title: Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy.
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'.
authors.affiliation: Neuromed Institute, Neuropharmacology Unit, Parco Technologico, Località Camerelle 86077, Pozzilli, Isernia, Italy. richardngomba@neuromed.it
authors.forename: R T
authors.initials: RT
authors.lastname: Ngomba
authors.forename: I
authors.initials: I
authors.lastname: Santolini
authors.forename: F
authors.initials: F
authors.lastname: Biagioni
authors.forename: G
authors.initials: G
authors.lastname: Molinaro
authors.forename: A
authors.initials: A
authors.lastname: Simonyi
authors.forename: C M
authors.initials: CM
authors.lastname: van Rijn
authors.forename: V
authors.initials: V
authors.lastname: D'Amore
authors.forename: F
authors.initials: F
authors.lastname: Mastroiacovo
authors.forename: G
authors.initials: G
authors.lastname: Olivieri
authors.forename: R
authors.initials: R
authors.lastname: Gradini
authors.forename: F
authors.initials: F
authors.lastname: Ferraguti
authors.forename: G
authors.initials: G
authors.lastname: Battaglia
authors.forename: V
authors.initials: V
authors.lastname: Bruno
authors.forename: A
authors.initials: A
authors.lastname: Puliti
authors.forename: G
authors.initials: G
authors.lastname: van Luijtelaar
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002939:Ciprofloxacin / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D004832:Epilepsy, Absence / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011912:Rats, Inbred ACI; D011919:Rats, Inbred Strains; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013787:Thalamic Nuclei / Q000378:metabolism / Q000503:physiopathology; D013788:Thalamus / Q000378:metabolism / Q000503:physiopathology
chemical_list: C495417:(3,4-dihydro-2H-pyrano(2,3)b-quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone; D018691:Excitatory Amino Acid Antagonists; D019384:Nucleic Acid Synthesis Inhibitors; D011804:Quinolines; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; C097465:SYN-1193; C104077:metabotropic glutamate receptor type 1; D002939:Ciprofloxacin