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Matthew Nichols
PhD student, Pharmacology

 
Drug target may lessen stroke-related brain damage 

Stroke is the second leading cause of death globally. Each year, about 16 million people have a stroke for the first time. Half are permanently disabled. 
 
What if this damage could be lessened? Research from pharmacology PhD student Matthew Nichols is pointing the way to a potential drug therapy that could reduce or even prevent stroke-related brain damage by targeting mitochondria, the energy powerhouse of cells. He’s conducting this research under the supervision of Dr. George S. Robertson.
 
Blood clots that block oxygen supply to the brain are the most common cause of a stroke. The only therapy that can currently lessen this damage is tissue plasminogen activator (TPA), an enzyme that restores blood flow to the brain by dissolving blood clots. TPA cannot be used in patients who have a suffered a hemorrhagic stroke caused by a burst blood vessel in the brain, however, because TPA increases the risk of excessive bleeding. TPA can only be used after a brain scan has ruled out the possibility of bleeding. Adding to the complications, TPA must be given within three hours of stroke onset to be effective. A better solution could be on the horizon.
 
The potential new drug target is called the mitochondrial calcium uniporter. This protein forms a channel that transports calcium into mitochondria, stimulating energy production essential to meeting the dynamic metabolic demands of the brain. However, excessive calcium uptake by mitochondria triggers cell death. Drugs that block the mitochondrial calcium uniporter may therefore reduce brain damage after a stroke.
 
“The brain itself, although it occupies only two percent of your body mass, consumes twenty per cent of resting calories,” says Matthew. “It is one of the most energetically expensive organs we have by weight. Anytime you compromise that you will have adverse effects.”
 
The recent genetic identification of the mitochondrial calcium uniporter has made it possible to create mice that lack this channel. Dr. Robertson and his team have examined the effects of an experimental stroke on mice deficient for the mitochondrial calcium uniporter. They’ve found that these mice develop adaptations to protect the brain from stroke damage.
 
“A drug that blocks the mitochondrial calcium uniporter may therefore reduce stroke-related brain injury,” notes Matthew. “My work suggests that such a drug would best be suited to short-term use to decrease brain injury after stroke.” He adds that it may even be possible to extend the therapeutic time-window for TPA, if paramedics were to give this drug to patients as soon as possible following stroke.
 
The benefits may extend beyond stroke. “The cardiac community was investigating this area before the neurology community,” says Matthew. “They have shown that blocking the mitochondrial calcium uniporter protects cardiac muscle cells from damage following an experimental heart attack. So drugs that block the mitochondrial calcium uniporter may also be useful in the prevention of cardiac damage following a heart attack.” This pioneering research was recently published online in Journal of Cerebral Blood Flow & Metabolism. The research was funded by the Heart and Stroke Foundation of Canada, American Heart Association, Brain Canada, and the MS Society of Canada.

 

 

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