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 fa ctor-beta (TGF-beta) in brain tissue after acute brain injury. However, the role of endogenously produced TGF-beta after brain damage to the CNS remai ns to be clearly established. Here, the authors examine the influence of TG F-beta produced after an episode of cerebral ischemia by injecting a solubl e TGF-beta type II receptor fused with the Fc region of a human immunoglobu lin (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 corti cal cell cultures. The addition of 1 mu g/mL of T beta RIIs-Fc to the expos ure medium antagonized the neuroprotective activity of TGF-beta 1 in N-meth yl-(D)-aspartate (NMDA)-induced excitotoxic cell death. These results are c onsistent with the hypothesis that TGF-beta 1 exerts a negative modulatory action on NMDA receptor-mediated excitotoxicity. To determine the role of T GF-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 inje ction of NMDA was demonstrated to induce an early upregulation of the expre ssion of TGF-beta 1 mRNA. Furthermore, when added to the excitotoxin, T bet a RIIs-Fc increased (by 2.2-fold, P < 0.05) the lesion size. These observat ions were strengthened by the fact that an intracortical injection of T bet a RIIs-Fc in rats subjected to a 30-minute reversible cerebral focal ischem ia 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 ant agonizing the influence of TGF-beta in brain tissue subjected to excitotoxi c or ischemic lesion, the authors markedly exacerbated the resulting extent of necrosis. These results suggest that, in response to such insults, brai n tissue responds by the synthesis of a neuroprotective cytokine, TGF-beta, which is involved in the Limitation of the extent of the injury. The pharm acologic potentiation of this endogenous defensive mechanism might represen t an alternative and novel strategy for the therapy of hypoxic-ischemic cer ebral injury.