Published online 1 April 2008 | Nature | doi:10.1038/news.2008.719

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Botox toxin gets into rat brains

Botilinum can travel along nerves and degrade proteins in the brain stem.

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.

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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. 

  • References

    1. Antonucci, F., Rossi, C., Gianfranceschi, L., Rossetto, O. & Caleo, M. J. Neurosci. 28, 3689-3696 (2008).
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