Small-molecule protein tyrosine phosphatase inhibition as a neuroprotective treatment after spinal cord injury in adult rats.
Small-molecule protein tyrosine phosphatase inhibition as a neuroprotective treatment after spinal cord injury in adult rats.
复制标题
成年大鼠脊髓损伤后，小分子酪氨酸磷酸酶抑制作用作为神经保护剂。
DOI：
10.1523/jneurosci.1826-08.2008
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发表时间：
2008-07-16
期刊：
影响因子：
--
通讯作者：
Hagg T
中科院分区：
文献类型：
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作者：
Nakashima S;Arnold SA;Mahoney ET;Sithu SD;Zhang YP;D'Souza SE;Shields CB;Hagg T
脊髓损伤导致进行性继发性组织变性，使许多受伤的人患有神经残疾。没有令人满意的神经保护治疗。蛋白质酪氨酸磷酸酶-神经营养因子受体和下游细胞内信号分子。因此，我们测试了过氧钒化合物bpV（phen），一种稳定的，有效的和选择性的蛋白酪氨酸磷酸酶抑制剂，是否在成年大鼠胸脊髓挫伤后具有神经保护作用。通过腰椎穿刺鞘内注射bpV（phen）可以挽救支配薄束核的背柱感觉轴突和损伤中心的白色物质。在最有效的剂量下，基本上所有这些轴突和震中的大部分白色物质都幸免于难（而对照注射约为60%）。挫伤后4小时开始的BpV（phen）治疗完全有效。这种治疗在网格行走试验中大大改善和正常化了感觉运动功能，并在6周内提供了完全的轴突保护。治疗挽救了背柱横断后消失的感觉诱发电位。BpV（phen）影响早期退行性机制，因为在第7天观察到主要效应，并持续超过给药期。神经保护似乎是通过挽救血管介导的。BpV（phen）可减少内皮细胞凋亡。这些结果表明，以临床相关方式使用的小分子在与人类最常见类型的脊髓损伤相关的模型中减少了长突出轴突、髓鞘、血管和功能的损失。他们揭示了一种新的脊髓变性机制，涉及蛋白酪氨酸磷酸酶，可以用治疗药物靶向。
Spinal cord injury causes progressive secondary tissue degeneration leaving many injured people with neurological disabilities. There are no satisfactory neuroprotective treatments. Protein tyrosine phosphatases inactivate neurotrophic factor receptors and downstream intracellular signaling molecules. Thus, we tested whether the peroxovanadium compound bpV(phen), a stable, potent and selective protein tyrosine phosphatase inhibitor, would be neuroprotective following a thoracic spinal cord contusion in adult rats. Intrathecal bpV(phen) infusions through a lumbar puncture rescued dorsal column sensory axons innervating the nucleus gracilis and white matter at the injury epicenter. At the most effective dose, essentially all of these axons and most of the white matter at the epicenter were spared (vs. ~60% with control infusions). BpV(phen) treatments started 4 hours after contusion were fully effective. This treatment greatly improved and normalized sensory-motor function in a grid walking test and provided complete axonal protection over 6 weeks. The treatment rescued sensory evoked potentials which disappeared after dorsal column transection. BpV(phen) affected early degenerative mechanisms, as the main effects were seen at 7 days and lasted beyond the treatment period. The neuroprotection appeared to be mediated by rescue of blood vessels. BpV(phen) reduced apoptosis of cultured endothelial cells. These results show that a small molecule, used in a clinically relevant manner, reduces loss of long-projecting axons, myelin, blood vessels and function in a model relevant to the most common type of spinal cord injury in humans. They reveal a novel mechanism of spinal cord degeneration involving protein tyrosine phosphatases that can be targeted with therapeutic drugs.