Glutamate AMPA receptors change in motor neurons of SOD1G93A transgenic mice and their inhibition by a noncompetitive antagonist ameliorates the progression of amytrophic lateral sclerosis-like disease

Massimo Tortarolo; Giuliano Grignaschi; Novella Calvaresi; Eleonora Zennaro; Gabriella Spaltro; Milena Colovic; Claudia Fracasso; Giovanna Guiso; Bernd Elger; Herbert Schneider; Bernd Seilheimer; Silvio Caccia; Caterina Bendotti

doi:10.1002/jnr.20715

Glutamate AMPA receptors change in motor neurons of SOD1G93A transgenic mice and their inhibition by a noncompetitive antagonist ameliorates the progression of amytrophic lateral sclerosis-like disease

J Neurosci Res. 2006 Jan;83(1):134-46. doi: 10.1002/jnr.20715.

Authors

Massimo Tortarolo¹, Giuliano Grignaschi, Novella Calvaresi, Eleonora Zennaro, Gabriella Spaltro, Milena Colovic, Claudia Fracasso, Giovanna Guiso, Bernd Elger, Herbert Schneider, Bernd Seilheimer, Silvio Caccia, Caterina Bendotti

Affiliation

¹ Mario Negri Institute for Pharmacological Research, Milano, Italy. [email protected]

PMID: 16323214
DOI: 10.1002/jnr.20715

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder involving the selective degeneration of motor neurons. In a small proportion of patients, ALS is caused by mutations in copper/zinc superoxide dismutase (SOD1), and mice overexpressing SOD1(G93A) mutant develop a syndrome that closely resembles the human disease. Excitotoxicity mediated by glutamate AMPA receptors has been suggested to be implicated in the selective susceptibility of motor neurons occurring in ALS. In SOD1(G93A) mice, we found that levels of GluR2 AMPA subunit, which plays a pivotal role in the maintenance of calcium impermeability of AMPA receptors, are decreased in spinal motor neurons before symptom onset in concomitance with a modest increase of GluR3 expression, a calcium-permeable AMPA subunit. This effect can result in a higher number of calcium-permeable AMPA receptors on motor neurons of SOD1(G93A) mice, predisposing these cells to be injured by AMPA-mediated glutamate firing. In support of this, we showed that treatment with a new noncompetitive AMPA antagonist, ZK 187638, partially protected motor neurons, improved motor function, and prolonged the survival of SOD1(G93A) mice.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / drug therapy*
Amyotrophic Lateral Sclerosis / mortality
Amyotrophic Lateral Sclerosis / pathology
Animals
Behavior, Animal / drug effects
Benzodiazepines / pharmacokinetics
Benzodiazepines / therapeutic use*
Blotting, Western
Choline O-Acetyltransferase / genetics
Choline O-Acetyltransferase / metabolism
Dioxoles / pharmacokinetics
Dioxoles / therapeutic use*
Excitatory Amino Acid Antagonists / pharmacokinetics
Excitatory Amino Acid Antagonists / therapeutic use*
Humans
Immunohistochemistry
In Situ Hybridization
Locomotion / drug effects
Locomotion / genetics
Locomotion / physiology
Mice
Mice, Transgenic
Motor Neurons / physiology*
Postural Balance / drug effects
Postural Balance / physiology
RNA, Messenger / biosynthesis
RNA, Messenger / genetics
Receptors, AMPA / antagonists & inhibitors*
Receptors, AMPA / biosynthesis
Receptors, AMPA / genetics
Superoxide Dismutase / genetics*
Superoxide Dismutase-1
Survival

Substances

2,3-dimethyl-6-phenyl-12H-(1,3)dioxolo(4,5-h)imidazo(1,2-c)(2,3)benzodiazepine
Dioxoles
Excitatory Amino Acid Antagonists
RNA, Messenger
Receptors, AMPA
SOD1 protein, human
glutamate receptor ionotropic, AMPA 3
Benzodiazepines
Sod1 protein, mouse
Superoxide Dismutase
Superoxide Dismutase-1
Choline O-Acetyltransferase
glutamate receptor ionotropic, AMPA 2