Selective mGluR1 Antagonist EMQMCM Inhibits the Kainate-Induced Excitotoxicity in Primary Neuronal Cultures and in the Rat Hippocampus

• Published in: Neurotoxicity research Vol. 21; no. 4; pp. 379 - 392
• Main Authors: Śmiałowska, Maria, Gołembiowska, Krystyna, Kajta, Małgorzata, Zięba, Barbara, Dziubina, Anna, Domin, Helena
• Format: Journal Article
• Language: English
• Published: New York Springer-Verlag 01.05.2012
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Biomedical and Life Sciences; Biomedicine; Caspase 3 - metabolism; Caspase-3; Cell Biology; Cell culture; Cerebral Cortex - drug effects; Cerebral Cortex - pathology; Degeneration; Dose-Response Relationship, Drug; Drug Interactions; Enumeration; Excitotoxicity; gamma -Aminobutyric acid; gamma-Aminobutyric Acid - metabolism; Glutamatergic transmission; Glutamic acid; Glutamic Acid - metabolism; Glutamic acid receptors (metabotropic); Hippocampus; Hippocampus - drug effects; Hippocampus - pathology; Kainic Acid - administration & dosage; Kainic Acid - antagonists & inhibitors; Kainic Acid - toxicity; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - metabolism; Male; Metabotropic receptors; Mice; Microdialysis; Microinjections; Nerve Degeneration - chemically induced; Nerve Degeneration - pathology; Neurobiology; Neurochemistry; Neurology; Neurons; Neuroprotection; Neuroprotective Agents - pharmacology; Neurosciences; Neurotoxicity; Neurotransmission; Pharmacology/Toxicology; Primary Cell Culture; Quinolines - administration & dosage; Quinolines - pharmacology; Rats; Rats, Wistar; Neuroprotection; Metabotropic glutamate receptors; mGlu1 antagonist; Kainic acid; Excitotoxicity; EMQMCM
• ISSN: 1029-8428; 1476-3524
• DOI: 10.1007/s12640-011-9293-4

Abundant evidence suggests that indirect inhibitory modulation of glutamatergic transmission, via metabotropic glutamatergic receptors (mGluR), may induce neuroprotection. The present study was designed to determine whether the selective antagonist of mGluR1 (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM), showed neuroprotection against the kainate (KA)-induced excitotoxicity in vitro and in vivo. In in vitro studies on mouse primary cortical and hippocampal neuronal cultures, incubation with KA (150 μM) induced strong degeneration [measured as lactate dehydrogenase (LDH) efflux] and apoptosis (measured as caspase-3 activity). EMQMCM (0.1–100 μM) added 30 min to 6 h after KA, significantly attenuated the KA-induced LDH release and prevented the increase in caspase-3 activity in the cultures. Those effects were dose- and time-dependent. In in vivo studies KA (2.5 nmol/1 μl) was unilaterally injected into the rat dorsal CA1 hippocampal region. Degeneration was calculated by counting surviving neurons in the CA pyramidal layer using stereological methods. It was found that EMQMCM (5–10 nmol/1 μl) injected into the dorsal hippocampus 30 min, 1 h, or 3 h (the higher dose only) after KA significantly prevented the KA-induced neuronal degeneration. In vivo microdialysis studies in rat hippocampus showed that EMQMCM (100 μM) significantly increased γ-aminobutyric acid (GABA) and decreased glutamate release. When perfused simultaneously with KA, EMQMCM substantially increased GABA release and prevented the KA-induced glutamate release. The obtained results indicate that the mGluR1 antagonist, EMQMCM, may exert neuroprotection against excitotoxicity after delayed treatment (30 min to 6 h). The role of enhanced GABAergic transmission in the neuroprotection is postulated.