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

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 μM, 95% confidence limits 3–15) and relatively selective mGlu1 receptor antagonist. When tested on mGlu2, mGlu4 or mGlu5 receptors its IC 50 was >300 μM. When tested in cortical wedges, however, 3-MATIDA was also able to antagonize AMPA or NMDA responses with an IC 50 of 250 μM. When present in the incubation medium of cultured murine cortical cells, 3-MATIDA (1–100 μM) 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 μM 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.