Does Botox® go to the brain?
“Does Botox® go to the brain?”
This is a question that has been bounced around quite a bit since the paper published by an Antonucci, et al. in the April 2, 2008 issue of Journal of Neuroscience.
Having published in this journal myself, I know that it is very highly regarded in scientific circles. So I wanted to read this article myself.
Before going any further, it is worth pointing out that Botox® is a term that should be reserved for botulinum toxin type A (there are multiple types) that has been purified and is approved for use in humans, and is produced by the company Allergan. The material used in the study noted above is indeed botulinum toxin type A, but it is a research grade (ie, not for human use) product whose composition may differ (based on purification methods and units of activity per weight of product). So, Botox® itself was never tested in this study.
Having said that, the botulinum toxin type A (hereafter referred to as BoNT/A, for brevity) used in the study is the same basic molecule, so we can make some assumptions regarding the mechanisms. It’s just that using a differently purified product in another species can complicate matters.
BoNT/A works by blocking the signal from the end of the nerve that causes the associated muscle to contract. The signal is the neurotransmitter acetylcholine (ACh) and BoNT/A blocks its release from the end of the nerve (the nerve terminal) by altering a molecule that is necessary for the machinery that is involved in releasing ACh. That molecule is SNAP-25.
Each BoNT/A can alter many SNAP-25s. Because so very little BoNT/A is around after injection, and thus is very hard to detect, the researchers in the study measured the amount of altered SNAP-25 present instead.
Before we go further, you must realize that cells in the brain (neurons) are wired to each other by sending long projections to other parts of the brain or out to muscles in the body. These projections are called axons. For example, the neurons that cause your face to move are located in the brain, and send out axons to the muscles of your forehead, etc. There, the nerve terminals that activate the muscles release ACh to cause the muscles to contract. That’s why Botox® is injected into the muscles…it finds its way to the nerve terminals and deactivates them. (Funny thing…my honors thesis at the University of Michigan as an undergraduate was a study of ACh in rat neurons.)
Here’s where it gets interesting. The axons have transport mechanisms that allow molecules to move back and forth between the nerve terminal and the cell body, in the brain. The researchers in this study propose that BoNT/A is transported along the axons back to the brain.
As I mentioned above, there is no good way to measure BoNT/A, as the amounts used are so minute. So, the researchers measured SNAP-25 that had been altered by BoNT/A. They injected BoNT/A directly into the brain (something we do not do routinely!) and measured altered SNAP-25. They found altered SNAP-25 in other regions of the brain—regions that were connected by axons to the areas injected. In addition, they injected the whiskers of the rats, and found altered SNAP-25 in the neurons (in the brain) involved in whisker movement. If you are following this, you realize that this does not prove that BoNT/A is actually moved along the axon to the brain, but that SNAP-25 is. This is a big issue, because it is not surprising at all the the degraded SNAP-25 would be moved along the axon.
To address this, the authors devised an indirect way to examine if it is actually BoNT/A or just altered SNAP-25 that is transported along the axons. This was done with the direct brain injections, not with the facial muscle injections. Without getting into the details, I thought this experiment (which was a small portion of the study) was the weakest and found the results less than convincing.
What does this all mean?
First, we should remember that these studies were done in animals, and any time you try to compare animals studies to human studies you can get into trouble. Second, the composition and concentrations used may differ from that Botox®. Third, the primary molecule measured was NOT BoNT/A, it was the molecule it alters—this is a big difference. Fourth, no direct evidence of active BoNT/A in the brain was shown. Fifth, only a small part of the study was done in a system similar to the muscle injections performed in humans, and the results there were not that surprising.
Finally, it is worthwhile to remember that millions of cosmetic injections of Botox® have been performed over the last decade(s) and (to my knowledge) no adverse events related to effects on the brain have been reported.
With any drug, it is always useful to have more studies to examine its mechanism of action. Hopefully, future studies will clarify some of the questions raised by this article.