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Cerebral Cortex Advance Access published online on December 5, 2007
Cerebral Cortex, doi:10.1093/cercor/bhm217
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© The Author 2007. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Neurotensin Receptor Involvement in the Rise of Extracellular Glutamate Levels and Apoptotic Nerve Cell Death in Primary Cortical Cultures after Oxygen and Glucose Deprivation

Tiziana Antonelli1, Maria C. Tomasini1, Jacqueline Fournier2, Roberta Mazza1, Sergio Tanganelli1, Stefania Pirondi3, Kjell Fuxe4 and Ferraro Luca1

1 Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, 44100 Ferrara, Italy, 2 Sanofi-Aventis Recherche, 40064 Toulose, France, 3 Department of Veterinary Morphophysiology and Animal Production, University of Bologna, S-171 77 Bologna, Italy, 4 Department of Neuroscience, Karolinska Institute, 31071 Stockholm, Sweden

Address correspondence to Dr Luca Ferraro, Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy. Email: frl{at}unife.it.

In view of the ability of neurotensin (NT) to increase glutamate release, the role of NT receptor mechanisms in oxygen–glucose deprivation (OGD)–induced neuronal degeneration in cortical cultures has been evaluated by measuring lactate dehydrogenase (LDH) levels, mitochondrial dehydrogenase activity with 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide levels, and microtubule-associated protein 2 (MAP2) immunoreactivity. Apoptotic nerve cell death was analyzed measuring chromatin condensation with Hoechst 33258, annexin V staining, and caspase-3 activity. Furthermore, the involvement of glutamate excitotoxicity in the neurodegeneration-enhancing actions of NT was analyzed by measurement of extracellular glutamate levels. NT enhanced the OGD-induced increase of LDH, endogenous extracellular glutamate levels, and apoptotic nerve cell death. In addition, the peptide enhanced the OGD-induced loss of mitochondrial functionality and increase of MAP2 aggregations. These effects were blocked by the neurotensin receptor 1 (NTR1) antagonist SR48692. Unexpectedly, the antagonist at 100 nM counteracted not only the NT effects but also some OGD-induced biochemical and morphological alterations. These results suggest that NTR1 receptors may participate in neurodegenerative events induced by OGD in cortical cultures, used as an in vitro model of cortical ischemia. The NTR1 receptor antagonists could provide a new tool to explore the clinical possibilities and thus to move from chemical compound to effective drug.

Key Words: cortical cell cultures • ischemia • lactate dehydrogenase • MAP2 immunoreactivity • neurotensin receptor antagonist


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