Get access

Dextromethorphan is protective against sensitized N-methyl-d-aspartate receptor-mediated excitotoxic brain damage in the developing mouse brain

Authors

  • Matthias Keller,

    1. Department of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria
    Search for more papers by this author
    • *

      M.K. and G.S. contributed equally to this work.

  • Elke Griesmaier,

    1. Department of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria
    Search for more papers by this author
  • Maria Auer,

    1. Department of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria
    Search for more papers by this author
  • Gerald Schlager,

    1. Department of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria
    Search for more papers by this author
  • Martina Urbanek,

    1. Department of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria
    Search for more papers by this author
  • Georg Simbruner,

    1. Department of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria
    Search for more papers by this author
  • Pierre Gressens,

    1. INSERM U 676 and Service de Neurologie Pediatrique, Hôpital Robert Debre, Paris, France
    Search for more papers by this author
  • Gergely Sárközy

    1. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
    Search for more papers by this author
    • *

      M.K. and G.S. contributed equally to this work.


Dr Matthias Keller, as above.
E-mail: Matthias.Keller@i-med.ac.at

Abstract

Enhanced glutamate release and inflammation play an important role in the pathogenesis of developmental brain injury. Although N-methyl-d-aspartate receptor (NMDAR) antagonists potently attenuate neonatal brain damage in several animal models, they can also impact trophic functions in the developing brain. As a consequence, high-affinity NMDAR antagonists have been shown to trigger widespread apoptotic neurodegeneration in the newborn brain. Dextromethorphan (DM), a low-affinity NMDAR antagonist with anti-inflammatory properties, may be neuroprotective against excitotoxic and inflammation-enhanced excitotoxic brain injury, without the associated stimulation of apoptotic degeneration. Using an established newborn mouse model of excitotoxic brain damage, we determined whether systemic injection of DM significantly attenuates excitotoxic lesion size. We investigated several doses and time regimens; a dose of 5 µg/g DM given in a combination of both pre-injury and repetitive post-injury treatment proved most effective. DM treatment significantly reduced lesion size in gray and white matter by reducing cell death as shown by a decreased Fluoro-Jade B staining and caspase-3 activation. Pre-treatment with interleukin-1β and lipopolysaccharide enhanced NMDAR-mediated excitotoxic brain injury and microglial cell activation. This sensitizing effect was abolished by DM treatment, as the effectiveness of DM in reducing lesion size and microglial cell activation was similar to phosphate-buffered saline-pre-treated controls. In all cases, no gender-specific differences were detected. DM treatment did not trigger any apoptotic neurodegeneration (caspase-3 cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Fluoro-Jade B staining). Although functional parameters were not measured, our data corroborate reports that DM is neuroprotective and that it may therefore improve functional outcome following perinatal brain injury.

Get access to the full text of this article

Ancillary