For many people in the west, a nematode infestation is an unpleasant, but rare event. Unfortunately, the same cannot be said for the inhabitants of many less developed countries, where nematodes are rife and cause many crippling diseases. Fortunately, modern medicine is equipped with a battery of drugs to rid patients of unwanted parasites. But the threat remains that the nematodes will eventually outsmart the pharmacologists and become resistant to the three major classes of drug currently in use. Which is why Richard Martin is keen to understand how one of these nematode targeting drugs, levamisole, attacks the nematode, Ascaris suum. He hopes this will help us to design new therapies to keep medicine ahead of the nematode in the race to beat resistance (p. 3979).
Martin explains that many of the drugs, called anthelmic drugs, which are currently so effective in treating roundworm infections, were originally developed for use in western veterinary practice. He explains that many of these drugs have been used to treat agricultural animals for many years. Most pharmacological and physiological studies on round worms have been carried out on parasites that infest agricultural animals. Ascaris suum is a pig parasite, and Martin explains that it is ideal to study because it is large and easily available from local abattoirs.
The drug levamisole cures animals and humans by paralysing the nematode so that it is flushed out of the host's body. The drug acts by specifically targeting an ion channel in the parasite's muscle, opening the ion channel, so that the muscle depolarises and contracts, paralysing the worm.
Fifteen years ago, Martin discovered that the drug targets an ion channel that is known as the nicotinic receptor. This type of channel opens when it binds the neurotransmitter acetylcholine. Many of nicotinic channels are also regulated by protein kinases, which phosphorylate the channel.
Martin knew the Ascaris suum ion channel might also be regulated by kinases, and he wondered if the level of kinase activity might also affect levamisole's potency. If he could find a link between a kinase and levamisole's affect on the ion channel, he might be able to find a way of reversing the nematode's resistance to the drug, should it ever develop.
But first he had to find out if kinases could regulate the protein's function. Martin's team used a technique where they could monitor the cell membrane's resistance and potential in response to the drug and kinase inhibitors.
First they treated muscle cells from the parasite with levamisole, and measured how the cells depolarized. Then they treated cells with levamisole and a kinase inhibiting drug, to see if switching the kinase off changed the drug's effect on the ion channel. By testing four inhibitor drugs that targeted different kinases, Martin and his team saw that when tyrosine kinase and calcium calmodulin kinase were inhibited, the depolarisation response decreased. When Martin repeated the experiments with acetylcholine instead of levamisole, the kinase inhibitors also reduced the depolarisation.
Martin explains that this means that both kinases somehow help the ion channels to open. He hopes eventually to find a way to use kinases to enhance the effects of levamisole to combat drug resistance. But fortunately, that day hasn't arrived yet.
