Article: article from journal or magazin.
Protective effect of metabotropic glutamate receptor inhibition on amyotrophic lateral sclerosis-cerebrospinal fluid toxicity in vitro.
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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.
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, 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/diagnostic use, Lectins/diagnostic use, Male, Middle Aged, Motor Neurons/drug effects, Motor Neurons/metabolism, Receptors, Metabotropic Glutamate/antagonists & inhibitors, Receptors, Metabotropic Glutamate/physiology, Spinal Cord/cytology, Time Factors
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