A Transforming Growth Factor-β Antagonist Unmasks the Neuroprotective Role of This Endogenous Cytokine in Excitotoxic and Ischemic Brain Injury

Abstract

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.

A Soluble Transforming Growth Factor-β (TGF-β) Type I Receptor Mimics TGF-β Responses

“…These observations are reinforced by findings showing that some epithelial cancers are resistant to TGF-␤; the mechanisms vary from mutation of type II receptor (41) to alteration of the TGF-␤ signaling pathway (42,43). Moreover, in a previous study, we have demonstrated that blocking the endogenously produced TGF-␤1 induced a large increase in the damaged tissue in a model of cerebral ischemia in rats (15,44).…”

“…In a previous study (13), we have generated a soluble type II receptor for TGF-␤ fused with the Fc region of human immunoglobulin and characterized its ability to prevent TGF-␤ signaling in mink lung epithelial cells by sequestering the TGF-␤ peptide. By using this tool, we have demonstrated that blockage of the activity of endogenously produced TGF-␤, in a model of cerebral ischemia in rats, enhanced the volume of the damaged tissue (15). These data suggest that the potentiation of the TGF-␤ signaling in ischemic brain tissues may represent an innovative approach for the treatment of stroke in man.…”

The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection

“…Astrocytic mGlu3 receptors could also be involved because systemic injection of LY379268 failed to enhance the formation of TGF-␤1 in the striatum of mGlu3 receptor knock-out mice. TGF-␤1, which is produced by astrocytes in response to mGlu3 receptor activation, is proven to be protective against neuronal degeneration induced by excitotoxins, oxygen-glucose deprivation, ␤-amyloid peptide, and the human immunodeficiency virus capsid protein gp 120 (Chao et al, 1994;Prehn et al, 1994Copani et al, 1995aCopani et al, ,b, 1998Henrich-Noack et al, 1996;Meucci and Miller, 1996;Ren et al, 1997;Scorziello et al, 1997;Bruno et al, 1998b;Flanders et al, 1998;Ruocco et al, 1999).…”

The HSV-2 protein ICP10PK prevents neuronal apoptosis and loss of function in an in vivo model of neurodegeneration associated with glutamate excitotoxicity

“…Glutamate over-stimulates the NMDA receptor to neurotoxic level (Lipton, 2004) and Ca 2+ influx through the NMDA receptors causes neuronal death by necrosis and apoptosis (Ankarcrona et al, 1995). Intrastriatal injection of NMDA is used as an ischemic model, where necrotic cell death induces an ischemic core, surrounded by an apoptotic penumbra (Black et al, 1994;Hara et al, 1997;Ruocco et al, 1999;Kunimatsu et al, 2001). To examine whether ΔRR can inhibit neuronal death caused by excitotoxic injury, mice were given NMDA, alone or NMDA with ΔRR, as described in Materials and Methods.…”