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N-Methyl-D-Aspartate Receptor Activation May Contribute to Glufosinate Neurotoxicity
Lantz, S., C. Mack, K. Wallace, E. Key, T. Shafer, AND J. Casida. N-Methyl-D-Aspartate Receptor Activation May Contribute to Glufosinate Neurotoxicity. Presented at Society of Toxicology Meeting, Phoenix, AZ, March 23 - 27, 2014.
N-Methyl-D-aspartate Receptor Activation May Contribute to Glufosinate Neurotoxicity Glufosinate (GLF) at high levels in mammals causes convulsions through a mechanism that is not completely understood. The structural similarity of GLF to glutamate (GLU) implicates the glutamatergic system as a target for GLF neurotoxicity. Therefore, the current work examined GLF interaction with N-methyl-D-aspartate subtype GLU receptors (NMDAR) and GLT-1 transporters via [3H]CGP39653 binding experiments and [3H]GLU uptake assays, respectively. GLF effects on neuronal network activity were assessed using microelectrode array (MEA) recordings in primary cultures of cortical neurons. GLF and its primary metabolite N-Ac-GLF bind to the NMDAR; the IC50 value for GLF was 668 µM. Concentrations of GLF greater than 1 mM were needed to decrease GLU uptake through GLT-I. In MEA recordings from networks of rat primary cortical neurons, the concentration-responses for NMDA, GLF and N-Ac-GLF on network mean firing rates (MFR) were biphasic, increasing at lower concentrations and decreasing below control levels at higher concentrations. Stimulation of MFR occurred between 1-10 µM NMDA (320% control, max), 100-300 µM N-Ac-GLF (190% control, max) and 3-1000 µM GLF (320% control, max). The NMDAR antagonist MK801 attenuated both NMDA and GLF increases in MFR. The GLF concentration required to alter GLU transport through GLT-I is not likely to be attained in vivo, and therefore not relevant to the neurotoxic mode of action. However, toxicokinetic data from reports of intentional human poisonings indicate that GLF concentrations in the CNS after acute exposure could reach levels high enough to lead to effects mediated via NMDA receptors. Furthermore, the newly characterized action of N-Ac-GLF at the NMDA receptor suggests that both the parent compound and metabolite could contribute to neurotoxicity via this pathway. This abstract does not reflect EPA Policy.
Abstract will be presented at the Society of Toxicology Meeting, March 23-27, 2014, Phoenix, AZ
URLs/Downloads:N-METHYL-D-ASPARTATE RECEPTOR ACTIVATION MAY CONTIRUBTE TO GLUFOSINATE NEUROTIXICITY.DOC
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION
SYSTEMS BIOLOGY BRANCH