mGlu3 Metabotropic Glutamate Receptors as a Target for the Treatment of Absence Epilepsy: Preclinical and Human Genetics Data.

Autor:	Celli R; I.R.C.C.S. Neuromed, Pozzilli, Italy., Striano P; Department Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy.; I.R.C.C.S. 'G. Gaslini' Institute, Genova, Italy., Citraro R; University of Catanzaro, School of Medicine, Science of Health Department, FAS@UMG Research Center, Catanzaro, Italy., Di Menna L; I.R.C.C.S. Neuromed, Pozzilli, Italy., Cannella M; I.R.C.C.S. Neuromed, Pozzilli, Italy., Imbriglio T; I.R.C.C.S. Neuromed, Pozzilli, Italy., Koko M; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany., Euro Epinomics-Cogie Consortium; SEE Appendix 1 EuroEPINOMICS-CoGIE Consortium., De Sarro G; University of Catanzaro, School of Medicine, Science of Health Department, FAS@UMG Research Center, Catanzaro, Italy., Monn JA; I.R.C.C.S. Neuromed, Pozzilli, Italy., Battaglia G; I.R.C.C.S. Neuromed, Pozzilli, Italy.; Department of Physiology and Pharmacology, University Sapienza, Rome, Italy., Luijtelaar GV; Donders Center for Cognition, Radboud University, Nijmegen, the Netherlands., Nicoletti F; I.R.C.C.S. Neuromed, Pozzilli, Italy.; Department of Physiology and Pharmacology, University Sapienza, Rome, Italy., Russo E; University of Catanzaro, School of Medicine, Science of Health Department, FAS@UMG Research Center, Catanzaro, Italy., Leo A; University of Catanzaro, School of Medicine, Science of Health Department, FAS@UMG Research Center, Catanzaro, Italy.
Jazyk:	angličtina
Zdroj:	Current neuropharmacology [Curr Neuropharmacol] 2023; Vol. 21 (1), pp. 105-118.
DOI:	10.2174/1570159X20666220509160511
Abstrakt:	Background: Previous studies suggest that different metabotropic glutamate (mGlu) receptor subtypes are potential drug targets for treating absence epilepsy. However, no information is available on mGlu3 receptors. Objective: To examine whether (i) changes of mGlu3 receptor expression/signaling are found in the somatosensory cortex and thalamus of WAG/Rij rats developing spontaneous absence seizures; (ii) selective activation of mGlu3 receptors with LY2794193 affects the number and duration of spikewave discharges (SWDs) in WAG/Rij rats; and (iii) a genetic variant of GRM3 (encoding the mGlu3 receptor) is associated with absence epilepsy. Methods: Animals: immunoblot analysis of mGlu3 receptors, GAT-1, GLAST, and GLT-1; realtime PCR analysis of mGlu3 mRNA levels; assessment of mGlu3 receptor signaling; EEG analysis of SWDs; assessment of depressive-like behavior. Humans: search for GRM3 and GRM5 missense variants in 196 patients with absence epilepsy or other Idiopathic Generalized Epilepsy (IGE)/ Genetic Generalized Epilepsy (GGE) and 125,748 controls. Results: mGlu3 protein levels and mGlu3-mediated inhibition of cAMP formation were reduced in the thalamus and somatosensory cortex of pre-symptomatic (25-27 days old) and symptomatic (6-7 months old) WAG/Rij rats compared to age-matched controls. Treatment with LY2794193 (1 or 10 mg/kg, i.p.) reduced absence seizures and depressive-like behavior in WAG/Rij rats. LY2794193 also enhanced GAT1, GLAST, and GLT-1 protein levels in the thalamus and somatosensory cortex. GRM3 and GRM5 gene variants did not differ between epileptic patients and controls. Conclusion: We suggest that mGlu3 receptors modulate the activity of the cortico-thalamo-cortical circuit underlying SWDs and that selective mGlu3 receptor agonists are promising candidate drugs for absence epilepsy treatment. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
Databáze:	MEDLINE
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