Yin Wei, Cao Guodong, Johnnides Michael J, Signore Armando P, Luo Yumin, Hickey Robert W, Chen Jun
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Neurobiol Dis. 2006 Feb;21(2):358-71. doi: 10.1016/j.nbd.2005.07.015. Epub 2005 Sep 6.
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.
含有TAT蛋白转导结构域的重组Bcl-xL融合蛋白的全身给药减轻了缺氧缺血（H-I）后的新生大鼠脑损伤。在向7日龄大鼠腹腔注射TAT-Bcl-xL蛋白后30分钟内，在几个脑区发现Bcl-xL水平显著升高。在H-I损伤结束时给予TAT-Bcl-xL，以剂量依赖的方式减少了1周和8周后测量的脑组织损失。TAT-Bcl-xL提供的神经保护作用明显大于泛半胱天冬酶抑制剂BAF，这表明保护作用仅部分归因于TAT-Bcl-xL对半胱天冬酶的抑制。TAT-Bcl-xL不仅抑制H-I后的半胱天冬酶-3和-9活性，还阻止了AIF的核转位。综上所述，这些结果证实了将抗凋亡因子经外周给药至新生动物脑内以减少H-I诱导的脑损伤的可行性。
