A cell-permeable phosphine-borane complex delays retinal ganglion cell death after axonal injury through activation of the pro-survival extracellular signal-regulated kinases 1/2 pathway.
A cell-permeable phosphine-borane complex delays retinal ganglion cell death after axonal injury through activation of the pro-survival extracellular signal-regulated kinases 1/2 pathway.
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可渗透的细胞磷酸硼烷复合物通过激活促卵巢外信号调节激酶1/2途径，轴突损伤后视网膜神经节细胞死亡延迟。
DOI：
10.1111/j.1471-4159.2011.07382.x
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发表时间：
2011-09
影响因子：
4.7
通讯作者：
Di Polo A
中科院分区：
文献类型：
--
作者：
Almasieh M;Lieven CJ;Levin LA;Di Polo A
活性氧物质超氧化物已被确认为轴突损伤后触发视网膜神经节细胞（RGC）死亡的关键信号。尽管超氧化物的下游靶点尚不清楚，但氧化巯基的化学还原已被证明对受损的RGC具有神经保护作用。基于此，我们开发了新型的膦 - 硼烷络合物，它们具有细胞渗透性且高度稳定。在此，我们报道我们的先导化合物，双（3 - 丙酸甲酯）苯基膦硼烷络合物1（PB1），可促进视神经轴突切断大鼠模型和实验性青光眼模型中RGC的存活。PB1介导的RGC神经保护作用与应激激活蛋白激酶信号通路（包括ASK1、JNK或p38）的抑制无关。相反，PB1导致视网膜脑源性神经营养因子（BDNF）水平显著升高以及细胞外调节蛋白激酶1/2（ERK1/2）通路的下游激活。对ERK1/2的药理抑制完全阻断了PB1诱导的RGC神经保护作用。我们得出结论，PB1通过激活促存活信号来保护受损的RGC。这些数据支持氧化还原稳态和神经营养因子相关通路之间可能存在的相互作用，这种相互作用导致轴突损伤后RGC的存活。
The reactive oxygen species superoxide has been recognized as a critical signal triggering retinal ganglion cell (RGC) death after axonal injury. Although the downstream targets of superoxide are unknown, chemical reduction of oxidized sulfhydryls has been shown to be neuroprotective for injured RGCs. Based on this, we developed novel phosphine-borane complex compounds that are cell permeable and highly stable. Here, we report that our lead compound, bis (3-propionic acid methyl ester) phenylphosphine borane complex 1 (PB1), promotes RGC survival in rat models of optic nerve axotomy and in experimental glaucoma. PB1-mediated RGC neuroprotection did not correlate with inhibition of stress-activated protein kinase signaling, including ASK1, JNK or p38. Instead, PB1 led to a striking increase in retinal BDNF levels and downstream activation of the ERK1/2 pathway. Pharmacological inhibition of ERK1/2 entirely blocked RGC neuroprotection induced by PB1. We conclude that PB1 protects damaged RGCs through activation of pro-survival signals. These data support a potential cross-talk between redox homeostasis and neurotrophin-related pathways leading to RGC survival after axonal injury.
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DOI：
10.1073/pnas.95.7.3978
发表时间：
1998-03-31
影响因子：
11.1
作者：
Di Polo, A;Aigner, LJ;Aguayo, AJ
通讯作者：
Aguayo, AJ
DOI：
10.1002/neu.480240907
发表时间：
1993-09-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
JELSMA, TN;FRIEDMAN, HH;AGUAYO, AJ
通讯作者：
AGUAYO, AJ
影响因子：
4.8
作者：
Bedogni, B;Pani, G;Galeotti, T
通讯作者：
Galeotti, T
影响因子：
12.4
作者：
Harada, C.;Namekata, K.;Harada, T.
通讯作者：
Harada, T.
DOI：
10.1073/pnas.92.17.7686
发表时间：
1995-08-15
影响因子：
11.1
作者：
DUDLEY, DT;PANG, L;SALTIEL, AR
通讯作者：
SALTIEL, AR