A Novel Neuroprotective Mechanism for Lithium That Prevents Association of the p75(NTR)-Sortilin Receptor Complex and Attenuates proNGF-Induced Neuronal Death In Vitro and In Vivo.
A Novel Neuroprotective Mechanism for Lithium That Prevents Association of the p75(NTR)-Sortilin Receptor Complex and Attenuates proNGF-Induced Neuronal Death In Vitro and In Vivo.
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锂的一种新型神经保护机制，可防止 p75(NTR)-Sortilin 受体复合物的结合，并在体外和体内减轻 proNGF 诱导的神经元死亡。
DOI：
10.1523/eneuro.0257-17.2017
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发表时间：
2018-01
期刊：
影响因子：
3.4
通讯作者：
Friedman WJ
中科院分区：
文献类型：
--
作者：
Greenwood SG;Montroull L;Volosin M;Scharfman HE;Teng KK;Light M;Torkin R;Maxfield F;Hempstead BL;Friedman WJ
神经营养因子在神经元的存活、维持和死亡中起关键作用。特别地，已显示原神经营养素介导大鼠中由癫痫持续状态（SE）诱导的脑损伤后的细胞死亡。先前的研究表明，匹鲁卡品诱导的癫痫发作导致proNGF水平升高，proNGF与p75 NTR-分拣蛋白受体复合物结合以引发细胞凋亡。筛选以鉴定阻断proNGF结合和摄取到表达p75和分拣蛋白的细胞中的化合物，将柠檬酸锂鉴定为proNGF和p75 NTR介导的细胞死亡的潜在抑制剂。在这项研究中，我们证明，低，亚微摩尔剂量的柠檬酸锂有效地抑制proNGF诱导的细胞死亡，在培养的神经元和保护海马神经元毛果芸香碱诱导的SE在体内。我们分析了柠檬酸锂提供神经保护的具体机制，并确定柠檬酸锂阻止了p75 NTR-分拣蛋白受体复合物的缔合和内化。我们的研究结果证明了一种新的机制，通过这种机制，低剂量的柠檬酸锂治疗在体外和体内有效地减弱p75 NTR介导的细胞死亡。
Neurotrophins play critical roles in the survival, maintenance and death of neurons. In particular, proneurotrophins have been shown to mediate cell death following brain injury induced by status epilepticus (SE) in rats. Previous studies have shown that pilocarpine-induced seizures lead to increased levels of proNGF, which binds to the p75NTR-sortilin receptor complex to elicit apoptosis. A screen to identify compounds that block proNGF binding and uptake into cells expressing p75 and sortilin identified lithium citrate as a potential inhibitor of proNGF and p75NTR-mediated cell death. In this study, we demonstrate that low, submicromolar doses of lithium citrate effectively inhibited proNGF-induced cell death in cultured neurons and protected hippocampal neurons following pilocarpine-induced SE in vivo. We analyzed specific mechanisms by which lithium citrate afforded neuroprotection and determined that lithium citrate prevented the association and internalization of the p75NTR-sortilin receptor complex. Our results demonstrate a novel mechanism by which low-dose treatments of lithium citrate are effective in attenuating p75NTR-mediated cell death in vitro and in vivo.