Intracranial V. cholerae sialidase protects against excitotoxic neurodegeneration.
Intracranial V. cholerae sialidase protects against excitotoxic neurodegeneration.
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DOI：
10.1371/journal.pone.0029285
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
McDonald MP
中科院分区：
文献类型：
--
作者：
Dhanushkodi A;McDonald MP
越来越多的证据表明，GD3神经节苷脂在许多凋亡通路中是一个关键的效应器，而GM1神经节苷脂具有神经保护和noötropic特性。GD3合成酶（GD3S）的靶向删除消除了GD3并增加了GM1水平。GD3S - / -小鼠的原代神经元对淀粉样蛋白-β或高同型半胱氨酸血症诱导的神经毒性具有抗性，当APP/PSEN1双转基因阿尔茨海默病模型中消除GD3S时，斑块相关的氧化应激和炎症反应消失。到目前为止，还没有发现GD3S的小分子抑制剂。在本研究中，我们使用来自霍乱弧菌（VCS）的唾液酸酶来产生与GD3S缺失近似的脑神经节苷脂谱。VCS将GD1a和复杂的b系列神经节苷水解为GM1，并降解致凋亡的GD3。用渗透性微型泵向小鼠背侧第三脑室灌注VCS，持续4周。vcs治疗小鼠的感觉运动行为、焦虑和认知均未受影响。为了确定VCS在体内是否具有神经保护作用，我们在给药第25天注射kainic酸诱导癫痫持续状态。Kainic acid诱导acsf处理的对照小鼠海马CA3亚区出现明显损伤。相比之下，vcs治疗小鼠的所有海马区域基本完好无损。VCS不能防止癫痫发作。这些结果表明，复杂神经节苷脂和GD3的战略性降解可以在不影响行为的情况下实现神经保护。
Converging evidence shows that GD3 ganglioside is a critical effector in a number of apoptotic pathways, and GM1 ganglioside has neuroprotective and noötropic properties. Targeted deletion of GD3 synthase (GD3S) eliminates GD3 and increases GM1 levels. Primary neurons from GD3S−/− mice are resistant to neurotoxicity induced by amyloid-β or hyperhomocysteinemia, and when GD3S is eliminated in the APP/PSEN1 double-transgenic model of Alzheimer's disease the plaque-associated oxidative stress and inflammatory response are absent. To date, no small-molecule inhibitor of GD3S exists. In the present study we used sialidase from Vibrio cholerae (VCS) to produce a brain ganglioside profile that approximates that of GD3S deletion. VCS hydrolyzes GD1a and complex b-series gangliosides to GM1, and the apoptogenic GD3 is degraded. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. Sensorimotor behaviors, anxiety, and cognition were unaffected in VCS-treated mice. To determine whether VCS was neuroprotective in vivo, we injected kainic acid on the 25th day of infusion to induce status epilepticus. Kainic acid induced a robust lesion of the CA3 hippocampal subfield in aCSF-treated controls. In contrast, all hippocampal regions in VCS-treated mice were largely intact. VCS did not protect against seizures. These results demonstrate that strategic degradation of complex gangliosides and GD3 can be used to achieve neuroprotection without adversely affecting behavior.
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影响因子：
1.9
作者：
GALLAGHER, M;BURWELL, RD;BURCHINAL, M
通讯作者：
BURCHINAL, M
影响因子：
3.6
作者：
Harrison, F. E.;Hosseini, A. H.;May, J. M.
通讯作者：
May, J. M.
影响因子：
3.7
作者：
Bachis, Alessia;Rabin, Stuart J.;Mocchetti, Italo
通讯作者：
Mocchetti, Italo
DOI：
10.1073/pnas.85.19.7351
发表时间：
1988-10-01
影响因子：
11.1
作者：
FAVARON, M;MANEV, H;COSTA, E
通讯作者：
COSTA, E
影响因子：
3.6
作者：
Harrison, F. E.;May, J. M.;McDonald, M. P.
通讯作者：
McDonald, M. P.