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ToxSci Advance Access published online on October 12, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj008
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 15, 2005
Accepted September 28, 2005

Neurotoxicology

Sequential Involvement of Distinct Glutamate Receptors in Domoic Acid-Induced Neurotoxicity in Rat Mixed Cortical Cultures: Effect of Multiple Dose/Duration Paradigms, Chronological Age and Repeated Exposure

Shenfeng Qiu 1, C. Wook Pak 2, and Margarita C. Currás-Collazo 3*

1 Environmental Toxicology Graduate Program, University of California, Riverside
2 Department of Cell Biology & Neuroscience, University of California, Riverside
3 Environmental Toxicology Graduate Program, University of California, Riverside; Department of Cell Biology & Neuroscience, University of California, Riverside

* To whom correspondence should be addressed.
Margarita C. Currás-Collazo, E-mail: margarita.curras{at}ucr.edu


  Abstract

The increasing occurrence of poisoning accidents in marine animals caused by the amnesic shellfish toxin, domoic acid (DOM), necessitates a better understanding of the factors contributing to DOM neurotoxicity. Here we evaluated the contribution and temporal involvement of NMDA, non-NMDA- and metabotropic-type glutamate receptors (GluRs) in DOM-induced neuronal death using rat primary mixed cortical cultures. Co-application of antagonists for AMPA/kainate- (NBQX) and NMDA-type GluRs (D-AP5) but not metabotropic GluRs reduced DOM toxicity induced by either of three EC50 dose/duration exposure paradigms. Maximal protection offered by D-AP5 and NBQX either extended or not to the 30 to 60 min period after DOM exposure, respectively. Antagonists were ineffective if applied with a 2 hr delay indicating the presence of a critical time window for neuronal protection after DOM exposure. Early effects correlated with neuronal swelling seen as early as 10 min post-DOM, and which has been linked to non-NMDAR-mediated depolarization and release of endogenous glutamate. That DOM toxicity is dictated by iGluRs is supported by the finding that increased efficacy and potency of DOM with in vitro neuronal maturation are positively correlated with elevated protein levels of iGluR subunits, including NR1, GluR1, GluR2/3, GluR5 and GluR6/7. We determined the timecourse of DOM excitotoxicity: At > 10 µM maximal neuronal death occurs within 2 hr while doses ≤ 10 µM continue to produce death during the subsequent 22 hr washout period, indicating a quicker progression of the neuronal death cascade with high DOM concentrations. Accordingly, NBQX applied 30 min post-DOM afforded better protection against low dose/prolonged duration (3 µM/24 h) than against high dose/brief duration exposure (50 µM/10 min). Interestingly, prior exposure to subthreshold DOM dose-dependently aggravated toxicity produced by a subsequent exposure to DOM. These findings provide greater insight into the complex properties underlying DOM toxicity, including the sequential involvement of multiple GluRs, degree of neuronal maturation and protein levels of iGluRs, dose and duration and prior history of DOM exposure.

Keywords: excitotoxicity; metabotropic glutamate receptors; AMPA receptors; NMDA receptors; development; amnesic shellfish poisoning.
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