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Neuroprotective effects of the mGlu5R antagonist MPEP towards quinolinic acid‐induced striatal toxicity: involvement of pre‐ and post‐synaptic mechanisms and lack of direct NMDA blocking activity
Author(s) -
Popoli Patrizia,
Pintor Annita,
Tebano Maria Teresa,
Frank Claudio,
Pepponi Rita,
Nazzicone Valeria,
Grieco Rosa,
Pèzzola Antonella,
Reggio Rosaria,
Minghetti Luisa,
De Berardinis Maria Anna,
Martire Alberto,
Potenza Rosa Luisa,
Domenici Maria Rosaria,
Massotti Marino
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02448.x
Subject(s) - neuroprotection , quinolinic acid , glutamate receptor , pharmacology , nmda receptor , chemistry , excitotoxicity , microdialysis , metabotropic glutamate receptor , metabotropic glutamate receptor 5 , neuroscience , biochemistry , receptor , medicine , biology , extracellular , amino acid , tryptophan
Abstract The aim of this work was to investigate the potential neuroprotective effects of the metabotropic glutamate receptor 5 (mGlu5R) antagonist 2‐Methyl‐6‐(phenylethynyl)‐pyridine (MPEP) towards quinolinic acid (QA)–induced striatal excitoxicity. Intrastriatal MPEP (5 nmol/0.5 µL) significantly attenuated the body weight loss, the electroencephalographic alterations, the impairment in spatial memory and the striatal damage induced by bilateral striatal injection of QA (210 nmol/0.7 µL). In a second set of experiments, we aimed to elucidate the mechanisms underlying the neuroprotective effects of MPEP. In microdialysis studies in naive rats MPEP (80–250 µ m through the dialysis probe) significantly reduced the increase in glutamate levels induced by 5 m m QA. In primary cultures of striatal neurons MPEP (50 µ m ) reduced the toxicity induced by direct application of glutamate [measured as release of lactate dehydrogenase [LDH]). Finally, we found that 50 µ m MPEP was unable to directly block NMDA‐induced effects (namely field potential reduction in corticostriatal slices, as well as LDH release and intracellular calcium increase in striatal neurons). We conclude that: (i) MPEP has neuroprotective effects towards QA‐induced striatal excitotoxicity; (ii) both pre‐ and post‐synaptic mechanisms are involved; (iii) the neuroprotective effects of MPEP do not appear to involve a direct blockade of NMDA receptors.