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The Journal of Neuroscience, September 1, 2000, 20(17):6413-6420

Selective Activation of mGlu4 Metabotropic Glutamate Receptors Is Protective against Excitotoxic Neuronal Death

V. Bruno¹, G. Battaglia¹, I. Ksiazek², H. van der Putten², M. V. Catania³, R. Giuffrida³, S. Lukic², T. Leonhardt², W. Inderbitzin², F. Gasparini², R. Kuhn², D. R. Hampson⁴, F. Nicoletti^{1, 5}, and P. J. Flor²

¹ Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy, ² Novartis Pharma AG, Nervous System Research, CH-4002 Basel, Switzerland, ³ Istituto di Bioimmagini e Fisiopatologia del Sistema Nervoso Centrale, Consiglio Nazionale delle Ricerche, 95125 Catania, Italy, ⁴ Faculty of Pharmacy, University of Toronto, Canada M5S 2S2, and ⁵ Department of Pharmaceutical Sciences, University of Catania, 95125 Catania, Italy

Activation of group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, and mGluR8) has been established to be neuroprotective in vitro and in vivo. To disclose the identity of the receptor subtype(s) that exert(s) the protective effect, we have used group III agonists in combination with mGluR4 subtype-deficient mice (/). In cortical cultures prepared from wild-type (+/+) mice and exposed to a toxic pulse of NMDA, the selective group III agonist (+)-4-phosphonophenylglycine [(+)-PPG] reversed excitotoxicity with an EC₅₀ value of 4.9 µM, whereas its enantiomer ()-PPG was inactive. This correlated closely with the potency of (+)-PPG in activating recombinant mGluR4a. In cortical neurons from / mice, (+)-PPG showed no protection against the NMDA insult up to 300 µM, whereas group I/II mGluR ligands still retained their protective activity. Classical group III agonists (L-2-amino-4-phosphonobutyrate and L-serine-O-phosphate) were also substantially neuroprotective against NMDA toxicity in +/+ and heterozygous (+/) cultures but were inactive in / cultures. Interestingly, / cultures were more vulnerable to low concentrations of NMDA and showed higher extracellular glutamate levels compared with +/+ cultures.

We have also examined neurodegeneration induced by intrastriatal infusion of NMDA in wild-type or mGluR4-deficient mice. Low doses of (R,S)-PPG (10 nmol/0.5 µl) substantially reduced NMDA toxicity in +/+ mice but were ineffective in / mice. Higher doses of (R,S)-PPG were neuroprotective in both strains of animals. Finally, microdialysis studies showed that intrastriatal infusion of NMDA increased extracellular glutamate levels to a greater extent in / than in +/+ mice, supporting the hypothesis that the mGluR4 subtype is necessary for the maintenance of the homeostasis of extracellular glutamate levels.

Key words: neurodegeneration; knock-out mice; cortical cultures; metabotropic glutamate receptors; gene targeting; excitotoxicity

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20176413-08$05.00/0

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