Targeted delivery of neurogenin-2 protein in the treatment for cerebral ischemia-reperfusion injury.
Neurogenin-2 (Ngn2), as a proneural gene that promotes the survival and differentiation of neural precursor cells, is an attractive candidate for therapy against cerebral ischemia-reperfusion injury. However, the delivery approach limits its clinical application. To deliver Ngn2 protein into the cerebral ischemic region and exert a therapeutic effect on injured neurons after ischemia, we here reported that the fusion protein TAT-LBD-Ngn2 was constructed by fusing a transactivator of transcription (TAT) domain and a laminin-binding domain (LBD) to Ngn2. TAT-LBD-Ngn2 promoted the outgrowth of neuronal neurite, increased the survival rate and alleviated apoptosis of hippocampal neurons exposed to oxygen glucose deprivation in vitro. Furthermore, a focal cerebral ischemia model in C57BL/6 mice showed that TAT-LBD-Ngn2 efficiently crossed the blood brain barrier, aggregated in the ischemic zone and was consistently incorporated into neurons. Moreover, TAT-LBD-Ngn2 transduced into brains attenuated neuronal degeneration and apoptosis in the ischemic zone. TAT-LBD-Ngn2 treatment resulted in a reduction of infarct volume that was associated with a parallel improvement in neurological functional outcomes after reperfusion. In conclusion, the targeted delivery of TAT-LBD-Ngn2 into the ischemic zone attenuated cerebral ischemia-reperfusion injury through the inhibition of neuronal degeneration and apoptosis, suggesting that TAT-LBD-Ngn2 is a promising target candidate for the treatment of ischemic stroke.
Department of Anesthesiology, Stomatological College, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
Bin
B
Deng
Xingchun
X
Gou
Hai
H
Chen
Liya
L
Li
Haixing
H
Zhong
Hao
H
Xu
Fengliang
F
Jiang
Zhijing
Z
Zhao
Qiang
Q
Wang
Lixian
L
Xu
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology / Q000628:therapy*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D004195:Disease Models, Animal; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D018014:Gene Transfer Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000473:pathology / Q000628:therapy; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000627:therapeutic use*; D058953:Neural Stem Cells / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D020521:Stroke / Q000473:pathology / Q000628:therapy; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D015696:Gene Products, tat; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D051028:bcl-2-Associated X Protein; C494827:Bax protein, mouse; C102938:Neurog2 protein, mouse; C505409:Casp3 protein, mouse
Apoptosis; Laminin-binding domain; Neurogenin-2; Stroke; Targeted delivery; Trans-activator of transcription domain