This Article Full Text Full Text (PDF) All Versions of this Article: 34/5/1304    most recent 01.STR.0000066869.45310.50v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kilic, U. Articles by Bähr, M. Search for Related Content PubMed PubMed Citation Articles by Kilic, U. Articles by Bähr, M. Related Collections Animal models of human disease Neuroprotectors Transient Ischemic Attacks

(Stroke. 2003;34:1304.)
© 2003 American Heart Association, Inc.

Original Contributions

Intravenous TAT-GDNF Is Protective After Focal Cerebral Ischemia in Mice

Ülkan Kilic, PhD; Ertugrul Kilic, PhD; Gunnar P.H. Dietz, PhD Mathias Bähr, MD

From the Department of Neurology, University of Göttingen, Göttingen, Germany.

Reprint requests to Dr Ertugrul Kilic, Department of Neurology, University of Zürich, Frauenklinik Str. 26 CH-8901 Zürich, Switzerland. E-mail ertugrul.kilic{at}usz.ch

Background and Purpose— Delivery of therapeutic proteins into tissues and across the blood-brain barrier is severely limited by their size and biochemical properties. The 11-amino acid human immunodeficiency virus TAT protein transduction domain is able to cross cell membranes and the blood-brain barrier, even when coupled with larger peptides. The present studies were done to evaluate whether TAT–glial line-derived neurotrophic factor (GDNF) fusion protein is protective in focal cerebral ischemia.

Methods— Anesthetized male C57BL/6j mice were submitted to intraluminal thread occlusion of the middle cerebral artery. Reperfusion was initiated 30 minutes later by thread retraction. Laser Doppler flow was monitored during the experiments. TAT-GDNF, TAT-GFP (0.6 nmol each), or vehicle was intravenously applied over 10 minutes immediately after reperfusion. After 3 days (30 minutes of ischemia), animals were reanesthetized and decapitated. Brain injury was evaluated by histochemical stainings.

Results— Immunocytochemical experiments confirmed the presence of TAT-GDNF protein in the brains of fusion protein–treated nonischemic control animals 3 to 4 hours after TAT fusion protein delivery. TAT-GDNF significantly reduced the number of caspase-3–immunoreactive and DNA-fragmented cells and increased the number of viable neurons in the striatum, where disseminated tissue injury was observed, compared with TAT-GFP– or vehicle-treated animals.

Conclusions— Our results demonstrate that TAT fusion proteins are powerful tools for the treatment of focal ischemia when delivered both before and after an ischemic insult. This approach may be of clinical interest because such fusion proteins can be intravenously applied and reach the ischemic brain regions. This approach may therefore offer new perspectives for future strategies in stroke therapy.

Key Words: brain-derived neurotrophic factor • fusion protein • glial cell line-derived neurotrophic factor • ischemia • protein transport • stroke

This article has been cited by other articles:

				Wei Xu, Miou Zhou, and M. Baudry Neuroprotection by Cell Permeable TAT-mGluR1 Peptide in Ischemia: Synergy between Carrier and Cargo Sequences Neuroscientist, October 1, 2008; 14(5): 409 - 414. [Abstract] [PDF]

				B. Neukamm, A. A. Miyakawa, S. Y. Fukada, C. R. de Andrade, F. P. Pacheco, T. G. da Silva, L. N. Z. Ramalho, A. M. de Oliveira, and J. E. Krieger Original Research: Local TAT-p27Kip1 Fusion protein inhibits cell proliferation in rat Carotid arteries Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 129 - 136. [Abstract] [PDF]

				E. Kubo, N. Fatma, Y. Akagi, D. R. Beier, S. P. Singh, and D. P. Singh TAT-mediated PRDX6 protein transduction protects against eye lens epithelial cell death and delays lens opacity Am J Physiol Cell Physiol, March 1, 2008; 294(3): C842 - C855. [Abstract] [Full Text] [PDF]

				T. Ogawa, S. Ono, T. Ichikawa, S. Arimitsu, K. Onoda, K. Tokunaga, K. Sugiu, K. Tomizawa, H. Matsui, and I. Date Novel Protein Transduction Method by Using 11R: An Effective New Drug Delivery System for the Treatment of Cerebrovascular Diseases Stroke, April 1, 2007; 38(4): 1354 - 1361. [Abstract] [Full Text] [PDF]

				E. M. Barnett, B. Elangovan, K. E. Bullok, and D. Piwnica-Worms Selective cell uptake of modified tat Peptide-fluorophore conjugates in rat retina in ex vivo and in vivo models. Invest. Ophthalmol. Vis. Sci., June 1, 2006; 47(6): 2589 - 2595. [Abstract] [Full Text] [PDF]

				S. Krautwald, E. Ziegler, K. Tiede, R. Pust, and U. Kunzendorf Transduction of the TAT-FLIP Fusion Protein Results in Transient Resistance to Fas-induced Apoptosis in Vivo J. Biol. Chem., October 15, 2004; 279(42): 44005 - 44011. [Abstract] [Full Text] [PDF]