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BDNF-TrkB and proBDNF-p75NTR/Sortilin Signaling Pathways are Involved in Mitochondria-Mediated Neuronal Apoptosis in Dorsal Root Ganglia after Sciatic Nerve Transection.
CNS & Neurological Disorders - Drug Targets ( IF 2.7 ) Pub Date : 2020-01-31 , DOI: 10.2174/1871527319666200117110056
Xianbin Wang 1, 2 , Wei Ma 1 , Tongtong Wang 1 , Jinwei Yang 3 , Zhen Wu 3 , Kuangpin Liu 1 , Yunfei Dai 1 , Chenghao Zang 3 , Wei Liu 1 , Jie Liu 1 , Yu Liang 1 , Jianhui Guo 3 , Liyan Li 1
中文翻译:
坐骨神经横断后,BDNF-TrkB和proBDNF-p75NTR / Sortilin信号通路参与了背根神经节的线粒体介导的神经元凋亡。
更新日期:2020-01-31
CNS & Neurological Disorders - Drug Targets ( IF 2.7 ) Pub Date : 2020-01-31 , DOI: 10.2174/1871527319666200117110056
Xianbin Wang 1, 2 , Wei Ma 1 , Tongtong Wang 1 , Jinwei Yang 3 , Zhen Wu 3 , Kuangpin Liu 1 , Yunfei Dai 1 , Chenghao Zang 3 , Wei Liu 1 , Jie Liu 1 , Yu Liang 1 , Jianhui Guo 3 , Liyan Li 1
Affiliation
Background: Brain-Derived Neurotrophic Factor (BDNF) plays critical roles during development of the central and peripheral nervous systems, as well as in neuronal survival after injury. Although proBDNF induces neuronal apoptosis after injury in vivo, whether it can also act as a death factor in vitro and in vivo under physiological conditions and after nerve injury, as well as its mechanism of inducing apoptosis, is still unclear.
Objective: In this study, we investigated the mechanisms by which proBDNF causes apoptosis in sensory neurons and Satellite Glial Cells (SGCs) in Dorsal Root Ganglia (DRG) After Sciatic Nerve Transection (SNT). Methods: SGCs cultures were prepared and a scratch model was established to analyze the role of proBDNF in sensory neurons and SGCs in DRG following SNT. Following treatment with proBDNF antiserum, TUNEL and immunohistochemistry staining were used to detect the expression of Glial Fibrillary Acidic Protein (GFAP) and Calcitonin Gene-Related Peptide (CGRP) in DRG tissue; immunocytochemistry and Cell Counting Kit-8 (CCK8) assay were used to detect GFAP expression and cell viability of SGCs, respectively. RT-qPCR, western blot, and ELISA were used to measure mRNA and protein levels, respectively, of key factors in BDNF-TrkB, proBDNF-p75NTR/sortilin, and apoptosis signaling pathways. Results: proBDNF induced mitochondrial apoptosis of SGCs and neurons by modulating BDNF-TrkB and proBDNF-p75NTR/sortilin signaling pathways. In addition, neuroprotection was achieved by inhibiting the biological activity of endogenous proBDNF protein by injection of anti-proBDNF serum. Furthermore, the anti-proBDNF serum inhibited the activation of SGCs and promoted their proliferation. Conclusion: proBDNF induced apoptosis in SGCs and sensory neurons in DRG following SNT. The proBDNF signaling pathway is a potential novel therapeutic target for reducing sensory neuron and SGCs loss following peripheral nerve injury.中文翻译:
坐骨神经横断后,BDNF-TrkB和proBDNF-p75NTR / Sortilin信号通路参与了背根神经节的线粒体介导的神经元凋亡。
背景:脑源性神经营养因子(BDNF)在中枢神经系统和周围神经系统的发育以及损伤后神经元的存活过程中起着至关重要的作用。尽管proBDNF在体内损伤后诱导神经元凋亡,但是在生理条件下和神经损伤后,proBDNF是否还可以在体外和体内充当死亡因子,还不清楚其诱导细胞凋亡的机制。
目的:在这项研究中,我们研究了proBDNF导致坐骨神经横断(SNT)后背根神经节(DRG)感觉神经元和卫星胶质细胞(SGC)凋亡的机制。 方法:制备SGCs培养物并建立刮擦模型以分析proBDNF在SNT后DRG中在DRG的感觉神经元和SGC中的作用。用proBDNF抗血清治疗后,使用TUNEL和免疫组织化学染色检测DRG组织中神经胶质纤维酸性蛋白(GFAP)和降钙素基因相关肽(CGRP)的表达。免疫细胞化学和细胞计数试剂盒8(CCK8)测定分别用于检测SGAP的GFAP表达和细胞活力。RT-qPCR,western blot和ELISA分别用于测量BDNF-TrkB,proBDNF-p75NTR / sortilin和凋亡信号通路中关键因子的mRNA和蛋白质水平。结果:proBDNF通过调节BDNF-TrkB和proBDNF-p75NTR / sortilin信号传导途径诱导SGCs和神经元的线粒体凋亡。另外,通过注射抗proBDNF血清来抑制内源性proBDNF蛋白的生物学活性来实现神经保护。此外,抗proBDNF血清抑制SGC的活化并促进其增殖。结论:proBDNF引起SNT后SGCs和DRG感觉神经元的凋亡。proBDNF信号通路是减少周围神经损伤后感觉神经元和SGC损失的潜在新治疗靶点。