A transforming growth factor-beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury.
Various studies describe increased concentrations of transforming growth factor-beta (TGF-beta) in brain tissue after acute brain injury. However, the role of endogenously produced TGF-beta after brain damage to the CNS remains to be clearly established. Here, the authors examine the influence of TGF-beta produced after an episode of cerebral ischemia by injecting a soluble TGF-beta type II receptor fused with the Fc region of a human immunoglobulin (TbetaRIIs-Fc). First, this molecular construct was characterized as a selective antagonist of TGF-beta. Then, the authors tested its ability to reverse the effect of TGF-beta1 on excitotoxic cell death in murine cortical cell cultures. The addition of 1 microg/mL of TbetaRIIs-Fc to the exposure medium antagonized the neuroprotective activity of TGF-beta1 in N-methyl-D-aspartate (NMDA)-induced excitotoxic cell death. These results are consistent with the hypothesis that TGF-beta1 exerts a negative modulatory action on NMDA receptor-mediated excitotoxicity. To determine the role of TGF-beta1 produced in response to brain damage, the authors used a model of an excitotoxic lesion induced by the intrastriatal injection of 75 nmol of NMDA in the presence of 1.5 microg of TbetaRIIs-Fc. The intrastriatal injection of NMDA was demonstrated to induce an early upregulation of the expression of TGF-beta1 mRNA. Furthermore, when added to the excitotoxin, TbetaRIIs-Fc increased (by 2.2-fold, P < 0.05) the lesion size. These observations were strengthened by the fact that an intracortical injection of TbetaRIIs-Fc in rats subjected to a 30-minute reversible cerebral focal ischemia aggravated the volume of infarction. In the group injected with the TGF-beta1 antagonist, a 3.5-fold increase was measured in the infarction size (43.3 +/- 9.5 versus 152.8 +/- 46.3 mm3; P < 0.05). In conclusion, by antagonizing the influence of TGF-beta in brain tissue subjected to excitotoxic or ischemic lesion, the authors markedly exacerbated the resulting extent of necrosis. These results suggest that, in response to such insults, brain tissue responds by the synthesis of a neuroprotective cytokine, TGF-beta1, which is involved in the limitation of the extent of the injury. The pharmacologic potentiation of this endogenous defensive mechanism might represent an alternative and novel strategy for the therapy of hypoxic-ischemic cerebral injury.
Ruocco
A
A
Université de Caen, France.
Nicole
O
O
Docagne
F
F
Ali
C
C
Chazalviel
L
L
Komesli
S
S
Yablonsky
F
F
Roussel
S
S
MacKenzie
E T
ET
Vivien
D
D
Buisson
A
A
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002544:Cerebral Infarction / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D005333:Fetus; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007141:Immunoglobulin Fc Fragments; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D020768:Middle Cerebral Artery; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D018696:Neuroprotective Agents; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*
D007141:Immunoglobulin Fc Fragments; D018696:Neuroprotective Agents; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D016202:N-Methylaspartate; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II