Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective.
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 beta-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.
Bruno
V
V
Istituto Neurologico Mediterraneo - Neuromed, Pozzilli, Italy.
Ksiazek
I
I
Battaglia
G
G
Lukic
S
S
Leonhardt
T
T
Sauer
D
D
Gasparini
F
F
Kuhn
R
R
Nicoletti
F
F
Flor
P J
PJ
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010621:Phenazopyridine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
D016229:Amyloid beta-Peptides; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C120147:SIB 1757; C120148:SIB 1893; D016202:N-Methylaspartate; D010621:Phenazopyridine