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Research ArticleNEUROPHARMACOLOGY

Insights into the Mechanisms of Ifosfamide Encephalopathy: Drug Metabolites Have Agonistic Effects on α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)/Kainate Receptors and Induce Cellular Acidification in Mouse Cortical Neurons

Jean-Yves Chatton, Jeffrey R. Idle, Cathrine Broberg Vågbø and Pierre J. Magistretti
Journal of Pharmacology and Experimental Therapeutics December 2001, 299 (3) 1161-1168;
Jean-Yves Chatton
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Jeffrey R. Idle
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Cathrine Broberg Vågbø
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Pierre J. Magistretti
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Abstract

Therapeutic value of the alkylating agent ifosfamide has been limited by major side effects including encephalopathy. Although the underlying biochemical processes of the neurotoxic side effects are still unclear, they could be attributed to metabolites rather than to ifosfamide itself. In the present study, the effects of selected ifosfamide metabolites on indices of neuronal activity have been investigated, in particular for S-carboxymethylcysteine (SCMC) and thiodiglycolic acid (TDGA). Because of structural similarities of SCMC with glutamate, the Ca2+i response of single mouse cortical neurons to SCMC and TDGA was investigated. SCMC, but not TDGA, evoked a robust increase in Ca2+iconcentration that could be abolished by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but only partly diminished by the N-methyl-d-aspartate receptor antagonist 10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK=801). Cyclothiazide (CYZ), used to prevent AMPA/kainate receptor desensitization, potentiated the response to SCMC. Because activation of AMPA/kainate receptors is known to induce proton influx, the intracellular pH (pHi) response to SCMC was investigated. SCMC caused a concentration-dependent acidification that was amplified by CYZ. Since H+/monocarboxylate transporter (MCT) activity leads to similar cellular acidification, we tested its potential involvement in the pHi response. Application of the lactate transport inhibitor quercetin diminished the pHi response to SCMC and TDGA by 43 and 51%, respectively, indicating that these compounds may be substrates of MCTs. Taken together, this study indicates that hitherto apparently inert ifosfamide metabolites, in particular SCMC, activate AMPA/kainate receptors and induce cellular acidification. Both processes could provide the biochemical basis of the observed ifosfamide-associated encephalopathy.

Footnotes

  • ↵1 Current address: Zlatá 34, 36005 Karlovy Vary, Czech Republic (on leave of absence).

  • This work was supported by Grant 31-55786.98 from the Swiss National Science Foundation (to J.-Y.C.).

  • Abbreviations:
    SCMC
    S-carboxymethylcysteine
    pHi
    intracellular pH
    Ca2+i
    intracellular Ca2+
    BCECF
    2′,7′-bis(carboxyethyl)-5,6-carboxyfluorescein
    NMDA
    N-methyl-d-aspartate
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    AM
    acetoxymethyl ester
    SCEC
    S-carboxyethylcysteine
    CNQX
    6-cyano-7-nitroquinoxaline-2,3-dione
    TDGA
    thiodiglycolic acid
    CYZ
    cyclothiazide
    MESNA
    sodium 2-mercaptoethanesulfonate
    MCT
    monocarboxylate transporter
    MK-801
    10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine
    α-CIN
    α-cyano-4-hydroxycinnamate
    • Received May 14, 2001.
    • Accepted August 31, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 3
1 Dec 2001
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Research ArticleNEUROPHARMACOLOGY

Insights into the Mechanisms of Ifosfamide Encephalopathy: Drug Metabolites Have Agonistic Effects on α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)/Kainate Receptors and Induce Cellular Acidification in Mouse Cortical Neurons

Jean-Yves Chatton, Jeffrey R. Idle, Cathrine Broberg Vågbø and Pierre J. Magistretti
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 1161-1168;

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Research ArticleNEUROPHARMACOLOGY

Insights into the Mechanisms of Ifosfamide Encephalopathy: Drug Metabolites Have Agonistic Effects on α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)/Kainate Receptors and Induce Cellular Acidification in Mouse Cortical Neurons

Jean-Yves Chatton, Jeffrey R. Idle, Cathrine Broberg Vågbø and Pierre J. Magistretti
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 1161-1168;
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