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MGA News

Winter 2002

The debt Myasthenics owe to herbalists and poisoners

Dr Maria Elena Farrugia, Dr Ian Spreadbury and Professor Nick Willcox

The MGA/ MDC Centre, Oxford

In a recent article, we saw how researchers have taken advantage of venoms from creepie crawlies to help us in diagnosis and even treatment. Now it is the turn of the plants. As before, poisons have provided vital starting points for investigating how nerve ? muscle triggering works normally, and some have proved even more crucial friends in treating myasthenia.

A brief reminder

Figure 5: Nerve- Muscle Junction

The ignition system of our ‘voluntary muscles’ (See Fig 5) depends on the chemical transmitter ACh (the ‘ignition keys’) which is released when the nerve endings are switched on by impulses from the brain. The ACh then latches into special receptors (‘AChR’ = ‘ignition locks’) on the muscle surface – and that triggers the muscle to contract. The spare ACh is broken down by ACh esterase (AChE). The muscle AChR is called ‘nicotinic’ because it is targetted by nicotine from the tobacco plant (Nicotiana affinis). In most myasthenics, the numbers of these AChRs are too low – whether because of an immune attack or an inherited fault.

Licensed to kill…

How poisoned darts helped to explain the defects in MG

Fig1: One of the curare trees - Strychnos toxifera

Many poisons belong to the large family of 'alkaloids'. One key player is ‘curare’ (it rhymes with Harare in Zimbabwe). It has long been used as an arrow poison by South American Indians (eg in Ecuador and Peru); its name means a venomous decoction, and it is boiled down from the barks of various trees. Sir Walter Raleigh and others mentioned it, but its preparation was first described by the versatile Alexander von Humboldt, in 1807. He was one of the last universal scholars in the natural sciences – not only a geographer but also a naturalist, botanist, author, artist and sociologist. Derived from the trees Strychnos toxifera or Strychnos guianensis and Chondrodendron tomentosum . (See Fig 1), curare was used so much by warring tribes and hunters that it was very valuable. Using arrows and silent blowpipes, they could kill birds in only ~ two minutes, small mammals in ~ 10, and larger ones in ~ 20 minutes.

The famous French researcher, Claude Bernard, discovered in ~ 1855 that curare paralyses voluntary muscles but not the heart, and kills by stopping breathing. He concluded that it affected nerve ? muscle triggering. We now know that it simply blocks nicotinic AChRs, and so makes muscles floppy – exactly as in MG when the AChR numbers are too low.

….. and to save lives…

Figure 2: The Colabar Bean

Now we come back to our heroine, Dr Mary Walker. You may remember (from the last issue of MGA News) that she was discussing a new myasthenic (with the Neurologist Dr Denny Brown). They came to the conclusion that myasthenia seemed like poisoning with curare – to which myasthenics are super-sensitive. Desperate for some treatment – because MG was then often fatal – she injected another plant drug, physostigmine, because it had been the best known curare-antidote since ~ 1900 (as shown by the Viennese Dr J Pal). When she tried it, the patient improved dramatically, a breakthrough she published in the Lancet in 1934. That drug is very similar to 'Tensilon', and is a short-acting version of the myasthenics' dear friend Mestinon (properly called pyridostigmine); this relative of physostigmine was first used in 1954. Mary Walker quickly realised that these drugs worked by blocking AChE, so delaying the breakdown of the ACh and boosting its chances of triggering the muscles – rather like using more choke when the car is cold.

Figure 3: Physostigma venenosum

Physostigmine comes from the West African Calabar bean (Physostigma venenosum), and was used there for trial by ordeal, rather like ducking suspected witches under water in this country. (See Figure 2 and 3). In Edinburgh in ~ 1855, it had been shown to constrict the pupils (by enhancing the effects of ACh, as we now know). In 1927, an American myasthenic, Harriet Edgeworth, tested another herbal drug on herself called ephedrine; for the next few years, it was the best hope for myasthenics. It soups up the muscle ignition slightly because it mimics the effects of adrenalin – the ‘fight, fright, flight response’ that you all know so well (pounding heart, sweating, hair standing on end….). It also helped Harriet to tolerate heat much better.

Ephedrine is derived from various Ephedra species, especially E. sinica. Also known as Ma huang, it has been used in Chinese medicine, probably as far back as 2800 BC, to treat colds and asthma; its cousins are still used as de-congestants for ‘bunged-up’ noses and asthma. Ephedra was used by the Zen monks to encourage calm concentration during meditation and by Gengis Khan’s bodyguards to keep them alert on sentry duty. Other alkaloids have less desirable side-effects; some are dangerous in MG, eg muscle relaxants or pain-killers such as Acetaminophen and Oxycodone, and also some herbal remedies.

Understanding the side-efffects of Mestinon...

Fig 4:Amanita Muscara

Many ‘automatic functions’ also depend on ACh as transmitter; they include pupil contraction (in the eye), slowing of the heart and stimulating gut and bladder movements. They are not affected by the MG, because these ‘muscarinic’ AChRs are completely different from the nicotinic AChRs in muscle; unlike them, they are stimulated by the toadstool poison, muscarine. (See Figure 4). Its effects include diarrhoea, gut cramps and sweating – rather like a mestinon overdose (see below). It is one of several poisons in a toadstool you know well – the one with the red cap and white spots beloved of garden gnomes – the Fly Agaric (Amanita muscaria). Figure 5 shows the nicotinic and muscurinic Acetylcholine receptors.

…. and treating them too…

Two lovely big eyes?

Fig 6: Atropa Belladonna

Atropine comes from a plant you probably know, Deadly Nightshade (Figure 6); it was called Atropa belladonna because the wide pupils enhance the beauty of a comely girl. It is now used as a ‘pre-med’ before anaesthetics/surgery because it dries up the juices in the mouth and lungs, and so prevents blockages and infections in the airways. In conclusion, no matter how lethal such poisons may be, they may well have their uses in diagnosis and treatment. What is more, we should all be grateful to all the herbalists, collectors and researchers for investigating them. How many further valuable drugs are now at risk because of extinctions?

MGA NEWS Winter 2002
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