Prevention of ischemic brain injury by treatment with the membrane penetrating apoptosis inhibitor, TAT-BH4
Volume 8, Issue 8
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April 15, 2009
Pages 1271 - 1278http://dx.doi.org/10.4161/cc.8.8.8301
Authors: Sandra Donnini, Raffaella Solito, Martina Monti, Walter Balduini, Silvia Carloni, Mauro Cimino, Edward T. W. Bampton, Lucia G.P. Pinon, Pierluigi Nicotera, Philip E. Thorpe and Marina Ziche View affiliations
In acute thromboembolic stroke, neurological damage is due to ischemia-induced apoptotic death of neuronal cells and the surrounding vascular network. Here, we demonstrate that the BH4 domain of the anti-apoptotic protein, Bcl-xL, attached to the membrane transport peptide, TAT, reduces stroke injury after intracerebroventricular infusion into immature rats subjected to carotid artery ligation and additional exposure to hypoxia. The injected TAT-BH4 entered neuron bodies, maintained brain architecture, protected neuronal and endothelial cells from apoptosis and promoted neuronal stem cell recruitment. In vitro, TAT-BH4 enhanced the survival of endothelial cells exposed to H2O2, increased neuronal differentiation, and induced axonal remodelling of adult neuronal stem cells. These findings indicate that TAT-BH4 administration protects against acute hypoxia/ischemia injury in the brain by preventing endothelial and neuron cell apoptosis and by inducing neuronal plasticity.
Received: January 28, 2009; Accepted: February 26, 2009