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The Journal of Neuroscience, July 1, 2002, 22(13):5423-5431

In Vivo Delivery of a Bcl-xL Fusion Protein Containing the TAT Protein Transduction Domain Protects against Ischemic Brain Injury and Neuronal Apoptosis

Guodong Cao^{1, 2}, Wei Pei^{1, 2}, Hailiang Ge^{1, 2}, Qinhua Liang^{1, 2}, Yumin Luo^{1, 2}, Frank R. Sharp³, Aigang Lu³, Ruiqiong Ran³, Steven H. Graham^{1, 2, 4}, and Jun Chen^{1, 2, 4}

¹ Department of Neurology and ² Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, ³ Department of Neurology, University of Cincinnati Medical College, Cincinnati, Ohio 45267, and ⁴ Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania 15261

Bcl-xL is a well characterized death-suppressing molecule of the Bcl-2 family. Bcl-xL is expressed in embryonic and adult neurons of the CNS and may play a critical role in preventing neuronal apoptosis that occurs during brain development or results from diverse pathologic stimuli, including cerebral ischemia. In this study, we used a novel approach to study the potential neuroprotective effect of Bcl-xL as a therapeutic agent in the murine model of focal ischemia/reperfusion. We created a Bcl-xL fusion protein, designated as PTD-HA-Bcl-xL, which contains the protein transduction domain (PTD) derived from the human immunodeficiency TAT protein. We demonstrated that this fusion protein is highly efficient in transducing into primary neurons in cultures and potently inhibited staurosporin-induced neuronal apoptosis. Furthermore, intraperitoneal injection of PTD-HA-Bcl-xL into mice resulted in robust protein transduction in neurons in various brain regions within 1-2 hr, and decreased cerebral infarction (up to ~40%) in a dose-dependent manner, as determined at 3 d after 90 min of focal ischemia. PTD-HA-Bcl-xL was effective even when it was administered after the completion of ischemia (up to 45 min), and the protective effect was independent of the changes in cerebral blood flow or other physiological parameters. Finally, as shown by immunohistochemistry, Western blotting, and substrate-cleavage assays, PTD-HA-Bcl-xL attenuated ischemia-induced caspase-3 activation in ischemic neurons. These results thus confirm the neuroprotective effect of Bcl-xL against ischemic brain injury and provide the first evidence that the PTD can be used to efficiently transduce a biologically active neuroprotectant in experimental cerebral ischemia.

Key words: cerebral ischemia; stroke; protein transduction; Bcl-2; caspase-3, cytochrome c

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22135423-09$05.00/0

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