Protective role for type 4 metabotropic glutamate receptors against ischemic brain damage

Moyanova, S. G. and Mastroiacovo, F. and Kortenska, L. V. and Mitreva, R. G. and Fardone, E. and Santolini, I. and Sobrado, M. and Battaglia, G. and Bruno, V. and Nicoletti, F. and Ngomba, R. T. (2011) Protective role for type 4 metabotropic glutamate receptors against ischemic brain damage. Journal of Cerebral Blood Flow and Metabolism, 31 (4). pp. 1107-1118. ISSN 0271-678X

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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)cyclopropabchromen-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. © 2011 ISCBFM All rights reserved.

Keywords:endothelin 1, metabotropic receptor 4, metabotropic receptor agonist, n phenyl 7 (hydroxyimino)cyclopropabchromen 1a caboxamide, unclassified drug, animal experiment, animal model, animal tissue, article, brain cortex, brain damage, brain infarction size, brain ischemia, brain protection, caudate nucleus, controlled study, convalescence, drug receptor binding, electrocorticography, electroencephalography, gene inactivation, male, middle cerebral artery occlusion, mouse, nonhuman, priority journal, protein function, putamen, rat, sensorimotor function, wild type, Animals, Behavior, Animal, Brain, Cerebral Infarction, Coloring Agents, Evans Blue, Female, Forelimb, Hindlimb, Infarction, Middle Cerebral Artery, Ischemic Attack, Transient, Mice, Mice, Inbred C57BL, Mice, Knockout, Postural Balance, Psychomotor Performance, Rats, Rats, Wistar, Receptors, Metabotropic Glutamate, Reflex
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:22155
Deposited On:04 Feb 2016 20:05

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