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.
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 micro L) 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 micro L). 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 micro m through the dialysis probe) significantly reduced the increase in glutamate levels induced by 5 mm QA. In primary cultures of striatal neurons MPEP (50 micro m) reduced the toxicity induced by direct application of glutamate [measured as release of lactate dehydrogenase [LDH]). Finally, we found that 50 micro 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.
Popoli
Patrizia
P
Department of Pharmacology, Istituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy. patrizia.popoli@iss.it
Pintor
Annita
A
Tebano
Maria Teresa
MT
Frank
Claudio
C
Pepponi
Rita
R
Nazzicone
Valeria
V
Grieco
Rosa
R
Pèzzola
Antonella
A
Reggio
Rosaria
R
Minghetti
Luisa
L
De Berardinis
Maria Anna
MA
Martire
Alberto
A
Potenza
Rosa Luisa
RL
Domenici
Maria Rosaria
MR
Massotti
Marino
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004569:Electroencephalography / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D017551:Microdialysis; D016202:N-Methylaspartate / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D011725:Pyridines / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D016202:N-Methylaspartate; C121465:6-methyl-2-(phenylethynyl)pyridine; D007770:L-Lactate Dehydrogenase; D017378:Quinolinic Acid; D002118:Calcium