Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures

Ngomba, Richard T. and Ferraguti, F. and Badura, A. and Citraro, R. and Santolini, I. and Battaglia, G. and Bruno, V. and De Sarro, G. and Simonyi, A. and van Luijtelaar, G. and Nicoletti, F. (2008) Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures. Neuropharmacology, 54 (2). pp. 344-354. ISSN 0028-3908

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Abstract

Individual metabotropic glutamate (mGlu) receptor subtypes have been implicated in the pathophysiology of epileptic seizures, and are potential targets for novel antiepileptic drugs. Here, we examined the role of the mGlu4 receptor subtype in absence seizures using as models: (i) WAG/Rij rats, which develop spontaneous absence seizures after 2-3 months of age; and (ii) mice treated with pentylentetrazole (PTZ, 30 mg/kg, s.c.). Expression of mGlu4 receptors was enhanced in the reticular thalamic nucleus (RTN) of symptomatic WAG/Rij rats as compared with age-matched controls, as assessed by immunoblotting and immunohistochemistry. No changes were found in other regions of WAG/Rij rats including ventrobasal thalamic nuclei, somatosensory cortex, and hippocampus. Electron microscopy and in situ hybridization data suggested that mGlu4 receptors in the RTN are localized on excitatory cortical afferents. Systemic injection of the selective mGlu4 receptor positive allosteric modulator, N-phenyl-7-(hydroxyimino)cyclopropabchromen1a-carboxamide (PHCCC, 10 mg/kg, s.c.), substantially enhanced the number of spike-and-wave discharges (SWDs) in WAG/Rij rats. Injection of PHCCC also enhanced absence-like seizures in PTZ-treated mice, whereas it was totally inactive in mGlu4 receptor knockout mice, which were intrinsically resistant to PTZ-induced seizures, as expected. This data supports the hypothesis that activation of mGlu4 receptors participates in the generation of absence seizures which can be exacerbated with the use of a positive allosteric modulator.

Keywords:amide, metabotropic receptor 4, n phenyl 7 (hydroxyimino)cyclopropabchromen1a carboxamide, pentetrazole, unclassified drug, allosterism, animal experiment, animal model, animal tissue, article, cellular distribution, controlled study, electron microscopy, hippocampus, immunoblotting, immunohistochemistry, immunoreactivity, in situ hybridization, male, mouse, nonhuman, priority journal, protein expression, protein function, protein localization, rat, seizure, somatosensory cortex, spike wave, Sprague Dawley rat, thalamus nucleus, Wistar albino Glaxo rat, Animals, Benzopyrans, Blotting, Western, Convulsants, Densitometry, Electroencephalography, Epilepsy, Absence, GABA Antagonists, Microscopy, Electron, Pentylenetetrazole, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Tissue Fixation
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:22159
Deposited On:12 Feb 2016 12:18

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