Neuroprotection mediated by glial group-II metabotropic glutamate receptors requires the activation of the MAP kinase and the phosphatidylinositol-3-kinase pathways

• Published in: Journal of neurochemistry Vol. 78; no. 3; pp. 435 - 445
• Main Authors: D'ONOFRIO, M, CUOMO, L, BRUNO, V, BATTAGLIA, G, NGOMBA, R. T, STORTO, M, KINGSTON, A. E, ORZI, F, DE BLASI, A, DI IORIO, P, NICOLETTI, F
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell 01.08.2001
• Subjects: Amino Acids - pharmacology; Animals; Astrocytes - drug effects; Astrocytes - metabolism; Biological and medical sciences; Blotting, Northern; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cells, Cultured; Chromones - pharmacology; Corpus Striatum - cytology; Corpus Striatum - metabolism; Enzyme Inhibitors - pharmacology; Excitatory Amino Acid Agonists - pharmacology; Flavonoids - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); Glycine - analogs & derivatives; Glycine - pharmacology; Immunoblotting; Immunohistochemistry; Male; MAP Kinase Signaling System - physiology; Medical sciences; Mice; Morpholines - pharmacology; N-Methyl-D-aspartic acid; N-Methylaspartate - toxicity; Neurons - drug effects; Neurons - metabolism; Neuropharmacology; Neuroprotective Agents - pharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate - metabolism; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1; Neuroprotection; Enzyme; Toxicity; Neuroglia; Transferases; Rodentia; Mitogen-activated protein kinase; Glutamate receptor; Astrocyte; 1-Phosphatidylinositol 3-kinase; Vertebrata; Mammalia; Metabotropic receptor; Mouse; Excitotoxicity; Transforming growth factor β1; EC 2.7.1.137
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2001.00435.x

The mGlu2/3 receptor agonists 4-carboxy-3-hydroxyphenylglycine (4C3HPG) and LY379268 attenuated NMDA toxicity in primary cultures containing both neurons and astrocytes. Neuroprotection was abrogated by PD98059 and LY294002, which inhibit the mitogen activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI-3-K) pathways, respectively. Cultured astrocytes lost the ability to produce transforming growth factor-beta1 (TGF-beta1) in response to mGlu2/3 receptor agonists when co-incubated with PD98059 or LY294002. As a result, the glial medium was no longer protective against NMDA toxicity. Activation of the MAPK and PI-3-K pathways in cultured astrocytes treated with 4C3HPG or LY379268 was directly demonstrated by an increase in the phosphorylated forms of ERK-1/2 and Akt. Similarly to that observed in the culture, intracerebral or systemic injections of mGlu2/3 receptor agonists enhanced TGF-beta1 formation in the rat or mouse caudate nucleus, and this effect was reduced by PD98059. PD98059 also reduced the ability of LY379268 to protect striatal neurons against NMDA toxicity. These results suggest that activation of glial mGlu2/3 receptors induces neuroprotection through the activation of the MAPK and PI-3-K pathways leading to the induction of TGF-beta.