TAT-Hsp70-mediated neuroprotection and increased survival of neuronal precursor cells after focal cerebral ischemia in mice
TAT-Hsp70-mediated neuroprotection and increased survival of neuronal precursor cells after focal cerebral ischemia in mice
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DOI：
10.1038/jcbfm.2009.44
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发表时间：
2009-06-01
影响因子：
6.3
通讯作者：
Baehr, Mathias
中科院分区：
文献类型：
--
作者：
Doeppner, Thorsten R.;Nagel, Florian;Baehr, Mathias
脑缺血刺激成年啮齿动物脑室下区和海马齿状回内的内源性神经发生。然而，这些新生成的细胞在脑缺血后很快死亡。为了增强神经前体细胞（NPC）的缺血后存活和持久的神经再生，我们应用了抗凋亡分子伴侣热休克蛋白70（Hsp 70）融合到来自HIV达特的细胞穿透肽，以确保穿过血脑屏障和细胞膜。在小鼠短暂局灶性脑缺血后，静脉注射TAT-Hsp 70，同时再灌注，并在中风后第14天额外注射。TAT-Hsp 70治疗导致较小的梗死面积（27.1 ± 9.0 vs 109.0 ± 14.0和88.5 ± 26.0 mm（3）），并且与盐水和TAT-血凝素治疗的对照组相比，通过旋转杆、紧绳和水迷宫测试评估功能改善。此外，在TAT-Hsp 70治疗的动物的损伤纹状体内，内源性双皮质素（Dcx）阳性NPC的缺血后存活率在中风后长达4周的时间内得到改善，而不会改变BrdU（+）细胞的总体细胞增殖。因此，TAT-Hsp 70治疗中风后可能是一个有前途的工具，以发挥神经保护作用，改善缺血后的功能结果，并增加内源性鼻咽癌中风后的生存。脑血流与代谢杂志（2009）29，1187-1196; doi：10.1038/jcbfm.2009.44; 2009年4月22日在线发表
Cerebral ischemia stimulates endogenous neurogenesis within the subventricular zone and the hippocampal dentate gyrus of the adult rodent brain. However, such newly generated cells soon die after cerebral ischemia. To enhance postischemic survival of neural precursor cells (NPC) and long-lasting neural regeneration, we applied the antiapoptotic chaperone heat shock protein 70 (Hsp70) fused to a cell-penetrating peptide derived from the HIV TAT to ensure delivery across the blood-brain barrier and the cell membrane. After transient focal cerebral ischemia in mice, TAT-Hsp70 was intravenously injected concomitant with reperfusion and additionally on day 14 after stroke. TAT-Hsp70 treatment resulted in smaller infarct size (27.1 +/- 9.0 versus 109.0 +/- 14.0 and 88.5 +/- 26.0 mm(3) in controls) and in functional improvement as assessed by the rota rod, tight rope, and water maze tests when compared with saline-and TAT-hemagglutinin- treated controls. In addition, postischemic survival of endogenous doublecortin (Dcx)-positive NPC was improved within the lesioned striatum of TAT-Hsp70-treated animals for up to 4 weeks after stroke without changing overall cell proliferation of BrdU(+) cells. Thus, TAT-Hsp70 treatment after stroke may be a promising tool to act neuroprotective and improve postischemic functional outcome, and also to increase survival of endogenous NPC after stroke. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1187-1196; doi: 10.1038/jcbfm.2009.44; published online 22 April 2009