NEUROPROTECTION BY GLIAL METABOTROPIC GLUTAMATE RECEPTORS IS MEDIATEDBY TRANSFORMING-GROWTH-FACTOR-BETA

The medium collected from cultured astrocytes transiently exposed to t he group-ii metabotropic glutamate (mGlu) receptor agonists ),2'(R),3' (R))-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) or (S)-4-carboxy-3-h ydroxyphenylglycine (4C3HPG) is neuroprotective when transferred to mi xed cortical cultures challenged with NMDA (Bruno et al., 1997). The f ollowing data indicate that this particular form of neuroprotection is mediated by transforming growth factor-beta (TGF beta). (1) TGF beta 1 and -beta 2 were highly neuroprotective against NMDA toxicity, and t heir action was less than additive with that produced by the medium co llected from astrocytes treated with DCG-IV or 4C3HPG (GM/DCG-IV or GM /4C3HPG); (2) antibodies that specifically neutralized the actions of TGF beta 1 or -beta 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 4C3HP G led to a delayed increase in both intracellular and extracellular le vels of TGF beta. We therefore conclude that a transient activation of group-II mGlu receptors (presumably mGlu3 receptors) in astrocytes le ads to an increased formation and release of TGF beta, which in turn p rotects neighbor neurons against excitotoxic death. These results offe r a new strategy for increasing the local production of neuroprotectiv e factors in the CNS.