Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators
Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators
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DOI：
10.1096/fj.07-8386com
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发表时间：
2007-12-01
期刊：
影响因子：
4.8
通讯作者：
Le, Weidong
中科院分区：
文献类型：
--
作者：
Zhu, Wen;Xie, Wenjie;Le, Weidong
泛素-蛋白酶体系统（UPS）的功能障碍和黑质（SN）中铁的蓄积与帕金森病（PD）的发病机制有关。UPS功能障碍和铁的失调可能会加强对方的贡献多巴胺（DA）神经元的退化。在本研究中，我们使用一种新的脑渗透性铁螯合剂，VK- 28 [ 5-（4-（2-羟乙基）哌嗪-1-基（甲基）-8-羟基喹啉]，及其衍生物M30 [ 5-（N-甲基- N-炔丙基氨基甲基）-8-羟基喹啉]来测试它们对蛋白酶体抑制剂的神经保护和神经恢复特性（lactacystin）诱导的黑质纹状体变性。将lactacystin（1.25 μ g/侧）双侧微量注射到小鼠内侧前脑束中。在lactacystin显微注射之前或之后7天腹膜内施用VK- 28（5 mg/kg，每天一次）或M30（5 mg/ kg，每天一次），直到显微注射后28天处死小鼠。我们发现，VK- 28和M30都显着改善行为表现和衰减乳酸-胱氨酸诱导的DA神经元的损失，蛋白酶体抑制，铁积累，和小胶质细胞活化的SN。此外，M30恢复了注射lactacystin后受到抑制的Bcl-2水平。这些发现表明，脑渗透性铁螯合剂可以改善UPS损伤下DA神经元的存活。此外，M30，VK- 28和神经保护剂雷沙吉兰的衍生物，可能作为一个更好的神经保护治疗PD。
Dysfunction of the ubiquitin- proteasome system ( UPS) and accumulation of iron in substantia nigra ( SN) are implicated in the pathogenesis of Parkinson's disease ( PD). UPS dysfunction and iron misregulation may reinforce each other's contribution to the degeneration of dopamine ( DA) neurons. In the present study, we use a new brain- permeable iron chelator, VK- 28 [ 5-( 4-( 2- hydroxyethyl) piperazin- 1- yl ( methyl)- 8- hydroxyquinoline], and its derivative M30 [ 5-( N- methyl- N- propargyaminomethyl)- 8- hydroxyquinoline] in vivo to test their neuroprotective and neurorestorative properties against proteasome inhibitor ( lactacystin) - induced nigrostriatal degeneration. Bilateral microinjections of lactacystin ( 1.25 mu g/side) into the mouse medial forebrain bundle were performed. Administration of VK- 28 ( 5 mg/ kg, once a day) or M30 ( 5 mg/ kg, once a day) was applied intraperitoneally 7 days before or after the lactacystin microinjection until the mice were sacrificed 28 days after microinjection. We found that VK- 28 and M30 both significantly improved behavioral performances and attenuated lacta-cystin-induced DA neuron loss, proteasomal inhibition, iron accumulation, and microglial activation in SN. In addition, M30 restored the Bcl-2 level, which was suppressed after lactacystin injection. These findings suggest that brain- permeable iron chelators can improve DA neuron survival under UPS impairment. Furthermore, M30, a derivative of VK- 28 and neuroprotective agent rasagiline, may serve as a better neuroprotective therapy for PD.