Botulinum toxin may help relieve chronic pain
An inflammatory problem
ARTHRITIS is the bane of millions of lives. Though it comes in many forms, their common theme is inflammation of the tissues around a joint in the skeleton. Treatment is merely palliative: anti-inflammatory drugs, painkillers or both. But a piece of research published this week in Biochemistry, by Edwin Chapman of the University of Wisconsin and his colleagues, offers arthritis sufferers hope from a strange quarter: botulinum toxin.
This toxin is one of the most dangerous substances on earth. It is made by a bacterium called Clostridium botulinum. Even a small amount (less than a microgram) is enough to kill a healthy adult. The toxin molecules attach themselves to a protein called synaptotagmin, which is found on the surface membranes of nerve cells at their junctions with muscle cells. Thence they are ingested into the cell, where they disable another protein, SNAP-25, the role of which is to help release a chemical messenger called acetylcholine. This messenger’s job is to tell muscle cells to contract. Without that signal, muscles stops working. If this happens all over the body, death is rapid.
Inject the toxin locally, though, and you can do some good. It wipes away frown lines and other wrinkles, which are caused by overstimulated muscles, thus allowing ageing celebs to appear on the covers of gossip magazines without embarrassment. More seriously, it is used to treat disorders ranging from headaches to muscle spasms. It only works, however, in cells that have synaptotagmin on their surfaces. Which is where Dr Chapman comes in.
Inflammation is also caused by chemical signalling. Cells called macrophages summon all sorts of others to an injury, to try to repair it. If repair cannot be effected, though (as is the case in arthritis), the signalling never stops. The swelling causes pain, and the patient suffers. But macrophage signalling also involves SNAP-25, so Dr Chapman thinks he can use botulinum toxin to shut the cells up.
The problem is that macrophages have no synaptotagmin on their surfaces. They do, though, have other proteins, called Fc receptors. What is needed is a way to get toxin molecules to attach themselves to Fc receptors. And this is what Dr Chapman thinks he has managed. His trick is to link each molecule to an antibody. An antibody is a protein that binds to a hostile invading organism. If this does not kill the invader outright, then it acts as a flag for the bug in question to be eaten by a macrophage. That happens when the antibody that is attached to the invader also attaches itself to an Fc-receptor molecule. This done, the invader is ingested.
Dr Chapman’s plan was to use this mechanism to get macrophages to eat toxin molecules. Once inside, they would disable SNAP-25 and thus stop the release of signalling molecules in the way they do in nerve cells. The result, the theory goes, would be an end to the chronic inflammation that arthritis causes, and thus to the chronic pain.
The first stage works. The toxin/antibody complex successfully gloms onto the macrophages. The toxin does get inside them. And the cells do stop signalling. It is a long way from there to a treatment, but Dr Chapman has made the trick work in mice as well as Petri dishes (injecting the complex does, indeed, stop macrophages recruiting). Many more animal trials will be needed before it can be tested on people. But for those who suffer the chronic pain of arthritis, it is a hopeful start.