The causes of amyotrophic lateral sclerosis (ALS) are mostly undefined; however, excitotoxic injury and astrogliosis may contribute to motor neuron (MN) degeneration. Group I metabotropic glutamate (mGlu) receptors are over-expressed in reactive astrocytes in ALS, but the functional significance of this over-expression is presently unknown. We examined the role of group I mGlu receptors on excitotoxic death of spinal cord MNs grown in cultures enriched of astrocytes bearing a reactive phenotype. A prolonged exposure to the selective non-competitive mGlu5 receptor antagonist MPEP reduced AMPA-mediated toxicity and cobalt uptake in MNs. Expression levels of the GluR1 (but not GluR2) AMPA receptor subunit and levels of brain-derived neurotrophic factor (BDNF) were reduced in mixed spinal cord cultures pretreated with MPEP. In addition, neuroprotection by MPEP was less than additive with that produced by a neutralizing anti-BDNF antibody and a treatment with exogenous BDNF masked the protective effect of MPEP, suggesting that mGlu5 receptors and BDNF converge in facilitating excitotoxic MN death. The protective effect of MPEP was absent in cultures with a reduced number of astrocytes. We suggest that blocking astrocytic mGlu5 receptors is a potential therapeutic strategy in ALS. © 2011 Elsevier Inc.

A prolonged pharmacological blockade of type-5 metabotropic glutamate receptors protects cultured spinal cord motor neurons against excitotoxic death / Simona, D'Antoni; Antonio, Berretta; Giovanna, Seminara; Patrizia, Longone; Anna Maria Giuffrida, Stella; Battaglia, Giuseppe; Maria A., Sortino; Nicoletti, Ferdinando; Maria V., Catania. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 42:3(2011), pp. 252-264. [10.1016/j.nbd.2011.01.013]

A prolonged pharmacological blockade of type-5 metabotropic glutamate receptors protects cultured spinal cord motor neurons against excitotoxic death

BATTAGLIA, Giuseppe;NICOLETTI, Ferdinando;
2011

Abstract

The causes of amyotrophic lateral sclerosis (ALS) are mostly undefined; however, excitotoxic injury and astrogliosis may contribute to motor neuron (MN) degeneration. Group I metabotropic glutamate (mGlu) receptors are over-expressed in reactive astrocytes in ALS, but the functional significance of this over-expression is presently unknown. We examined the role of group I mGlu receptors on excitotoxic death of spinal cord MNs grown in cultures enriched of astrocytes bearing a reactive phenotype. A prolonged exposure to the selective non-competitive mGlu5 receptor antagonist MPEP reduced AMPA-mediated toxicity and cobalt uptake in MNs. Expression levels of the GluR1 (but not GluR2) AMPA receptor subunit and levels of brain-derived neurotrophic factor (BDNF) were reduced in mixed spinal cord cultures pretreated with MPEP. In addition, neuroprotection by MPEP was less than additive with that produced by a neutralizing anti-BDNF antibody and a treatment with exogenous BDNF masked the protective effect of MPEP, suggesting that mGlu5 receptors and BDNF converge in facilitating excitotoxic MN death. The protective effect of MPEP was absent in cultures with a reduced number of astrocytes. We suggest that blocking astrocytic mGlu5 receptors is a potential therapeutic strategy in ALS. © 2011 Elsevier Inc.
2011
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; amyotrophic lateral sclerosis; analysis of variance; animals; antagonists /&/ inhibitors/metabolism; astrocyte; astrocytes; bdnf; blotting; brain-derived neurotrophic factor; cell death; cells; chromones; cultured; cytology/drug effects/metabolism; drug effects; enzyme-linked immunosorbent assay; excitatory amino acid agonists; excitatory amino acid antagonists; excitotoxicity; immunohistochemistry; metabolism; metabotropic glutamate; metabotropic glutamate receptor 5; motor neuron; motor neurons; mpep; neuroprotective agents; pharmacology; pyridines; rats; receptors; spinal cord; western; wistar
01 Pubblicazione su rivista::01a Articolo in rivista
A prolonged pharmacological blockade of type-5 metabotropic glutamate receptors protects cultured spinal cord motor neurons against excitotoxic death / Simona, D'Antoni; Antonio, Berretta; Giovanna, Seminara; Patrizia, Longone; Anna Maria Giuffrida, Stella; Battaglia, Giuseppe; Maria A., Sortino; Nicoletti, Ferdinando; Maria V., Catania. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 42:3(2011), pp. 252-264. [10.1016/j.nbd.2011.01.013]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/469106
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