A transforming growth factor-β antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury

被引:124
作者
Ruocco, A
Nicole, O
Docagne, F
Ali, C
Chazalviel, L
Komesli, S
Yablonsky, F
Roussel, S
MacKenzie, ET
Vivien, D
Buisson, A
机构
[1] Univ Caen, UMR CNRS 6551, Neurosci Lab, F-14074 Caen, France
[2] Labs Fournier SA, Dept Immunol, Daix, France
关键词
TGF-beta; excitotoxicity; ischemia; cytokine;
D O I
10.1097/00004647-199912000-00008
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (T beta RIIs-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-beta 1 on excitotoxic cell death in murine cortical cell cultures. The addition of 1 mu g/mL of T beta RIIs-Fc to the exposure medium antagonized the neuroprotective activity of TGF-beta 1 in N-methyl-(D)-aspartate (NMDA)-induced excitotoxic cell death. These results are consistent with the hypothesis that TGF-beta 1 exerts a negative modulatory action on NMDA receptor-mediated excitotoxicity. To determine the role of TGF-beta 1 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 mu g of T beta RIIs-Fc. The intrastriatal injection of NMDA was demonstrated to induce an early upregulation of the expression of TGF-beta 1 mRNA. Furthermore, when added to the excitotoxin, T beta RIIs-Fc increased (by 2.2-fold, P < 0.05) the lesion size. These observations were strengthened by the fact that an intracortical injection of T beta RIIs-Fc in rats subjected to a 30-minute reversible cerebral focal ischemia aggravated the volume of infarction. In the group injected with the TGF-beta 1 antagonist, a 3.5-fold increase was measured in the infarction size (43.3 +/- 9.5 versus 152.8 +/- 46.3 mm(3); 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-beta, 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.
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收藏
页码:1345 / 1353
页数:9
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