Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy

Ngomba, R. T. and Santolini, I. and Biagioni, F. and Molinaro, G. and Simonyi, A. and Van Rijn, C. M. and D'Amore, V. and Mastroiacovo, F. and Olivieri, G. and Gradini, R. and Ferraguti, F. and Battaglia, G. and Bruno, V. and Puliti, A. and Van Luijtelaar, G. and Nicoletti, F. (2011) Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy. Neuropharmacology, 60 (7-8). pp. 1281-1291. ISSN 0028-3908

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Abstract

Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1α receptors than age-matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs. This article is part of a Special Issue entitled 'Trends in Neuropharmacology: In Memory of Erminio Costa'. © 2011 Elsevier Ltd. All rights reserved.

Keywords:9h xanthene 9 carboxylic acid(4 trifluoromethyloxazol 2 yl)amide, metabotropic receptor 1, metabotropic receptor agonist, ro 0711401, syn 119, unclassified drug, (3,4 dihydro 2h pyranol2,3 bquinolin 7yl)(cis 4 ethoxycycloexyl) methanone, 2 methyl 6 (phenylethynyl)pyridine, 3,5 dihydroxyphenylglycine, 9h xanthene 9 carboxylix acid (4 trifluoromethyl oxazol 2 yl)amide, messenger RNA, metabotropic receptor 1alpha, metabotropic receptor 5, metabotropic receptor antagonist, polyphosphoinositide, absence, animal experiment, animal model, animal tissue, article, brain level, controlled study, dose response, drug dose comparison, drug mechanism, electroencephalogram, male, nonhuman, priority journal, protein expression, protein function, rat, spike wave discharge, thalamus, Wistar albino Glaxo rat, absence, hydrolysis, immunoblotting, immunohistochemistry, in situ hybridization, in vivo study, neuroprotection, protein localization, receptor down regulation, spike wave, thalamus nucleus, thalamus reticular nucleus, ventroposterolateral nucleus, Allosteric Regulation, Animals, Ciprofloxacin, Disease Models, Animal, Dose-Response Relationship, Drug, Electroencephalography, Epilepsy, Absence, Excitatory Amino Acid Antagonists, Motor Activity, Nucleic Acid Synthesis Inhibitors, Quinolines, Rats, Rats, Inbred ACI, Rats, Inbred Strains, Receptors, Metabotropic Glutamate, RNA, Messenger, Signal Transduction, Thalamic Nuclei
Subjects:B Subjects allied to Medicine > B210 Pharmacology
B Subjects allied to Medicine > B140 Neuroscience
Divisions:College of Science > School of Pharmacy
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ID Code:22154
Deposited On:04 Feb 2016 19:58

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