Intravenous TAT-Bcl-Xl is protective after middle cerebral artery occlusion in mice.
The delivery of proteins across the blood-brain barrier is severely limited by the proteins' size and biochemical properties. Eleven-amino acid human immunodeficiency virus TAT protein is able to cross cell membranes even when coupled with larger peptides. We evaluated whether TAT-Bcl-X(L) fusion protein is protective in focal ischemia. Mice underwent 30 or 90 minutes of intraluminal middle cerebral artery thread occlusion. TAT-Bcl-X(L), TAT-beta-galactosidase, or TAT-GFP (0.6 nmol each) were applied intravenously over 10 minutes either 1 hour before or immediately after ischemia. Additional animals received no TAT protein infusions. We show that the brain tissue is progressively transduced with TAT proteins within 3 to 4 hours after intravenous delivery. We provide evidence that TAT-Bcl-X(L) treatment reduces infarct volume and neurological deficits after long ischemic insults lasting 90 minutes, when applied both before and after ischemia. After short insults, lasting only 30 minutes, TAT-Bcl-X(L) further diminishes the number of caspase-3-reactive and DNA fragmented cells and increases the number of viable neurons in the striatum. Our results indicate that TAT fusion proteins are elegant and powerful tools that might be of clinical interest for stroke treatment, because factors may be intravenously applied. Thus, fusion proteins may open fascinating perspectives for future research.
Kilic
Ertugrul
E
Department of Neurology, University of Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany. ertogrul.kilic@med.uni-goettingen.de
Dietz
Gunnar P H
GP
Hermann
Dirk M
DM
Bähr
Mathias
M
D000818:Animals; D001921:Brain / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002560:Cerebrovascular Circulation; D004334:Drug Administration Schedule; D004789:Enzyme Activation; D015696:Gene Products, tat / Q000235:genetics*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009422:Nervous System Diseases / Q000209:etiology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013997:Time Factors; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D015696:Gene Products, tat; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases