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

Roberta      Celli; Pasquale      Striano; Rita      Citraro; Luisa      Di Menna; Milena      Cannella; Tiziana      Imbriglio; Mahmoud      Koko; Euro Epinomics-Cogie Consortium; Giovambattista      De Sarro; James   A.   Monn; Giuseppe      Battaglia; Gilles   Van   Luijtelaar; Ferdinando      Nicoletti; Emilio      Russo; Antonio      Leo

doi:10.2174/1570159X20666220509160511

Abstract

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.

Keywords: absence epilepsy, mGlu3 receptors, cortico-thalamo-cortical network, EEG, GABA, glutamate, human genetics

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Graphical Abstract

[1]
Crunelli, V.; Leresche, N. Childhood absence epilepsy: Genes, channels, neurons and networks. Nat. Rev. Neurosci.,  2002, 3(5), 371-382.
 [http://dx.doi.org/10.1038/nrn811] [PMID:  11988776]

[2]
Fisher, R.S.; Cross, J.H.; French, J.A.; Higurashi, N.; Hirsch, E.; Jansen, F.E.; Lagae, L.; Moshé, S.L.; Peltola, J.; Roulet Perez, E.; Scheffer, I.E.; Zuberi, S.M. Operational classification of seizure types by the international league against epilepsy: Position paper of the ILAE commission for classification and terminology. Epilepsia,  2017, 58(4), 522-530.
 [http://dx.doi.org/10.1111/epi.13670] [PMID:  28276060]

[3]
Meeren, H.K.M.; Pijn, J.P.M.; Van Luijtelaar, E.L.J.M.; Coenen, A.M.L.; Lopes da Silva, F.H. Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats. J. Neurosci.,  2002, 22(4), 1480-1495.
 [http://dx.doi.org/10.1523/JNEUROSCI.22-04-01480.2002] [PMID:  11850474]

[4]
Blumenfeld, H. Cellular and network mechanisms of spike-wave seizures. Epilepsia,  2005, 9(9), 21-33.
 [http://dx.doi.org/10.1111/j.1528-1167.2005.00311.x] [PMID:  16302873]

[5]
Mikati, M.A.; Holmes, G.L. Lamotrigine in absence and primary generalized epilepsies. J. Child Neurol.,  1997, 12(Suppl. 1), S29-S37.
 [http://dx.doi.org/10.1177/0883073897012001081] [PMID:  9429128]

[6]
Ollivier, M.L.; Dubois, M.F.; Krajinovic, M.; Cossette, P.; Carmant, L. Risk factors for valproic acid resistance in childhood absence epilepsy. Seizure,  2009, 18(10), 690-694.
 [http://dx.doi.org/10.1016/j.seizure.2009.09.007] [PMID:  19836978]

[7]
Tenney, J.R.; Glauser, T.A. The current state of absence epilepsy: Can we have your attention? Epilepsy Curr.,  2013, 13(3), 135-140.
 [http://dx.doi.org/10.5698/1535-7511-13.3.135] [PMID:  23840175]

[8]
Ngomba, R.T.; Santolini, I.; Salt, T.E.; Ferraguti, F.; Battaglia, G.; Nicoletti, F.; van Luijtelaar, G. Metabotropic glutamate receptors in the thalamocortical network: Strategic targets for the treatment of absence epilepsy. Epilepsia,  2011, 52(7), 1211-1222.
 [http://dx.doi.org/10.1111/j.1528-1167.2011.03082.x] [PMID:  21569017]

[9]
Celli, R.; Santolini, I.; Van Luijtelaar, G.; Ngomba, R.T.; Bruno, V.; Nicoletti, F. Targeting metabotropic glutamate receptors in the treatment of epilepsy: Rationale and current status. Expert Opin. Ther. Targets,  2019, 23(4), 341-351.
 [http://dx.doi.org/10.1080/14728222.2019.1586885] [PMID:  30801204]

[10]
van Luijtelaar, E.L.J.M.; Coenen, A.M.L. Two types of electrocortical paroxysms in an inbred strain of rats. Neurosci. Lett.,  1986, 70(3), 393-397.
 [http://dx.doi.org/10.1016/0304-3940(86)90586-0] [PMID:  3095713]

[11]
van Luijtelaar, G.; Zobeiri, M. Progress and outlooks in a genetic absence epilepsy model (WAG/Rij). Curr. Med. Chem.,  2014, 21(6), 704-721.
 [http://dx.doi.org/10.2174/0929867320666131119152913] [PMID:  24251564]

[12]
Russo, E.; Citraro, R.; Constanti, A.; Leo, A.; Lüttjohann, A.; van Luijtelaar, G.; De Sarro, G. Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development. Neurosci. Biobehav. Rev.,  2016, 71, 388-408.
 [http://dx.doi.org/10.1016/j.neubiorev.2016.09.017] [PMID:  27687816]

[13]
Panayiotopoulos, C.P. Typical absence seizures and their treatment. Arch. Dis. Child.,  1999, 81(4), 351-355.
 [http://dx.doi.org/10.1136/adc.81.4.351] [PMID:  10490445]

[14]
Glauser, T.A.; Cnaan, A.; Shinnar, S.; Hirtz, D.G.; Dlugos, D.; Masur, D.; Clark, P.O.; Capparelli, E.V.; Adamson, P.C. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N. Engl. J. Med.,  2010, 362(9), 790-799.
 [http://dx.doi.org/10.1056/NEJMoa0902014] [PMID:  20200383]

[15]
Coenen, A.M.L.; van Luijtelaar, E.L.J.M. Genetic animal models for absence epilepsy: A review of the WAG/Rij strain of rats. Behav. Genet.,  2003, 33(6), 635-655.
 [http://dx.doi.org/10.1023/a:1026179013847] [PMID:  14574120]

[16]
Russo, E.; Citraro, R.; Scicchitano, F.; de Fazio, S.; Perrotta, I.; di Paola, E.D.; Constanti, A.; De Sarro, G. Effects of early long-term treatment with antiepileptic drugs on development of seizures and depressive-like behavior in a rat genetic absence epilepsy model. Epilepsia,  2011, 52(7), 1341-1350.
 [http://dx.doi.org/10.1111/j.1528-1167.2011.03112.x] [PMID:  21635238]

[17]
Bouwman, B.M.; Suffczynski, P.; Lopes Da Silva, F.H.; Maris, E.; van Rijn, C.M. GABAergic mechanisms in absence epilepsy: A computational model of absence epilepsy simulating spike and wave discharges after vigabatrin in WAG/Rij rats. Eur. J. Neurosci.,  2007, 25(9), 2783-2790.
 [http://dx.doi.org/10.1111/j.1460-9568.2007.05533.x] [PMID:  17561843]

[18]
Coenen, A.M.L.; Blezer, E.H.M.; van Luijtelaar, E.L.J.M. Effects of the GABA-uptake inhibitor tiagabine on electroencephalogram, spike-wave discharges and behaviour of rats. Epilepsy Res.,  1995, 21(2), 89-94.
 [http://dx.doi.org/10.1016/0920-1211(95)00015-3] [PMID:  7588592]

[19]
Ngomba, R.T.; Ferraguti, F.; Badura, A.; Citraro, R.; Santolini, I.; Battaglia, G.; Bruno, V.; De Sarro, G.; Simonyi, A.; van Luijtelaar, G.; Nicoletti, F. Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures. Neuropharmacology,  2008, 54(2), 344-354.
 [http://dx.doi.org/10.1016/j.neuropharm.2007.10.004] [PMID:  18022649]

[20]
Ngomba, R.T.; Santolini, I.; Biagioni, F.; Molinaro, G.; Simonyi, A.; van Rijn, C.M.; D’Amore, V.; Mastroiacovo, F.; Olivieri, G.; Gradini, R.; Ferraguti, F.; Battaglia, G.; Bruno, V.; Puliti, A.; van Luijtelaar, G.; Nicoletti, F. Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy. Neuropharmacology,  2011, 60(7-8), 1281-1291.
 [http://dx.doi.org/10.1016/j.neuropharm.2011.01.007] [PMID:  21277877]

[21]
D’Amore, V.; Santolini, I.; van Rijn, C.M.; Biagioni, F.; Molinaro, G.; Prete, A.; Conn, P.J.; Lindsley, C.W.; Zhou, Y.; Vinson, P.N.; Rodriguez, A.L.; Jones, C.K.; Stauffer, S.R.; Nicoletti, F.; van Luijtelaar, G.; Ngomba, R.T. Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats. Neuropharmacology,  2013, 66, 330-338.
 [http://dx.doi.org/10.1016/j.neuropharm.2012.05.044] [PMID:  22705340]

[22]
D’Amore, V.; Santolini, I.; Celli, R.; Lionetto, L.; De Fusco, A.; Simmaco, M.; van Rijn, C.M.; Vieira, E.; Stauffer, S.R.; Conn, P.J.; Bosco, P.; Nicoletti, F.; van Luijtelaar, G.; Ngomba, R.T. Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats. Neuropharmacology,  2014, 85, 91-103.
 [http://dx.doi.org/10.1016/j.neuropharm.2014.05.005] [PMID:  24859611]

[23]
D’Amore, V.; von Randow, C.; Nicoletti, F.; Ngomba, R.T.; van Luijtelaar, G. Anti-absence activity of mGlu1 and mGlu5 receptor enhancers and their interaction with a GABA reuptake inhibitor: Effect of local infusions in the somatosensory cortex and thalamus. Epilepsia,  2015, 56(7), 1141-1151.
 [http://dx.doi.org/10.1111/epi.13024] [PMID:  26040777]

[24]
Celli, R.; Wall, M.J.; Santolini, I.; Vergassola, M.; Di Menna, L.; Mascio, G.; Cannella, M.; van Luijtelaar, G.; Pittaluga, A.; Ciruela, F.; Bruno, V.; Nicoletti, F.; Ngomba, R.T. Pharmacological activation of mGlu5 receptors with the positive allosteric modulator VU0360172, modulates thalamic GABAergic transmission. Neuropharmacology,  2020, 178, 108240.
 [http://dx.doi.org/10.1016/j.neuropharm.2020.108240] [PMID:  32768418]

[25]
Ngomba, R.T.; Biagioni, F.; Casciato, S.; Willems-Van Bree, E.; Battaglia, G.; Bruno, V.; Nicoletti, F.; van Luijtelaar, E.L.J.M.  The
preferential mGlu2/3 receptor antagonist, LY341495, reduces the
frequency of spike-wave discharges in the WAG/Rij rat model of
absence epilepsy Neuropharmacology, 2005, Suppl 1(SUPPL.), 89-
103.
 [http://dx.doi.org/10.1016/j.neuropharm.2005.05.019] [PMID:  16043198]

[26]
Di Menna, L.; Joffe, M.E.; Iacovelli, L.; Orlando, R.; Lindsley, C.W.; Mairesse, J.; Gressèns, P.; Cannella, M.; Caraci, F.; Copani, A.; Bruno, V.; Battaglia, G.; Conn, P.J.; Nicoletti, F. Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system. Neuropharmacology,  2018, 128, 301-313.
 [http://dx.doi.org/10.1016/j.neuropharm.2017.10.026] [PMID:  29079293]

[27]
Joffe, M.E.; Santiago, C.I.; Stansley, B.J.; Maksymetz, J.; Gogliotti, R.G.; Engers, J.L.; Nicoletti, F.; Lindsley, C.W.; Conn, P.J. Mechanisms underlying prelimbic prefrontal cortex mGlu3/mGlu5-dependent plasticity and reversal learning deficits following acute stress. Neuropharmacology,  2019, 144, 19-28.
 [http://dx.doi.org/10.1016/j.neuropharm.2018.10.013] [PMID:  30326237]

[28]
Dogra, S.; Stansley, B.J.; Xiang, Z.; Qian, W.; Gogliotti, R.G.; Nicoletti, F.; Lindsley, C.W.; Niswender, C.M.; Joffe, M.E.; Conn, P.J. Activating mGlu3 metabotropic glutamate receptors rescues schizophrenia-like cognitive deficits through metaplastic adaptations within the hippocampus. Biol. Psychiatry,  2021, 90(6), 385-398.
 [http://dx.doi.org/10.1016/j.biopsych.2021.02.970] [PMID:  33965197]

[29]
Bruno, V.; Battaglia, G.; Casabona, G.; Copani, A.; Caciagli, F.; Nicoletti, F. Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta. J. Neurosci.,  1998, 18(23), 9594-9600.
 [http://dx.doi.org/10.1523/JNEUROSCI.18-23-09594.1998] [PMID:  9822720]

[30]
Aronica, E.; van Vliet, E.A.; Mayboroda, O.A.; Troost, D.; da Silva, F.H.; Gorter, J.A. Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy. Eur. J. Neurosci.,  2000, 12(7), 2333-2344.
 [http://dx.doi.org/10.1046/j.1460-9568.2000.00131.x] [PMID:  10947812]

[31]
Zinni, M.; Mairesse, J.; Pansiot, J.; Fazio, F.; Iacovelli, L.; Antenucci, N.; Orlando, R.; Nicoletti, F.; Vaiman, D.; Baud, O. mGlu3 receptor regulates microglial cell reactivity in neonatal rats. J. Neuroinflammation,  2021, 18(1), 13.
 [http://dx.doi.org/10.1186/s12974-020-02049-z] [PMID:  33407565]

[32]
Monn, J.A.; Henry, S.S.; Massey, S.M.; Clawson, D.K.; Chen, Q.; Diseroad, B.A.; Bhardwaj, R.M.; Atwell, S.; Lu, F.; Wang, J.; Russell, M.; Heinz, B.A.; Wang, X.S.; Carter, J.H.; Getman, B.G.; Adragni, K.; Broad, L.M.; Sanger, H.E.; Ursu, D.; Catlow, J.T.; Swanson, S.; Johnson, B.G.; Shaw, D.B.; McKinzie, D.L.; Hao, J. Synthesis and pharmacological characterization of C4β-amide-substituted 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S,2 S,4 S,5 R,6 S)-2-amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY2794193), a highly potent and selective mGlu3 receptor agonist. J. Med. Chem.,  2018, 61(6), 2303-2328.
 [http://dx.doi.org/10.1021/acs.jmedchem.7b01481] [PMID:  29350927]

[33]
Sarkisova, K.; van Luijtelaar, G. The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression [corrected]. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2011, 35(4), 854-876.
 [http://dx.doi.org/10.1016/j.pnpbp.2010.11.010] [PMID:  21093520]

[34]
Russo, E.; Citraro, R. Pharmacology of epileptogenesis and related comorbidities in the WAG/Rij rat model of genetic absence epilepsy. J. Neurosci. Methods,  2018, 310, 54-62.
 [http://dx.doi.org/10.1016/j.jneumeth.2018.05.020] [PMID:  29857008]

[35]
Fujii, Y.; Shibata, H.; Kikuta, R.; Makino, C.; Tani, A.; Hirata, N.; Shibata, A.; Ninomiya, H.; Tashiro, N.; Fukumaki, Y. Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia. Psychiatr. Genet.,  2003, 13(2), 71-76.
 [http://dx.doi.org/10.1097/01.ypg.0000056682.82896.b0] [PMID:  12782962]

[36]
Egan, M.F.; Straub, R.E.; Goldberg, T.E.; Yakub, I.; Callicott, J.H.; Hariri, A.R.; Mattay, V.S.; Bertolino, A.; Hyde, T.M.; Shannon-Weickert, C.; Akil, M.; Crook, J.; Vakkalanka, R.K.; Balkissoon, R.; Gibbs, R.A.; Kleinman, J.E.; Weinberger, D.R. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc. Natl. Acad. Sci. USA,  2004, 101(34), 12604-12609.
 [http://dx.doi.org/10.1073/pnas.0405077101] [PMID:  15310849]

[37]
Chen, Q.; He, G.; Chen, Q.; Wu, S.; Xu, Y.; Feng, G.; Li, Y.; Wang, L.; He, L. A case-control study of the relationship between the metabotropic glutamate receptor 3 gene and schizophrenia in the Chinese population. Schizophr. Res.,  2005, 73(1), 21-26.
 [http://dx.doi.org/10.1016/j.schres.2004.07.002] [PMID:  15567072]

[38]
Norton, N.; Williams, H.J.; Dwyer, S.; Ivanov, D.; Preece, A.C.; Gerrish, A.; Williams, N.M.; Yerassimou, P.; Zammit, S.; O’Donovan, M.C.; Owen, M.J. No evidence for association between polymorphisms in GRM3 and schizophrenia. BMC Psychiatry,  2005, 5, 23.
 [http://dx.doi.org/10.1186/1471-244X-5-23] [PMID:  15892884]

[39]
Bishop, J.R.; Wang, K.; Moline, J.; Ellingrod, V.L. Association analysis of the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia. Psychiatr. Genet.,  2007, 17(6), 358.
 [http://dx.doi.org/10.1097/YPG.0b013e3281ac231e] [PMID:  18075480]

[40]
Schwab, S.G.; Plummer, C.; Albus, M.; Borrmann-Hassenbach, M.; Lerer, B.; Trixler, M.; Maier, W.; Wildenauer, D.B. DNA sequence variants in the metabotropic glutamate receptor 3 and risk to schizophrenia: An association study. Psychiatr. Genet.,  2008, 18(1), 25-30.
 [http://dx.doi.org/10.1097/YPG.0b013e3282ef48d9] [PMID:  18197082]

[41]
Maj, C.; Minelli, A.; Giacopuzzi, E.; Sacchetti, E.; Gennarelli, M. The role of metabotropic glutamate receptor genes in schizophrenia. Curr. Neuropharmacol.,  2016, 14(5), 540-550.
 [http://dx.doi.org/10.2174/1570159X13666150514232745] [PMID:  27296644]

[42]
Saini, S.M.; Mancuso, S.G.; Mostaid, M.S.; Liu, C.; Pantelis, C.; Everall, I.P.; Bousman, C.A. Meta-analysis supports GWAS-implicated link between GRM3 and schizophrenia risk. Transl. Psychiatry,  2017, 7(8), e1196.
 [http://dx.doi.org/10.1038/tp.2017.172] [PMID:  28786982]

[43]
Coenen, A.M.L.; Van Luijtelaar, E.L.J.M. The WAG/Rij rat model for absence epilepsy: Age and sex factors. Epilepsy Res.,  1987, 1(5), 297-301.
 [http://dx.doi.org/10.1016/0920-1211(87)90005-2] [PMID:  3143552]

[44]
Shaw, F.Z. 7-12 Hz high-voltage rhythmic spike discharges in rats evaluated by antiepileptic drugs and flicker stimulation. J. Neurophysiol.,  2007, 97(1), 238-247.
 [http://dx.doi.org/10.1152/jn.00340.2006] [PMID:  17035363]

[45]
Willoughby, J.O.; Mackenzie, L. Nonconvulsive electrocorticographic paroxysms (absence epilepsy) in rat strains. Lab. Anim. Sci.,  1992, 42(6), 551-554.
 [PMID:  1479805]

[46]
Santolini, I.; Celli, R.; Cannella, M.; Imbriglio, T.; Guiducci, M.; Parisi, P.; Schubert, J.; Iacomino, M.; Zara, F.; Lerche, H.; Moyanova, S.; Ngomba, R.T.; van Luijtelaar, G.; Battaglia, G.; Bruno, V.; Striano, P.; Nicoletti, F. Alterations in the α2 δ ligand, thrombospondin-1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies. Epilepsia,  2017, 58(11), 1993-2001.
 [http://dx.doi.org/10.1111/epi.13898] [PMID:  28913875]

[47]
Lowry, O.H.; Rosebrough, N.J.; Farr, A.L.; Randall, R.J. Protein measurement with the Folin phenol reagent. J. Biol. Chem.,  1951, 193(1), 265-275.
 [http://dx.doi.org/10.1016/S0021-9258(19)52451-6] [PMID:  14907713]

[48]
Russo, E.; Citraro, R.; Scicchitano, F.; Urzino, A.; Marra, R.; Rispoli, V.; De Sarro, G. Vigabatrin has antiepileptogenic and antidepressant effects in an animal model of epilepsy and depression comorbidity. Behav. Brain Res.,  2011, 225(1), 373-376.
 [http://dx.doi.org/10.1016/j.bbr.2011.07.030] [PMID:  21807031]

[49]
Leo, A.; Citraro, R.; Amodio, N.; De Sarro, C.; Gallo Cantafio, M.E.; Constanti, A.; De Sarro, G.; Russo, E. Fingolimod exerts only temporary antiepileptogenic effects but longer-lasting positive effects on behavior in the WAG/Rij rat absence epilepsy model. Neurotherapeutics,  2017, 14(4), 1134-1147.
 [http://dx.doi.org/10.1007/s13311-017-0550-y] [PMID:  28653281]

[50]
Citraro, R.; Leo, A.; Franco, V.; Marchiselli, R.; Perucca, E.; De Sarro, G.; Russo, E. Perampanel effects in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and comorbid depressive-like behavior. Epilepsia,  2017, 58(2), 231-238.
 [http://dx.doi.org/10.1111/epi.13629] [PMID:  27988935]

[51]
Leo, A.; Nesci, V.; Tallarico, M.; Amodio, N.; Gallo Cantafio, E.M.; De Sarro, G.; Constanti, A.; Russo, E.; Citraro, R. IL-6 receptor blockade by tocilizumab has anti-absence and anti-epileptogenic effects in the WAG/Rij rat model of absence epilepsy. Neurotherapeutics,  2020, 17(4), 2004-2014.
 [http://dx.doi.org/10.1007/s13311-020-00893-8] [PMID:  32681356]

[52]
Niturad, C.E.; Lev, D.; Kalscheuer, V.M.; Charzewska, A.; Schubert, J.; Lerman-Sagie, T.; Kroes, H.Y.; Oegema, R.; Traverso, M.; Specchio, N.; Lassota, M.; Chelly, J.; Bennett-Back, O.; Carmi, N.; Koffler-Brill, T.; Iacomino, M.; Trivisano, M.; Capovilla, G.; Striano, P.; Nawara, M.; Rzonca, S.; Fischer, U.; Bienek, M.; Jensen, C.; Hu, H.; Thiele, H.; Altmüller, J.; Krause, R.; May, P.; Becker, F.; Balling, R.; Biskup, S.; Haas, S.A.; Nürnberg, P.; van Gassen, K.L.I.; Lerche, H.; Zara, F.; Maljevic, S.; Leshinsky-Silver, E. Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features. Brain,  2017, 140(11), 2879-2894.
 [http://dx.doi.org/10.1093/brain/awx236] [PMID:  29053855]

[53]
Rook, J.M.; Tantawy, M.N.; Ansari, M.S.; Felts, A.S.; Stauffer, S.R.; Emmitte, K.A.; Kessler, R.M.; Niswender, C.M.; Daniels, J.S.; Jones, C.K.; Lindsley, C.W.; Conn, P.J. Relationship between in vivo receptor occupancy and efficacy of metabotropic glutamate receptor subtype 5 allosteric modulators with different in vitro binding profiles. Neuropsychopharmacology,  2015, 40(3), 755-765.
 [http://dx.doi.org/10.1038/npp.2014.245] [PMID:  25241804]

[54]
Rodriguez, A.L.; Grier, M.D.; Jones, C.K.; Herman, E.J.; Kane, A.S.; Smith, R.L.; Williams, R.; Zhou, Y.; Marlo, J.E.; Days, E.L.; Blatt, T.N.; Jadhav, S.; Menon, U.N.; Vinson, P.N.; Rook, J.M.; Stauffer, S.R.; Niswender, C.M.; Lindsley, C.W.; Weaver, C.D.; Conn, P.J. Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. Mol. Pharmacol.,  2010, 78(6), 1105-1123.
 [http://dx.doi.org/10.1124/mol.110.067207] [PMID:  20923853]

[55]
Ciccarelli, R.; D’Alimonte, I.; Ballerini, P.; D’Auro, M.; Nargi, E.; Buccella, S.; Di Iorio, P.; Bruno, V.; Nicoletti, F.; Caciagli, F. Molecular signalling mediating the protective effect of A1 adenosine and mGlu3 metabotropic glutamate receptor activation against apoptosis by oxygen/glucose deprivation in cultured astrocytes. Mol. Pharmacol.,  2007, 71(5), 1369-1380.
 [http://dx.doi.org/10.1124/mol.106.031617] [PMID:  17293559]

[56]
Aronica, E.; Gorter, J.A.; Ijlst-Keizers, H.; Rozemuller, A.J.; Yankaya, B.; Leenstra, S.; Troost, D. Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: Opposite regulation of glutamate transporter proteins. Eur. J. Neurosci.,  2003, 17(10), 2106-2118.
 [http://dx.doi.org/10.1046/j.1460-9568.2003.02657.x] [PMID:  12786977]

[57]
van Luijtelaar, G.; Lyashenko, S.; Vastyanov, R.; Verbeek, G.; Oleinik, A.; van Rijn, C. Cytokines and absence seizures in a genetic rat model. Neurophysiology,  2012, 43(6), 478-486.
 [http://dx.doi.org/10.1007/s11062-012-9252-6]

[58]
Russo, E.; Andreozzi, F.; Iuliano, R.; Dattilo, V.; Procopio, T.; Fiume, G.; Mimmi, S.; Perrotti, N.; Citraro, R.; Sesti, G.; Constanti, A.; De Sarro, G. Early molecular and behavioral response to lipopolysaccharide in the WAG/Rij rat model of absence epilepsy and depressive-like behavior, involves interplay between AMPK, AKT/mTOR pathways and neuroinflammatory cytokine release. Brain Behav. Immun.,  2014, 42, 157-168.
 [http://dx.doi.org/10.1016/j.bbi.2014.06.016] [PMID:  24998197]

[59]
Kovács, Z.; D’Agostino, D.P.; Diamond, D.M.; Ari, C. Exogenous ketone supplementation decreased the lipopolysaccharide-induced increase in absence epileptic activity in wistar albino glaxo Rijswijk rats. Front. Mol. Neurosci.,  2019, 12, 45.
 [http://dx.doi.org/10.3389/fnmol.2019.00045] [PMID:  30930744]

[60]
Rimoli, M.G.; Russo, E.; Cataldi, M.; Citraro, R.; Ambrosino, P.; Melisi, D.; Curcio, A.; De Lucia, S.; Patrignani, P.; De Sarro, G.; Abignente, E. T-type channel blocking properties and antiabsence activity of two imidazo[1,2-b]pyridazine derivatives structurally related to indomethacin. Neuropharmacology,  2009, 56(3), 637-646.
 [http://dx.doi.org/10.1016/j.neuropharm.2008.11.003] [PMID:  19071141]

[61]
Citraro, R.; Leo, A.; Marra, R.; De Sarro, G.; Russo, E. Antiepileptogenic effects of the selective COX-2 inhibitor etoricoxib, on the development of spontaneous absence seizures in WAG/Rij rats. Brain Res. Bull.,  2015, 113, 1-7.
 [http://dx.doi.org/10.1016/j.brainresbull.2015.02.004] [PMID:  25701797]

[62]
Erdil, A.; Demirsoy, M.S.; Çolak, S.; Duman, E.; Sümbül, O.; Aygun, H. The effect of dexketoprofen trometamol on WAG/Rij rats with absence epilepsy (dexketoprofen in absence epilepsy). Neurol. Res.,  2021, 43(12), 1116-1125.
 [http://dx.doi.org/10.1080/01616412.2021.1952510] [PMID:  34278977]

[63]
Caplan, R.; Siddarth, P.; Gurbani, S.; Hanson, R.; Sankar, R.; Shields, W.D. Depression and anxiety disorders in pediatric epilepsy. Epilepsia,  2005, 46(5), 720-730.
 [http://dx.doi.org/10.1111/j.1528-1167.2005.43604.x] [PMID:  15857439]

[64]
Vega, C.; Guo, J.; Killory, B.; Danielson, N.; Vestal, M.; Berman, R.; Martin, L.; Gonzalez, J.L.; Blumenfeld, H.; Spann, M.N. Symptoms of anxiety and depression in childhood absence epilepsy. Epilepsia,  2011, 52(8), e70-e74.
 [http://dx.doi.org/10.1111/j.1528-1167.2011.03119.x] [PMID:  21635244]

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DOI https://dx.doi.org/10.2174/1570159X20666220509160511	Print ISSN 1570-159X
Publisher Name Bentham Science Publisher	Online ISSN 1875-6190

Current Neuropharmacology

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

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