Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-β

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 (Bruno et al., 1997). The following 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 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 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 4C3HPG led to a delayed increase in both intracellular and extracellular levels of TGF beta. 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 beta, 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.