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The Journal of Neuroscience, December 1, 1998, 18(23):9594-9600

Neuroprotection by Glial Metabotropic Glutamate Receptors Is Mediated by Transforming Growth Factor-

V. Bruno¹, G. Battaglia¹, G. Casabona¹, A. Copani², F. Caciagli³, and F. Nicoletti^{1, 2}

¹ Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy, ² Institute of Pharmacology, School of Pharmacy, University of Catania, 95125 Catania, Italy, and ³ Department of Pharmacological Sciences, University of Chieti, 66013 Chieti, Italy

The medium collected from cultured astrocytes transiently exposed to the group-II metabotropic glutamate (mGlu) receptor agonists (2_S,1'_R,2'_R,3'_R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) or (S)-4-carboxy-3-hydroxyphenylglycine (4C3HPG) is neuroprotective when transferred to mixed cortical cultures challenged with NMDA (). The following data indicate that this particular form of neuroprotection is mediated by transforming growth factor- (TGF). (1) TGF1 and -2 were highly neuroprotective against NMDA toxicity, and their action was less than additive with that produced by the medium collected from astrocytes treated with DCG-IV or 4C3HPG (GM/DCG-IV or GM/4C3HPG); (2) antibodies that specifically neutralized the actions of TGF1 or -2 prevented the neuroprotective activity of DCG-IV or 4C3HPG, as well as the activity of GM/DCG-IV or GM/4C3HPG; and (3) a transient exposure of cultured astrocytes to either DCG-IV or 4C3HPG led to a delayed increase in both intracellular and extracellular levels of TGF. We therefore conclude that a transient activation of group-II mGlu receptors (presumably mGlu3 receptors) in astrocytes leads to an increased formation and release of TGF, which in turn protects neighbor neurons against excitotoxic death. These results offer a new strategy for increasing the local production of neuroprotective factors in the CNS.

Key words: metabotropic glutamate receptors; glial cells; transforming growth factor-; neuroprotection; excitotoxic neuronal death; astrocyte; cortical cultures

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18239594-07$05.00/0

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