Protective effect of metabotropic glutamate receptor inhibition on amyotrophic lateral sclerosis-cerebrospinal fluid toxicity in vitro

Neuroscience. 2006 Sep 15;141(4):1879-86. doi: 10.1016/j.neuroscience.2006.05.044. Epub 2006 Jul 3.


Conflicting results have been reported concerning the toxicity of cerebrospinal fluid from patients with amyotrophic lateral sclerosis (ALS-CSF) when added to neuronal cultures. The possible toxic factor(s) and the exact mode of action (e.g. requirement of glial cells) have not been identified so far. Glutamate is a potential candidate for this toxic effect, since antagonists of ionotropic glutamate receptors have been shown to attenuate ALS-CSF toxicity. We studied the effects of ALS-CSF on mixed and motoneuron-enriched chick embryonic spinal cord cultures. We found a toxic action of ALS-CSF in both culture types which could not be attenuated by 5 kDa-filtration or 15 min 90 degrees C heating. Nevertheless, the metabotropic glutamate receptor (mGluR) group I antagonist 1-aminoindan-1,5-dicarboxylic acid, but also the group I agonist (s)-3,5-dihydroxyphenylglycine (DHPG) exerted protective effects against ALS-CSF toxicity. In this experimental setting, DHPG may functionally act via a receptor blockade due to sustained activation. No protective effect was seen with the mGluR group III inhibitor (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). Addition of DHPG did not increase the protective action of the AMPA inhibitor 6-chloro-4-hydroxyquinoline-2-carboxylic acid (6-CKU). Addition of l-glutamate did not mimic these toxic ALS-CSF effects in motoneuron-enriched cultures. Our experiments demonstrate that ALS-CSF toxicity is mediated by a small heat-resistant molecule which may act directly on neurons. Since blockade of group I mGluRs exerts a protective effect, the possibility of targeting these mGluRs pharmacologically in motoneuron disease should be kept in mind.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis / cerebrospinal fluid*
  • Animals
  • Cell Count / methods
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cells, Cultured
  • Cerebrospinal Fluid / chemistry
  • Cerebrospinal Fluid / drug effects*
  • Cerebrospinal Fluid / metabolism
  • Chick Embryo
  • Coculture Techniques / methods
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • Glutamic Acid / pharmacology
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Humans
  • Immunohistochemistry / methods
  • In Situ Nick-End Labeling
  • Indans / pharmacology
  • Indoles
  • Lectins
  • Male
  • Middle Aged
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism*
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / physiology
  • Spinal Cord / cytology
  • Time Factors


  • 1-aminoindan-1,5-dicarboxylic acid
  • Excitatory Amino Acid Antagonists
  • Indans
  • Indoles
  • Lectins
  • Receptors, Metabotropic Glutamate
  • cyclopropyl-4-phosphonophenylglycine
  • Glutamic Acid
  • DAPI
  • Glycine