Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta.
The medium collected from cultured astrocytes transiently exposed to the group-II metabotropic glutamate (mGlu) receptor agonists (2S,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-beta (TGFbeta). (1) TGFbeta1 and -beta2 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 TGFbeta1 or -beta2 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 TGFbeta. 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 TGFbeta, 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.
Bruno
V
V
Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy.
Battaglia
G
G
Casabona
G
G
Copani
A
A
Caciagli
F
F
Nicoletti
F
F
D000818:Animals; D001253:Astrocytes / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005333:Fetus / Q000166:cytology; D051379:Mice; D008809:Mice, Inbred C3H; D016202:N-Methylaspartate / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D017077:Culture Media, Conditioned; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018094:Receptors, Metabotropic Glutamate; D016212:Transforming Growth Factor beta; C102718:metabotropic glutamate receptor 3; D016202:N-Methylaspartate