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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

Insights into the Mechanisms of Ifosfamide Encephalopathy: Drug Metabolites Have Agonistic... 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 Ca 2+ i response of single mouse cortical neurons to SCMC and TDGA was investigated. SCMC, but not TDGA, evoked a robust increase in Ca 2+ i concentration 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-5 H -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 (pH i ) 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 pH i response. Application of the lactate transport inhibitor quercetin diminished the pH i 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Pharmacology and Experimental Therapeutics Am. Soc for Pharma & Experimental Therapeutics

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

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

The Journal of Pharmacology and Experimental Therapeutics , Volume 299 (3): 1161 – Dec 1, 2001

Abstract

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 Ca 2+ i response of single mouse cortical neurons to SCMC and TDGA was investigated. SCMC, but not TDGA, evoked a robust increase in Ca 2+ i concentration 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-5 H -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 (pH i ) 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 pH i response. Application of the lactate transport inhibitor quercetin diminished the pH i 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.

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Publisher
Am. Soc for Pharma & Experimental Therapeutics
Copyright
Copyright © Journal of Pharmacology and Experimental Therapeutics
ISSN
0022-3565
eISSN
1521-0103
Publisher site

Abstract

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 Ca 2+ i response of single mouse cortical neurons to SCMC and TDGA was investigated. SCMC, but not TDGA, evoked a robust increase in Ca 2+ i concentration 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-5 H -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 (pH i ) 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 pH i response. Application of the lactate transport inhibitor quercetin diminished the pH i 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.

Journal

The Journal of Pharmacology and Experimental TherapeuticsAm. Soc for Pharma & Experimental Therapeutics

Published: Dec 1, 2001

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