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Neurosteroids and glutamate toxicity in fibroblasts expressing human NMDA receptors

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Abstract

We charactrized glutamate receptor-mediated toxicity in mouse fibroblasts expressing the human NR1a/2A or NR1a/2B NMDA receptor. After induction of NMDA receptor, cells in both lines died over a 24 h time period. This toxicity was associated with a progressive increase in the glutamate content of the media. Cell death could be prevented by including either the non-competitive NMDA receptor antagonist ketamine or the competitive antagonist, d,l-AP-5. Cells expressing NR1a/2A receptors were maximally protected by 0.5 mM d,l-AP-5, while those expressing NR1a/2B receptors required 2 mM d,l-AP-5 for maximal protection. The neurosteroid pregnanolone sulfate, which negatively modulates NMDA receptor function, partially protected fibroblasts containing NR1a/2A or NR1a/2B NMDA receptor constructs. However, the neurosteroid pregnenolone sulfate, which has been reported to act as a positive allosteric modulator of the NMDA receptor, had no effect on the toxicity caused by endogenous glutamate. Our results on cells expressing human NMDA receptors suggest that certain neurosteriods may protect against NMDA induced toxicity while having low neurotoxic liabilities of their own.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Queen's University, K7L 3N6, Kingston, Ont., Canada

    M. Scott, J. J. Tanguay, K. Jhamandas & R. J. Boegman

  2. Department of Psychology, Queen's University, K7L 3N6, Kingston, Ont., Canada

    R. J. Beninger

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  1. M. Scott
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  2. J. J. Tanguay
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  3. R. J. Beninger
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  4. K. Jhamandas
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  5. R. J. Boegman
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Correspondence to R. J. Boegman.

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Scott, M., Tanguay, J.J., Beninger, R.J. et al. Neurosteroids and glutamate toxicity in fibroblasts expressing human NMDA receptors. neurotox res 4, 183–190 (2002). https://doi.org/10.1080/10298420290033223

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  • DOI: https://doi.org/10.1080/10298420290033223

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