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Testing new manic depression drugs in slime mould: an alternative to the current serendipitous approach

20 February 2006

Research by University College London (UCL) scientists could lead to the development of more effective drugs for treating manic depression thanks to a new screening approach developed in a ‘slime mould’ – a microbe that lives in leaves and dung on forest floors. The breakthrough using slime mould (Dictyostelium) is the first possible alternative to the current - accidental - method of discovering manic depression drugs. The findings are published today in the May 2005 issue of Molecular Pharmacology.

This research, carried out by a team led by Dr Robin Williams of the UCL Department of Biology, describes how the team tested variants of current drugs on the market in slime mould. It represents a first step towards the development of a scientific system for testing new treatments for manic depression. “Manic depression drugs on the market today have always been found serendipitously,” says Dr Williams. “Lithium was originally proposed as a treatment for gout in the late 1800s and by chance, it was later found that it helped balance moods and is now the most widely used manic depression drug on the market. Valproic acid, another drug commonly used to treat both epilepsy and manic depression, was also found accidentally, as it was initially used as a solvent for dissolving epilepsy drugs.

“With these results, we can now identify new compounds which we hope will have the same effect as other manic depression treatments without unwanted side effects. We are testing this using a simple microbe ─ a slime mould ─ which is much faster, easier and more reliable to use than human nerve cells.”

Current manic depression drugs like valproic acid have side-effects - an increased chance of liver damage, an increase in the chance of birth defects (embryonic malformations) if taken by mothers during the first trimester of pregnancy and may increase HIV infection. However, developing alternative manic depression drugs has so far proved impossible.

The scientists hope that their screening system, which involves testing possible drugs in slime mould and looking for a chemical change, will provide an important scientific building block that could lead to a better and safer range of manic depression drugs. The team is currently developing variants of valproic acid that they expect will have fewer harmful side-effects.

The origins of Dr Williams’ work in this field were set out in Nature in 2002, when he found a protein which may be involved in causing manic depression, called prolyl oligopeptidase. This protein is present in both slime mould and the mammalian nervous system - and according to a number of teams the protein functions abnormally in manic depressed patients.

The team went on to discover that the common way that all bipolar drugs work is by their ability to deplete the chemical inositol trisphosphate, found in the nervous system. This common effect caused by three very different drugs is the core of how manic depressive drugs work and the team has now used this discovery to develop a system for testing new manic depression drugs. Using this system, the team has found two possible alternatives to the current drugs on the market lithium, valproic acid and carbamazepine. The novel drugs are based on valproic acid. They still work to deplete the chemical inositol trisphosphate but the team has eliminated harmful side effects. Initial tests on slime mould were later confirmed in the animal nervous system and are now ready to be extended to comprehensive trials. The team is the first group of scientists working in this field to use a slime mould to design better manic depression drugs.

Dr Williams said: “Testing new drugs on slime mould is possible because cells function in a very similar way, be they from a human or from a slime mould. If a drug acts on a basic part of a cell’s function by, for example, inhibiting an enzyme, it should inhibit that enzyme in both human and slime mould cells. Working in slime mould is faster, easier and more reliable than the more complicated mammalian nerve cell.

“Although our system does not predict precisely how new drugs will impact on people – after all the brain is more complex than a single cell – we have made the first step in identifying new manic depression drugs and this has previously been impossible. This gives us some basis for believing that these new drugs could be useful and would warrant further testing. Testing the drug on slime mould initially acts as a reliable guide for scientists so for the first time we can screen drugs and identify better treatments for manic depression.”

Notes for Editors

1. The paper, “Effects of valproic acid derivatives on inositol trisphosphate depletion, teratogenicity, GSK-3{beta} inhibition and viral replication - A screening approach for new bipolar disorder drugs based on the valproic acid core structure,” appears in the May issue of Molecular Pharmacology.
2. Dr Williams, based in UCL’s Department of Biology and the Wolfson Institute for Biomedical Research, is funded by The Wellcome Trust. This project is carried out by a consortium of both UK and internationally based research scientists.
3. Contributors to the paper:
a. Eickholt BJ, Towers G, Ryves WJ, Eikel D, Adley K, Ylinen L, Chadborn N, Harwood A, Nau H, Williams RS.
b. BJE and NC: Molecular Neurobiology Group (E.B.J., N.H.C.), Medical Research Council Centre for Developmental Biology, King’s College London, London SE1 1UL, United Kingdom.
c. GJT and LMJY: Wohl Virion Centre (G.J.T., L.M.J.Y.), Department of Immunology and Molecular Pathology, University College London, W1T 4JF, United Kingdom.
d. WJR and AJH: Medical Research Council Laboratory of Molecular Cell Biology University College London, WC1E6BT, United Kingdom.
e. DE and HN: Institute for Food Toxicology and Chemical Analysis Centre of Systemic Neuroscience, School of Veterinary Medicine Hanover, 30169 Hanover, Germany.
f. KA and RSBW: Department of Biology and Wolfson Institute for Biomedical Research, University College London, WC1 E6BT, United Kingdom.
4. To speak to the author, Robin Williams, please contact him directly on +44 20 7679 7268 or robin.williams@ucl.ac.uk
5. For further information please contact Alex Brew at UCL’s press office on 020 7679 9726, 07747 565 056 (call this mobile number to speak to Robin Williams outside normal working hours) or a.brew@ucl.ac.uk