title: Selective mGluR1 antagonist EMQMCM inhibits the kainate-induced excitotoxicity in primary neuronal cultures and in the rat hippocampus.
abstract: 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.
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland. nfsmialo@cyf-kr.edu.pl
authors.forename: Maria
authors.initials: M
authors.lastname: Śmiałowska
authors.forename: Krystyna
authors.initials: K
authors.lastname: Gołembiowska
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Kajta
authors.forename: Barbara
authors.initials: B
authors.lastname: Zięba
authors.forename: Anna
authors.initials: A
authors.lastname: Dziubina
authors.forename: Helena
authors.initials: H
authors.lastname: Domin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007608:Kainic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008845:Microinjections; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D061251:Primary Cell Culture; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C502015:(3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxycyclohexyl)methanone methanesulfonate; D018696:Neuroprotective Agents; D011804:Quinolines; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D007608:Kainic Acid