title: Protective role for type 4 metabotropic glutamate receptors against ischemic brain damage.
abstract: We examined the influence of type 4 metabotropic glutamate (mGlu4) receptors on ischemic brain damage using the permanent middle cerebral artery occlusion (MCAO) model in mice and the endothelin-1 (Et-1) model of transient focal ischemia in rats. Mice lacking mGlu4 receptors showed a 25% to 30% increase in infarct volume after MCAO as compared with wild-type littermates. In normal mice, systemic injection of the selective mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-caboxamide (PHCCC; 10  mg/kg, subcutaneous, administered once 30  minutes before MCAO), reduced the extent of ischemic brain damage by 35% to 45%. The drug was inactive in mGlu4 receptor knockout mice. In the Et-1 model, PHCCC administered only once 20  minutes after ischemia reduced the infarct volume to a larger extent in the caudate/putamen than in the cerebral cortex. Ischemic rats treated with PHCCC showed a faster recovery of neuronal function, as shown by electrocorticographic recording and by a battery of specific tests, which assess sensorimotor deficits. These data indicate that activation of mGlu4 receptors limit the development of brain damage after permanent or transient focal ischemia. These findings are promising because selective mGlu4 receptor enhancers are under clinical development for the treatment of Parkinson's disease and other central nervous system disorders.
authors.affiliation: Department of Neurobiology of Processes of Adaptation, Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Slavianka G
authors.initials: SG
authors.lastname: Moyanova
authors.forename: Federica
authors.initials: F
authors.lastname: Mastroiacovo
authors.forename: Lidia V
authors.initials: LV
authors.lastname: Kortenska
authors.forename: Rumiana G
authors.initials: RG
authors.lastname: Mitreva
authors.forename: Erminia
authors.initials: E
authors.lastname: Fardone
authors.forename: Ines
authors.initials: I
authors.lastname: Santolini
authors.forename: Mónica
authors.initials: M
authors.lastname: Sobrado
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Richard T
authors.initials: RT
authors.lastname: Ngomba
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D004396:Coloring Agents; D004569:Electroencephalography; D005070:Evans Blue; D005260:Female; D005552:Forelimb / Q000502:physiology; D006614:Hindlimb / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004856:Postural Balance / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000502:physiology*; D012018:Reflex / Q000502:physiology
chemical_list: D004396:Coloring Agents; D018094:Receptors, Metabotropic Glutamate; D005070:Evans Blue; C108823:metabotropic glutamate receptor 4