Gangliosides prevent excitotoxicity through activation of TrkB receptor
Gangliosides prevent excitotoxicity through activation of TrkB receptor
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DOI：
10.1080/10298420290015836
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发表时间：
2002-01-01
影响因子：
3.7
通讯作者：
Mocchetti, Italo
中科院分区：
文献类型：
--
作者：
Bachis, Alessia;Rabin, Stuart J.;Mocchetti, Italo
神经节苷脂保护小脑颗粒细胞免受兴奋性毒性，然而，其作用机制仍有待充分表征。GM 1神经节苷脂已被证明激活Trk，酪氨酸激酶受体参与神经营养因子的神经保护特性。在这些研究中，我们使用小脑颗粒细胞的原代培养物来确定神经节苷脂是否通过激活Trk受体发挥神经保护作用。我们首先检查了神经营养因子、脑源性神经营养因子（BDNF）、神经营养因子-3和神经生长因子防止谷氨酸介导的细胞凋亡的相对效力。BDNF是唯一的神经营养因子，引起了一个完整的神经元保护谷氨酸。GM 1及其半合成化合物LIGA 20也可预防谷氨酸毒性，但LIGA 20比GM 1更有效。LIGA 20和BDNF都阻断了谷氨酸介导的caspase-3激活，从而导致细胞凋亡;然而，只有当这些化合物在谷氨酸前几小时加入培养物中时，才能观察到抗caspase-3活性，这表明LIGA 20和BDNF具有相同的分子机制。为了验证这一假设，我们比较了LIGA 20和BDNF激活TrkB的能力。两种化合物引起类似的时间依赖性增加的Trk酪氨酸磷酸化。此外，在暴露于Trk酪氨酸激酶抑制剂k252 a的神经元中，BDNF和LIGA 20的神经保护作用被消除，表明神经保护与Trk受体活化之间的关系。我们的数据表明，通过激活Trk神经营养因子受体，神经节苷脂可用作神经保护剂。
Gangliosides protect cerebellar granule cells from excitotoxicity; however, their mechanism of action remains to be fully characterized. GM1 ganglioside has been shown to activate Trk, the tyrosine kinase receptor implicated in the neuroprotective properties of the neurotrophins. In these studies, we used primary cultures of cerebellar granule cells to determine whether gangliosides exert neuroprotective effect via the activation of Trk receptors. We first examined the relative potency of the neurotrophins, brain derived neurotrophic factor (BDNF), neurotrophin-3 and nerve growth factor to prevent glutamate-mediated apoptosis. BDNF was the only neurotrophin that elicited a complete neuronal protection against glutamate. GM1 and its semisynthetic compound LIGA20 also prevented glutamate toxicity, however, LIGA20 was more potent than GM1. Both LIGA20 and BDNF blocked glutamate-mediated activation of caspase-3 and consequently apoptosis; however, the anticaspase-3 activity was seen only when these compounds were added to the cultures several hours before glutamate, suggesting that LIGA20 and BDNF share an identical molecular mechanism. To test this hypothesis, we compared the ability of LIGA20 and BDNF to activate TrkB. Both compounds elicited a similar time-dependent increase in Trk tyrosine phosphorylation. Moreover, the neuroprotective effect of BDNF and LIGA20 was abolished in neurons exposed to the Trk tyrosine kinase inhibitor k252a, demonstrating a relationship between neuroprotection and activation of Trk receptors. Our data suggest that by activating the Trk neurotrophin receptors, gangliosides may be used as neuroprotective agents.