TAT-mediated delivery of Bcl-xL protein is neuroprotective against neonatal hypoxic-ischemic brain injury via inhibition of caspases and AIF.
Systemic delivery of recombinant Bcl-xL fusion protein containing the TAT protein transduction domain attenuated neonatal brain damage following hypoxic ischemia (H-I). Within 30 min after intraperitoneal injection of TAT-Bcl-xL protein into 7-day-old rats, substantially enhanced levels of Bcl-xL were found in several brain regions. Administration of TAT-Bcl-xL at the conclusion of the H-I insult decreased cerebral tissue loss in a dose-dependent manner measured 1 and 8 weeks later. Neuroprotection provided by TAT-Bcl-xL was significantly greater than that of the pan-caspase inhibitor BAF, suggesting that protection is only partially attributable to caspase inhibition by TAT-Bcl-xL. TAT-Bcl-xL not only inhibited caspases-3 and -9 activities after H-I but also prevented nuclear translocation of AIF. Taken together, these results substantiate the feasibility of peripheral delivery of an anti-apoptotic factor into the brain of neonatal animals to reduce H-I-induced brain injury.
Yin
Wei
W
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Cao
Guodong
G
Johnnides
Michael J
MJ
Signore
Armando P
AP
Luo
Yumin
Y
Hickey
Robert W
RW
Chen
Jun
J
D000818:Animals; D000831:Animals, Newborn; D051033:Apoptosis Inducing Factor / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D015696:Gene Products, tat / Q000235:genetics*; D020925:Hypoxia-Ischemia, Brain / Q000517:prevention & control*; D007150:Immunohistochemistry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D051020:bcl-X Protein / Q000008:administration & dosage* / Q000235:genetics
C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; C494813:Bcl2l1 protein, rat; D015696:Gene Products, tat; D018696:Neuroprotective Agents; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D020169:Caspases