National Antivisection Society
New Aston University awards
In January the Lord Dowding Fund awarded grants for two neuroscience projects at Aston University. In the light of the Cambridge University plans to build a primate neuroscience research facility, these studies are timely and relevant to humans.
The design of novel neurotoxicity assays using human tissues
The study of toxicity to human nerves presents a challenge because of the uniqueness and complexity of the central nervous system (CNS), consisting of the brain and spinal cord. The distinct areas of the brain communicate with each other through a complex network of nerve tissues. These tissues have a limited ability to regenerate and are more vulnerable to irreversible damage when exposed to a toxin (poison) than other tissues. So it is essential to evaluate the potential toxicity of therapeutic drugs and their breakdown products in relevant models of the human brain.
Current evaluation of the toxicity of a substance to the nervous system involves administration of a substance to an animal and observing behavioural changes - meaning animal suffering and results that poorly predict the human situation. With Lord Dowding Fund support, Dr Mike Coleman at the School of Pharmacy is developing a system for testing potential neurotoxins using co-cultures of human nerve cells.
Many neurobehavioural studies have been conducted in a wide range of animal species. It is estimated that over 2 million mice are used in nerve toxicity studies annually worldwide. Chemicals tested in animals include new and old compounds, including those of known neurotoxicity. For example, mercury continues to be tested in animals despite its devastating effects on the nerves having been well documented in man since the 1960s. To test the neurotoxicity of mercury, monkeys are exposed to it whilst still in the womb. The long-term effects of mercury exposure on the eyesight and hearing are also measured in primates.
Despite a gradual decline in the use of primates for most procedures in the last decade, many are still used to test neurotoxic agents, such as the street drug ecstasy. In the UK in 2001 there were 2,468 experimental procedures involving toxicity evaluation in primates, of which 481 were concerned with the nervous system. In the USA, during 2000-2001, it is estimated approximately 4,000-5,000 primate neurotoxicity studies were carried out, with a worldwide figure of approximately 10,000 primates. Animal brain tissues are used widely in vitro (in culture) to study neurotoxicity. However, the effects of a specific toxin can differ widely between animal and human tissues. For example, although much research has been directed at the development of primate models of human parkinsonism using MPTP, the drug-induced condition still does not adequately mimic the human disease. Recent studies of human brain biochemistry indicate that many brain disorders and the fate of drugs designed to treat them depend upon biochemical systems unique to man. Therefore, as the consequences of CNS toxicity are so serious, there is a need for a dependable non-animal model for human neurotoxicity.
The design of in vitro tests which reflect the unique, sophistication of human brain tissue is in its infancy, due to the difficulty in obtaining human nerve tissue, its deterioration after death, inconsistency, high costs and risk of infection. Isolation of nerve cells from human embryonic tissues raises ethical concerns and data produced from waste tissues is not reproducible.
As a first step in the replacement of animals, Dr Coleman’s test system has been designed using human cell lines to reliably detect potential neurotoxicity. The project will use cells from a human teratocarcinoma (tumour type) cell line, chemically treated to form nerve cells, and human astrocytic cells - brain cells responsible for regulation of immunity and inflammation. Nerve cells are more resistant to toxicity when in contact with astrocytic cells. The astrocytic cells will be grown on cellulose inserts placed on top of the other cell lines. It is essential to determine whether toxic breakdown products can be produced from an apparently harmless substance. Therefore, to break down substances, enzymes normally present in the human brain will be placed in a compartment above that containing the cells, separated by a cellulose membrane barrier. The system will reflect the complexity of the human brain. Each unit will be contained in a metal frame and maintained at body temperature in a water bath.
The toxicity of a substance to the nerve cells will be detected by studying damage to mitochondria within the cells with the use of a fluorescent dye. Mitochondria are the principle energy store or .powerhouse9 of the cell and regulate nerve cell viability. Also, as a number of compounds are capable of inducing apoptosis, or selective cell death, flow cytometry (a method of counting cells and measuring their viability while they are in suspension) will be used to quantify the final stages of apoptosis in cell populations as well as cell viability.
Dr Coleman says this work intends to "help reinforce the UK’s position at the forefront of worldwide endeavour to design and implement novel in vitro neurotoxicity tests, sufficiently predictive of the human situation to meet society’s needs for safe and effective toxicity testing without animal suffering."
"If a novel human tissue neurotoxicity test were able to model successfully even a narrow aspect of human neural damage sufficiently well to gain worldwide regulatory acceptance, several thousand animal neurotoxicity experiments would become obsolete."
MEG and auditory processing
Much of the available knowledge of human auditory perception (hearing) of speech and music is based on animal research. Drs Caroline Witton and Paul Furlong at the Neurosciences Research Institute were awarded an LDF grant to conduct experiments expected to highlight the redundancy of animal models in hearing research and assist the shift towards non-invasive experimentation in humans. They propose magnetoencephalography (MEG) to investigate nerve responses to sound in the human brain, which will thereby reduce animal experiments.
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