When the brain’s oxygen supply is cut off, by a blood clot in the brain say, all bets are off. Ions of all kinds flood the brain, killing neurons and the all-important grey stuff. Dr. John MacDonald, however, chair of the department of physiology, is working to make sense of this chaos. His research in post-stroke treatment and schizophrenia have placed him at the forefront of his field, and have earned him election to the prestigious Royal Society of Canada.
In a paper published in the journal Cell in 2003, MacDonald and his team challenged the way scientists then thought about brain damage and cell death. When the brain is deprived of oxygen and glucose, often as result of a stroke or severe brain damage, a self-destruct mechanism is activated in the brain, which kills neurons and causes severe long-term damage.
Popular belief had held that neuronal death was caused by an influx of lethal calcium ions through the so-called NMDA receptors, which are found on the surface of brain cells. Drugs were developed based on the premise that by blocking the NMDA receptors, one could prevent cell death. But clinical trials showed these drugs were not only ineffective, but seemed to induce psychosis in patients as well.
MacDonald and his team instead showed that an ion channel on the surface of brain cells, known as TRPM7, plays a key role in cell death. Ion channels are proteins that act as gatekeepers to the cell, by controlling the flow of ions through the pores in a cell’s protective membrane. Excessive amounts of calcium ions kill brain cells by forcing them into a metabolic overdrive-causing them to literally work themselves to death.
By focusing on disrupting this mechanism of calcium entry into cells, MacDonald is optimistic that a potential new treatment for stroke victims could be ready within three years.
But MacDonald’s research in this area continues. In another Cell paper, published last September, he studied another ion channel, called ASIC. The channel is activated by the acidic conditions found in the brain during a stroke, and was shown to cause the same damage as the TRPM7 ion channel.
In an upcoming paper, MacDonald shows that a third channel, TRPM2, causes calcium entry into cells even when oxygen flow to the brain is restored. “There seems to be an almost orchestrated series of unfortunate events that leads to cell death,” said MacDonald. But he has undertaken the task of deconstructing these events, so that researchers can better understand and prevent them.
MacDonald has also contributed to our understanding of schizophrenia. He has compiled convincing evidence that the disorder is brought on by an excess of dopamine (a neurotransmitter) in the brain. This leads to reduced activity of NMDA receptors, resulting in psychosis. This may explain why patients receiving the post-stroke treatment that blocked their NMDA receptors experienced psychotic episodes.
As a future Fellow of the Royal Society of Canada, Dr. Macdonald has some ambitious aims for the future of Canadian scientific research. One goal “is the development of relationships with Asia and in particular with China,” he said. “China is an enormous country with a very small scientific base at this stage but the potential for growth is astronomical.”
Another is to steer Canada away from the growing trend towards goal-oriented research. Macdonald is concerned that basic research, which provides the groundwork for important breakthroughs later on, is being undermined.
