The novel and systemically active metabotropic glutamate 1 (mGlu1) receptor antagonist 3-MATIDA reduces post-ischemic neuronal death.

Abstract

We examined the pharmacological properties of 3-methyl-aminothiophene dicarboxylic acid (3-MATIDA) by measuring second messenger responses in baby hamster kidney cells stably transfected with mGlu1a, mGlu2, mGlu4a or mGlu5a receptors and ionotropic glutamate receptor agonist-induced depolarizations in mouse cortical wedges. 3-MATIDA was a potent (IC(50)=6.3 microM, 95% confidence limits 3-15) and relatively selective mGlu1 receptor antagonist. When tested on mGlu2, mGlu4 or mGlu5 receptors its IC(50) was >300 microM. When tested in cortical wedges, however, 3-MATIDA was also able to antagonize AMPA or NMDA responses with an IC(50) of 250 microM. When present in the incubation medium of cultured murine cortical cells, 3-MATIDA (1-100 microM) significantly reduced the death of neurons induced by 60 min of oxygen and glucose deprivation (OGD), even when added up to 60 min after OGD. A similar neuroprotective activity was observed when 3-MATIDA was present at 10-100 microM in the medium of rat organotypic hippocampal slice cultures exposed to 30 min OGD. Systemic administration of 3-MATIDA (3-10 mg/kg, immediately and 1 h after the onset of ischemia) reduced the volume of brain infarcts following permanent middle cerebral artery occlusion in rats. Our results show that 3-MATIDA is a potent and possibly selective mGlu 1 receptor antagonist that may be considered as a novel prototype neuroprotective agent.

• Authors: Flavio Moroni, Sabina Attucci, Andrea Cozzi, Elena Meli, Roberta Picca, Mark A Scheideler, Roberto Pellicciari, Christian Noe, Iran Sarichelou, Domenico E Pellegrini-Giampietro
• Journal: Neuropharmacology (Neuropharmacology) Vol. 42 Issue 6 Pg. 741-51 (May 2002) ISSN: 0028-3908 [Print] England
• PMID: 12015200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-methyl-aminothiophene dicarboxylic acid
• Excitatory Amino Acid Antagonists
• Receptors, Metabotropic Glutamate
• Thiophenes
• metabotropic glutamate receptor type 1

Topics

• Animals
• Brain Ischemia (drug therapy, pathology)
• Cell Death (drug effects)
• Cell Hypoxia (drug effects, physiology)
• Cells, Cultured
• Cricetinae
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Antagonists (chemistry, pharmacology, therapeutic use)
• Hippocampus (drug effects, pathology)
• Infarction, Middle Cerebral Artery (drug therapy, pathology)
• Mice
• Neurons (drug effects, pathology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Metabotropic Glutamate (antagonists & inhibitors, physiology)
• Thiophenes (chemistry, pharmacology, therapeutic use)