Post-intoxication inhibition of botulinum neurotoxin serotype A within neurons by small-molecule, non-peptidic inhibitors.
Post-intoxication inhibition of botulinum neurotoxin serotype A within neurons by small-molecule, non-peptidic inhibitors.
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DOI：
10.3390/toxins3030207
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发表时间：
2011-03
期刊：
影响因子：
4.2
通讯作者：
Bavari S
中科院分区：
文献类型：
--
作者：
Ruthel G;Burnett JC;Nuss JE;Wanner LM;Tressler LE;Torres-Melendez E;Sandwick SJ;Retterer CJ;Bavari S
肉毒神经毒素（BoNT）包括七种不同的血清型，它们抑制神经递质在神经肌肉接头上的释放，导致潜在的致命性弛缓性麻痹。BoNT血清型A（BoNT/A）靶向25 kDa的突触体相关蛋白（SNAP-25），在神经元内特别长寿，并且需要更长的时间来恢复神经肌肉功能。目前还没有治疗方法可以在BoNT/A进入神经元胞质溶胶后对抗它。在这项研究中，我们检查了小分子非肽抑制剂（SMNPI）防止神经元中毒后SNAP-25裂解的能力。通过添加SMNPI防止在1小时BoNT/A中毒后5小时内观察到的SNAP-25的进行性裂解。相比之下，当在中毒期间添加时强烈抑制SNAP-25切割的抗BoNT/A中和抗体在中毒后添加时完全无效。虽然巴弗洛霉素A1通过防止内体酸化来阻断BoNT/A进入胞质溶胶，抑制了中毒后SNAP-25裂解，但在中毒期间和中毒后，抑制程度与添加相比显著降低。另一方面，中毒后应用SMNPI的有效性几乎与中毒期间和中毒后应用相同。总之，结果表明BoNT/A轻链的竞争性SMNPI在中毒后的神经元内可以是有效的。
Botulinum neurotoxins (BoNTs) comprise seven distinct serotypes that inhibit the release of neurotransmitter across neuromuscular junctions, resulting in potentially fatal flaccid paralysis. BoNT serotype A (BoNT/A), which targets synaptosomal-associated protein of 25kDa (SNAP-25), is particularly long-lived within neurons and requires a longer time for recovery of neuromuscular function. There are currently no treatments available to counteract BoNT/A after it has entered the neuronal cytosol. In this study, we examined the ability of small molecule non-peptidic inhibitors (SMNPIs) to prevent SNAP-25 cleavage post-intoxication of neurons. The progressive cleavage of SNAP-25 observed over 5 h following 1 h BoNT/A intoxication was prevented by addition of SMNPIs. In contrast, anti-BoNT/A neutralizing antibodies that strongly inhibited SNAP-25 cleavage when added during intoxication were completely ineffective when added post-intoxication. Although Bafilomycin A1, which blocks entry of BoNT/A into the cytosol by preventing endosomal acidification, inhibited SNAP-25 cleavage post-intoxication, the degree of inhibition was significantly reduced versus addition both during and after intoxication. Post-intoxication application of SMNPIs, on the other hand, was nearly as effective as application both during and after intoxication. Taken together, the results indicate that competitive SMNPIs of BoNT/A light chain can be effective within neurons post-intoxication.
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影响因子：
3.1
作者：
Pless, DD;Torres, ER;Bavari, S
通讯作者：
Bavari, S
DOI：
10.1073/pnas.0408526102
发表时间：
2005-07-12
影响因子：
11.1
作者：
Wein, LM;Liu, YF
通讯作者：
Liu, YF
影响因子：
4.8
作者：
O'Sullivan, GA;Mohammed, N;Dolly, JO
通讯作者：
Dolly, JO
影响因子：
120.7
作者：
Chertow, Daniel S.;Tan, Esther T.;Braden, Christopher R.
通讯作者：
Braden, Christopher R.
影响因子：
4.8
作者：
Foran, PG;Mohammed, N;Dolly, JO
通讯作者：
Dolly, JO