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首页> 外文期刊>CNS neuroscience & therapeutics. >Substantial Neuroprotection Against K + Deprivation‐Induced Apoptosis in Primary Cerebellar Granule Neurons by Novel Dimer Bis(propyl)‐Cognitin Via the Activation of VEGFR ‐2 Signaling Pathway
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Substantial Neuroprotection Against K + Deprivation‐Induced Apoptosis in Primary Cerebellar Granule Neurons by Novel Dimer Bis(propyl)‐Cognitin Via the Activation of VEGFR ‐2 Signaling Pathway

机译：新型二聚体双（丙基）-认知素通过激活VEGFR-2信号通路对原代小脑颗粒神经元的K +剥夺诱导的细胞凋亡进行实质性神经保护。

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Summary Background Neuronal loss via apoptosis in CNS is the fundamental mechanism underlying various neurodegenerative diseases. Compounds with antiapoptotic property might have therapeutic effects for these diseases. In this study, bis(propyl)‐cognitin ( B 3 C ), a novel dimer that possesses anti‐ AC h E and anti‐ N ‐methyl‐ d ‐aspartate receptor activities, was investigated for its neuroprotective effect on K + deprivation‐induced apoptosis in cerebellar granule neurons ( CGN s). Methods Cerebellar granule neurons were switched to K + deprived medium with or without B 3 C . 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium assay, fluorescein diacetate ( FDA )/propidium iodide ( PI ) staining, H oechst staining, and DNA laddering assays were applied to detect cytotoxicity and apoptosis. Additionally, the expression of p‐ VEGFR ‐2, p‐ A kt, p‐glycogen synthase kinase 3β ( GSK 3β), and p‐extracellular signal‐regulated kinase ( ERK ) was examined in CGN s. Results Switching CGN s to K + deprived medium resulted in remarkable apoptosis, which could be substantially blocked by B 3 C treatment ( IC 50, 0.37 μM). Moreover, a rapid decrease in p‐ T yr1054‐ VEGFR ‐2 was observed after the switch. B 3 C significantly reversed the inhibition of p‐ T yr1054‐ VEGFR ‐2 as well as A kt and ERK pathways. VEGFR ‐2 inhibitor PTK 787/ ZK 222584, as well as PI 3‐ K inhibitor LY 294002 and MEK inhibitor PD 98059, each abolished the neuroprotective effect of B 3 C . Conclusions Our results demonstrate that B 3 C blocks K + deprivation‐induced apoptosis in CGN s through regulating VEGFR ‐2/ A kt/ GSK 3β and VEGFR ‐2/ ERK signaling pathways, providing a molecular insight into the therapeutic potential of B 3 C for the treatment of neurodegenerative diseases.
机译：发明背景中枢神经系统中经由细胞凋亡的神经元损失是各种神经退行性疾病的基本机制。具有抗凋亡特性的化合物可能对这些疾病有治疗作用。在这项研究中，研究了双（丙基）-认知素（B 3 C）是一种具有抗AC h E和抗N-甲基-d-天冬氨酸受体活性的新型二聚体对K +剥夺的神经保护作用。诱导小脑颗粒神经元（CGN）凋亡。方法将小脑颗粒神经元切换为含B 3 C或无B 3 C的缺钾培养基。 3-（4,5-二甲基噻唑-2-基）-2-，5-二苯基四氮唑测定，荧光素双乙酸酯（FDA）/碘化丙啶（PI）染色，霍斯特（H oechst）染色和DNA阶梯分析用于检测细胞毒性和凋亡。另外，在CGNs中检查了p-VEGFR-2，p-Akt，p-糖原合酶激酶3β（GSK3β）和p-细胞外信号调节激酶（ERK）的表达。结果将CGNs换成K +缺乏培养基会导致明显的细胞凋亡，而B 3 C处理可显着阻断细胞凋亡（IC 50，0.37μM）。此外，切换后观察到p-T yr1054-VEGFR-2的快速下降。 B 3 C显着逆转了对pTyr1054-VEGFR-2以及A kt和ERK途径的抑制作用。 VEGFR-2抑制剂PTK 787 / ZK 222584以及PI 3K抑制剂LY 294002和MEK抑制剂PD 98059均取消了B 3 C的神经保护作用。结论我们的结果表明，B 3 C通过调节VEGFR-2 / Akt / GSK3β和VEGFR-2 / ERK信号通路来阻断K +剥夺诱导的CGN细胞凋亡，从而为B 3 C的治疗潜力提供分子生物学见解。用于神经退行性疾病的治疗。

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