警惕：动物实验表明肉毒杆菌毒素可沿神经进入大脑并降解脑干蛋白质

Botox toxin gets into rat brains
Botilinum can travel along nerves and degrade proteins in the brain stem.

Kerri Smith

Researchers have seen how the nerve-blocking botilinum toxin, made famous by wrinkle-banishing Botox, can be carried from a site of injection in rats into the brain. Once there, the toxin can degrade proteins and act on nerves.

This previously unknown ability of botilinum to affect the brain “is certainly of concern”, says Matteo Caleo of the Italian National Research Council’s Institute of Neuroscience in Pisa, who reports the work.

Thus far, the study has been done only in rodents, which had no noticable behavioural reaction to the migration of the toxin to their brains. Only a fraction of the dose was carried through nerves, the researchers note, with the rest staying near the injection site. And the doses used in humans are small, presumably making effects — if any — negligable.

But the result shows that more work is needed to better understand how the toxin spreads along nerves, and how to prevent this or use it to therapeutic benefit, says Caleo.

Carried along
It was already known that botulinum toxin can migrate from one place to another within the body. The US Food and Drug Administration (FDA) is currently reviewing the safety of botulinum toxin after several reports of adverse affects, suggestive that the toxin had spread in the body beyond the site where it was injected. But exactly how it is transported in its active, nerve-blocking form has been a mystery.

Caleo's team injected botulinum neurotoxin A — the toxin commonly used to treat muscular disorders and in cosmetic procedures — into the whisker muscles of rats, and then looked at the connected brain areas for a tell-tale sign of the toxin: the remnants of a protein that botulinum breaks down. Three days after the injection, they found these remnants in an area in the brainstem1. The dilute amount of the toxin that reached these cells meant that there were no noticeable effects on the animals.

The fact that the toxin gets inside nerves allows it privileged access to the brain, which blood-borne drugs often have trouble reaching. “In this case, we have something like a Trojan horse,” says Caleo. Nerve cells send axons to the muscles, and these axons pick up the toxin. Then it is transported through them to back to nerves in the brain.

Trojan horse
This ‘Trojan horse’ manoeuvre is common to several toxins, says Christopher von Bartheld at the University of Nevada in Reno, who studies how proteins are trafficked along axons. Some researchers, he adds, are trying to use this property to deliver drugs to specific brain areas.

Caleo and his team also showed that botulinum can spread within the brain by injecting it into one of a pair of structures, the hippocampi, and tracing its spread to the other. They were interested in the toxin's internal effects, Caleo says, because one of their aims is to use it as a treatment for epilepsy, which is caused by excess electrical activity in certain areas of the brain.

Currently, Botox is used to treat disorders such as dystonia and spasticity, in which overactive nerves lead to muscular problems. Caleo reasons that if the toxin can treat overactive nerves in the body, it might also be useful for overactive neurons in the brain itself.

So the finding may have positive implications for some treatments. But for those having injections for some clinical or cosmetic reasons it may raise a warning flag. Caleo would still recommend the treatment for people with dystonia, because the evidence for its success is strong — but caution is advisable in light of the new findings, he says.

The FDA “will continue to monitor the drug as we review these findings,” says FDA spokesperson Rita Chappelle.
Botox的毒素进入大鼠脑内
肉毒杆菌毒素可沿神经进入大脑并降解脑干蛋白质
Kerri Smith 报道
研究人员发现因去皱商品Botox而闻名的有神经阻断作用的肉毒杆菌毒素，可以经大鼠某个部位注射而被携带入脑。一旦入脑，该毒素能分解蛋白质并作用于神经。
意大利国家研究理事会，比萨神经科学研究所的Matteo Caleo 报道此项工作。他说，肉毒杆菌毒素这个以前不为人知的对脑的影响，“绝对令人关注”。
到目前为止，这项研究只在啮齿动物完成，它们对肉毒杆菌毒素迁移入脑没有任何明显的行为反应。研究者指出，只有一小部分的剂量通过神经传输，而其它则停留在注射部位。用于人体剂量很小，推测其影响-如果有的话-可以忽略不计。
但研究结果表明，还有更多的工作需要做，以更好地了解毒素如何沿神经扩散，以及如何防止这种情况或者利用它来获得疗效，Caleo说。
沿线进行
肉毒杆菌毒素可以体内从一个地方到另一个迁移已为人所知。诸多报告提示了肉毒杆菌毒素不利影响，它可以在注射部位之外体内扩散。此后美国食品和药物管理局（ FDA ）正在重新审视其安全性。但到底它是如何以有效的神经阻断形式运送的，一直是一个谜。
肉毒杆菌神经毒素A通常用于治疗肌肉疾病，以及用于美容术。Caleo的团队把它注射到大鼠胡须肌肉，然后观察相关脑区此毒素神奇作用的标志：一种蛋白质被它降解后的残余物质。注射三天后，他们在脑干1区一个部位发现了这种残余物质。稀释量的毒素到达这些细胞对动物没有明显的影响。
毒素进入神经，使得它有特权进入大脑，而血液来源的药物往往被阻。 \"在这种情况下，它们就像特洛伊木马\" ，Caleo说。神经细胞的轴突延伸进入肌肉，并拾起毒素。然后毒素通过轴突传输一直返回到大脑中的神经。
特洛伊木马
这个'木马'策略与很多毒素相似，位于Reno的Nevada大学的Christopher von Bartheld 说。他们研究蛋白质如何沿轴突运输。他还说，一些研究人员正试图利用这一特性，使药物得以进入特定脑区。
Caleo 和他的团队的研究还显示肉毒杆菌可以在脑内传播，将其注射到一对海马中的一个，可以追踪到它传播到另一个。他们对这个毒素的内在影响感兴趣， Caleo 说，因为他们的一个目标是要利用它作为治疗癫痫的一种手段。癫痫是由大脑特定区域过量电活动引起的。
目前，Botox用于治疗肌张力障碍和痉挛状态这类神经过度活跃导致的肌肉疾病。Caleo推论，如果毒素能治疗体内神经过度活跃，它也可能对脑本身神的过度活跃的神经元。
因此这项发现可能对某些治疗方法有正面的启示。但对于那些临床或美容应用中注射了肉毒杆菌的人，可能就是个警告旗了。Caleo 说，依然推荐用它治疗肌张力障碍，但由于这项新发现，使用时还是小心点好。
FDA发言人Rita Chappelle说，FDA“将在回顾这些发现的同时继续监察此药物”