Tyrphostin A9 protects axons in experimental autoimmune encephalomyelitis through activation of ERKs.
Tyrphostin A9 protects axons in experimental autoimmune encephalomyelitis through activation of ERKs.
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DOI：
10.1016/j.lfs.2022.120383
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发表时间：
2022-04-01
期刊：
影响因子：
6.1
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Dai X;Wang Y;Li Y;Zhong Y;Pei M;Long J;Dong X;Chen YL;Wang Q;Wang G;Gold BG;Vandenbark AA;Neve KA;Offner H;Wang C
小分子化合物Tyrphostin A9(A9)是一种血小板衍生生长因子(PDGF)受体的抑制剂，本课题组曾报道以一种与PDGF受体无关的方式刺激神经细胞中的细胞外信号调节激酶1(ERK1)和细胞外信号调节蛋白2(ERK2)。本研究旨在探讨A9是否通过激活ERKs对实验性自身免疫性脑脊髓炎的轴突起到保护作用。分析了A9对神经毒素MPP+对SH-SY5Y神经母细胞瘤细胞和原代培养的黑质神经元突起生长的保护作用。验证复发缓解型实验性自身免疫性脑脊髓炎(EAE)模型的临床症状、ERK1/2激活、轴突保护诱导以及再生生物标记物GAP-43在中枢神经系统的丰度增加。A9可刺激SH-SY5Y神经母细胞瘤细胞突起生长，保护原代培养的黑质神经元免受神经毒素MPP+的损伤。在复发-缓解型EAE模型中，口服A9成功地改善了临床症状，激活了ERK1/2，诱导了轴突保护，并增加了再生生物标记物GAP-43在中枢神经系统的丰度。有趣的是，ERK1或ERK2的基因缺失阻断了A9在MOG-35-55诱导的EAE中的有利作用。这些结果表明，在体内外刺激ERK持续激活的小分子化合物在神经退行性疾病的保护或恢复性治疗中可能是有用的。
Small molecule compound tyrphostin A9 (A9), an inhibitor of platelet-derived growth factor (PDGF) receptor, was previously reported by our group to stimulate extracellular signal-regulated kinase 1 (ERK1) and 2 (ERK2) in neuronal cells in a PDGF receptor-irrelevant manner. The study aimed to investigate whether A9 could protect axons in experimental autoimmune encephalomyelitis through activation of ERKs. A9 treatment on the protection on neurite outgrowth in SH-SY5Y neuroblastoma cells and primary substantia nigra neuron cultures from the neurotoxin MPP+ were analyzed. Then, clinical symptoms as well as ERK1/2 activation, axonal protection induction, and the abundance increases of the regeneration biomarker GAP-43 in the CNS in the relapsing-remitting experimental autoimmune encephalomyelitis (EAE) model were verified. A9 treatment could stimulate neurite outgrowth in SH-SY5Y neuroblastoma cells and protect primary substantia nigra neuron cultures from the neurotoxin MPP+. In the relapsing-remitting EAE model, oral administration of A9 successfully ameliorated clinical symptoms, activated ERK1/2, induced axonal protection, and increased the abundance of the regeneration biomarker GAP-43 in the CNS. Interestingly, gene deficiency of ERK1 or ERK2 disrupted the beneficial effects of A9 in MOG-35–55-induced EAE. These results demonstrated that small molecule compounds that stimulate persistent ERK activation in vitro and in vivo may be useful in protective or restorative treatment for neurodegenerative diseases.
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DOI：
10.4049/jimmunol.1103015
发表时间：
2012-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chang CF;D'Souza WN;Ch'en IL;Pages G;Pouyssegur J;Hedrick SM
通讯作者：
Hedrick SM
影响因子：
--
作者：
Gold, BG;Zhong, YP
通讯作者：
Zhong, YP
影响因子：
2.9
作者：
Mazzio, EA;Reams, RR;Soliman, KFA
通讯作者：
Soliman, KFA
影响因子：
3.3
作者：
HEASLEY, LE;JOHNSON, GL
通讯作者：
JOHNSON, GL
影响因子：
13.8
作者：
LEVITZKI, A;GILON, C
通讯作者：
GILON, C