Development of nmdar antagonists with reduced neurotoxic side effects

A study on GK11

Delphine Vandame, Lauriane Ulmann, Marisa Teigell, Monica Prieto-Cappellini, Jacques Vignon, Alain Privat, Regino Perez-Polo, Olivera Nesic, Helene Hirbec

    Research output: Contribution to journalArticle

    6 Citations (Scopus)

    Abstract

    The NMDAR glutamate receptor subtype mediates various vital physiological neuronal functions. However, its excessive activation contributes to neuronal damage in a large variety of acute and chronic neurological disorders. NMDAR antagonists thus represent promising therapeutic tools that can counteract NMDARs' overactivation. Channel blockers are of special interest since they are use-dependent, thus being more potent at continuously activated NMDARs, as may be the case in pathological conditions. Nevertheless, it has been established that NMDAR antagonists, such as MK801, also have unacceptable neurotoxic effects. Presently only Memantine is considered a safe NMDAR antagonist and is used clinically. It has recently been speculated that antagonists that preferentially target extrasynaptic NMDARs would be less toxic. We previously demonstrated that the phencyclidine derivative GK11 preferentially inhibits extrasynaptic NMDARs. We thus anticipated that this compound would be safer than other known NMDAR antagonists. In this study we used whole-genome profiling of the rat cingulate cortex, a brain area that is particularly sensitive to NMDAR antagonists, to compare the potential adverse effects of GK11 and MK801. Our results showed that in contrast to GK11, the transcriptional profile of MK801 is characterized by a significant upregulation of inflammatory and stress-response genes, consistent with its high neurotoxicity. In addition, behavioural and immunohistochemical analyses confirmed marked inflammatory reactions (including astrogliosis and microglial activation) in MK801-treated, but not GK11-treated rats. Interestingly, we also showed that GK11 elicited less inflammation and neuronal damage, even when compared to Memantine, which like GK11, preferentially inhibits extrasynaptic NMDAR. As a whole, our study suggests that GK11 may be a more attractive therapeutic alternative in the treatment of CNS disorders characterized by the overactivation of glutamate receptors.

    Original languageEnglish (US)
    Article numbere81004
    JournalPLoS One
    Volume8
    Issue number11
    DOIs
    StatePublished - Nov 19 2013

    Fingerprint

    antagonists
    adverse effects
    Memantine
    Glutamate Receptors
    inflammation
    Rats
    Genes
    Chemical activation
    therapeutics
    neurotoxicity
    nervous system diseases
    rats
    Phencyclidine
    Poisons
    Gyrus Cinguli
    gacyclidine
    Nervous System Diseases
    stress response
    cortex
    Brain

    ASJC Scopus subject areas

    • Agricultural and Biological Sciences(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Medicine(all)

    Cite this

    Vandame, D., Ulmann, L., Teigell, M., Prieto-Cappellini, M., Vignon, J., Privat, A., ... Hirbec, H. (2013). Development of nmdar antagonists with reduced neurotoxic side effects: A study on GK11. PLoS One, 8(11), [e81004]. https://doi.org/10.1371/journal.pone.0081004

    Development of nmdar antagonists with reduced neurotoxic side effects : A study on GK11. / Vandame, Delphine; Ulmann, Lauriane; Teigell, Marisa; Prieto-Cappellini, Monica; Vignon, Jacques; Privat, Alain; Perez-Polo, Regino; Nesic, Olivera; Hirbec, Helene.

    In: PLoS One, Vol. 8, No. 11, e81004, 19.11.2013.

    Research output: Contribution to journalArticle

    Vandame, D, Ulmann, L, Teigell, M, Prieto-Cappellini, M, Vignon, J, Privat, A, Perez-Polo, R, Nesic, O & Hirbec, H 2013, 'Development of nmdar antagonists with reduced neurotoxic side effects: A study on GK11', PLoS One, vol. 8, no. 11, e81004. https://doi.org/10.1371/journal.pone.0081004
    Vandame D, Ulmann L, Teigell M, Prieto-Cappellini M, Vignon J, Privat A et al. Development of nmdar antagonists with reduced neurotoxic side effects: A study on GK11. PLoS One. 2013 Nov 19;8(11). e81004. https://doi.org/10.1371/journal.pone.0081004
    Vandame, Delphine ; Ulmann, Lauriane ; Teigell, Marisa ; Prieto-Cappellini, Monica ; Vignon, Jacques ; Privat, Alain ; Perez-Polo, Regino ; Nesic, Olivera ; Hirbec, Helene. / Development of nmdar antagonists with reduced neurotoxic side effects : A study on GK11. In: PLoS One. 2013 ; Vol. 8, No. 11.
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