Zinc pre-treatment enhances NMDAR-mediated excitotoxicity in cultured cortical neurons from SOD1 G93A mouse, a model of amyotrophic lateral sclerosis

Michele Nutini, Valerio Frazzini, Claudia Marini, Alida Spalloni, Stefano L. Sensi, Patrizia Longone

Research output: Contribution to journalArticle

Abstract

Zn 2+ is co-released at glutamatergic synapses throughout the central nervous system and acts as a neuromodulator for glutamatergic neurotransmission, as a key modulator of NMDA receptor functioning. Zn 2+ is also implicated in the neurotoxicity associated with several models of acute brain injury and neurodegeneration. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons in the spinal cord and cortex. In this study, we have investigated the modulatory role exerted by Zn 2+ in NMDA-mediated neurotoxicity in either near-pure or mixed cortical cultured neurons obtained from either mice over-expressing the G93A mutant form of Cu/Zn superoxide dismutase (SOD1) human gene, a gene linked to familial ALS, or wild type (WT) mice. To that aim, SOD1 G93A or WT cultures were exposed to either NMDA by itself or to Zn 2+ prior to a toxic challenge with NMDA, and neuronal loss evaluated 24 h later. While we failed to observe any significant difference between NMDA and Zn 2+/NMDA-mediated toxicity in mixed SOD1 G93A or WT cortical cultures, different vulnerability to these toxic paradigms was found in near-pure neuronal cultures. In the WT near-pure neuronal cultures, a brief exposure to sublethal concentrations of Zn 2+-enhanced NMDA receptor-mediated cell death, an effect that was far more pronounced in the SOD1 G93A cultures. This increased excitotoxicity in SOD1 G93A near-pure neuronal cultures appears to be mediated by a significant increase in NMDA-dependent rises of intraneuronal Ca 2+ levels as well as enhanced production of cytosolic reactive oxygen species, while the injurious process seems to be unrelated to activation of nNOS or ERK1/2 pathways. This article is part of a Special Issue entitled 'Trends in Neuropharmacology: In Memory of Erminio Costa'.

Original languageEnglish
Pages (from-to)1200-1208
Number of pages9
JournalNeuropharmacology
Volume60
Issue number7-8
DOIs
Publication statusPublished - Jun 2011

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Keywords

  • ALS
  • Calcium
  • Cortical neuron
  • NMDA neurotoxicity
  • Zinc

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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