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

J Neurochem. 2004 Jun;89(6):1479-89. doi: 10.1111/j.1471-4159.2004.02448.x.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Calcium / metabolism
  • Cells, Cultured
  • Electroencephalography / drug effects
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamic Acid / metabolism
  • Glutamic Acid / toxicity
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Maze Learning / drug effects
  • Microdialysis
  • N-Methylaspartate / pharmacology*
  • Neostriatum / drug effects*
  • Neostriatum / pathology
  • Neostriatum / physiopathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Neurotoxicity Syndromes / pathology
  • Neurotoxicity Syndromes / physiopathology
  • Neurotoxicity Syndromes / prevention & control*
  • Neurotoxins / antagonists & inhibitors
  • Neurotoxins / toxicity
  • Pyridines / pharmacology*
  • Quinolinic Acid / antagonists & inhibitors
  • Quinolinic Acid / toxicity
  • Rats
  • Rats, Wistar
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*

Substances

  • Excitatory Amino Acid Antagonists
  • Neuroprotective Agents
  • Neurotoxins
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Glutamic Acid
  • N-Methylaspartate
  • 6-methyl-2-(phenylethynyl)pyridine
  • L-Lactate Dehydrogenase
  • Quinolinic Acid
  • Calcium