured; Dopamine/metabolism; Dose-Response Relationship, Drug; Drug Synergism; GABA Antagonists/pharmacology*; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Malonates/antagonists & inhibitors*; Malonates/poisoning*; Mesencephalon/cytology; Mesencephalon/drug effects*; Mesencephalon/metabolism; Muscimol/pharmacology; Neurons/drug effects; Neurons/metabolism; Nipecotic Acids/pharmacology*; Oximes/pharmacology*; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species/metabolism; gamma-Aminobutyric Acid/metabolism

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