Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective

• Published in: Neuropharmacology 2000-11, Vol.39 (12), p.2223-2230
• Main Authors: Bruno, V, Ksiazek, I, Battaglia, G, Lukic, S, Leonhardt, T, Sauer, D, Gasparini, F, Kuhn, R, Nicoletti, F, Flor, P.J
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - toxicity; Animals; Biological and medical sciences; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Excitatory Amino Acid Antagonists - pharmacology; Excitotoxicity; Glutamatergic system (aspartate and other excitatory aminoacids); Male; Medical sciences; mGlu5 receptors; Mice; MPEP; N-Methylaspartate - antagonists & inhibitors; N-Methylaspartate - toxicity; Nerve Degeneration - pathology; Nerve Degeneration - prevention & control; Neuroglia - drug effects; Neurons - drug effects; Neurons - pathology; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neuroprotective Agents - pharmacology; Neurotransmitters. Neurotransmission. Receptors; Non-competitive antagonists; Pharmacology. Drug treatments; Phenazopyridine - pharmacology; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - antagonists & inhibitors; SIB-1757; SIB-1893; β-Amyloid toxicity
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(00)00079-4

We have used potent and selective non-competitive antagonists of metabotropic glutamate receptor subtype 5 (mGlu5) —- 2-methyl-6-phenylethynylpyridine (MPEP), [6-methyl-2-(phenylazo)-3-pyridinol] (SIB-1757) and [( E)-2-methyl-6-(2-phenylethenyl)pyridine] (SIB-1893) — to examine whether endogenous activation of this particular metabotropic glutamate receptor subtype contributes to neuronal degeneration. In cortical cultures challenged with N-methyl- d-aspartate (NMDA), all three mGlu5 receptor antagonists were neuroprotective. The effect of MPEP was highly specific because the close analogue, 3-methyl-6-phenylethynylpyridine (iso-MPEP), which did not antagonize heterologously expressed mGlu5 receptors, was devoid of activity on NMDA toxicity. Neuroprotection by mGlu5 receptor antagonists was also observed in cortical cultures challenged with a toxic concentration of β-amyloid peptide. We have also examined the effect of mGlu5 receptor antagonists in in vivo models of excitotoxic degeneration. MPEP and SIB-1893 were neuroprotective against neuronal damage induced by intrastriatal injection of NMDA or quinolinic acid. These results indicate that mGlu5 receptors represent a suitable target for novel neuroprotective agents of potential application in neurodegenerative disorders.