Excitotoxic motoneuron degeneration induced by glutamate receptor agonists and mitochondrial toxins in organotypic cultures of chick embryo spinal cord.

Full Abstract

Glutamate receptor-mediated excitotoxicity and mitochondrial dysfunction appear to play an important role in motoneuron (MN) degeneration in amyotrophic lateral sclerosis (ALS). In the present study we used an organotypic slice culture of chick embryo spinal cord to explore the responsiveness of mature MNs to different excitotoxic stimuli and mitrochondrial inhibition. We found that, in this system, MNs are highly vulnerable to excitotoxins such as glutamate, N-methyl-D-aspartate (NMDA), and kainate (KA), and that the neuroprotective drug riluzole rescues MNs from KA-mediated excitotoxic death. MNs are also sensitive to chronic mitochondrial inhibition induced by malonate and 3-nitropropionic acid (3-NP) in a dose-dependent manner. MN degeneration induced by treatment with mitochondrial toxins displays structural changes similar to those seen following excitotoxicity and can be prevented by applying either the antiexcitotoxic drug 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX) or riluzole. Excitotoxicity results in an increased frequency of normal spontaneous Ca2+ oscillations in MNs, which is followed by a sustained deregulation of intracellular Ca2+. Tolerance to excitotoxic MN death resulting from chronic exposure to excitotoxins correlates with a reduced excitotoxin-induced increase in intracellular Ca2+ and increased thapsigargin-sensitive Ca2+ stores.

Author information

Author/s: Brunet, Núria (N); Tarabal, Olga (O); Esquerda, Josep E (JE); Calderó, Jordi (J);

Affiliation: Unitat de Neurobiologia Cel.lular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), 25008 Lleida, Catalonia, Spain.

Journal and publication information

Publication Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't

Journal: The Journal of comparative neurology (J Comp Neurol), published in United States. (Language: eng)

Reference: 2009-Oct; vol 516 (issue 4) : pp 277-90

Dates: Created 2009/08/11; Completed 2009/11/02;

PMID: 19634179, status: MEDLINE (last retrieval date: 11/2/2009, IMS Date: )

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Calcium Signaling - drug effects
Chick Embryo
Disease Models, Animal
Dose-Response Relationship, Drug
Excitatory Amino Acid Agonists - toxicity
Glutamic Acid - toxicity
Kainic Acid - toxicity
Malonates - toxicity
Mitochondria - drug effects
Motor Neuron Disease - pathology

Motor Neuron Disease - pathology
Motor Neurons - drug effects; pathology
N-Methylaspartate - toxicity
Nerve Degeneration - chemically induced; pathology
Neuroprotective Agents - pharmacology
Neurotoxins - toxicity
Nitro Compounds - toxicity
Organ Culture Techniques
Propionic Acids - toxicity
Riluzole - pharmacology
Spinal Cord - drug effects; pathology

Associated Chemicals: Excitatory Amino Acid Agonists (0) ; Malonates (0) ; Neuroprotective Agents (0) ; Neurotoxins (0) ; Nitro Compounds (0) ; Propionic Acids (0) ; malonic acid (141-82-2) ; Riluzole (1744-22-5) ; Kainic Acid (487-79-6) ; 3-nitropropionic acid (504-88-1) ; Glutamic Acid (56-86-0) ; N-Methylaspartate (6384-92-5)

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