Diabetic drug used to promote neurogenesis


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This is good research into brain neurogenesis using existing endogenous stem cells in the brain.

TORONTO -- A drug commonly used to control Type 2 diabetes can help trigger stem cells to produce new brain cells, providing hope of a potential means to treat brain injuries and even neurodegenerative diseases like Alzheimer's, researchers say.
A study by scientists at Toronto's Hospital for Sick Children found the drug metformin helps activate the mechanism that signals stem cells to generate neurons and other brain cells.
“If you could take stem cells that normally reside in our brains and somehow use drugs to recruit them into becoming appropriate neural cell types, then you may be able to promote repair and recovery in at least some of the many brain disorders and injuries for which we currently have no treatment,” said principal investigator Freda Miller.
“This work is happening against a background of a lot of excitement in the stem cell field about the idea that since we now know that we have stem cells in many of our adult tissues, then perhaps if we could figure out how to pharmacologically tweak those stem cells, then perhaps we could help to promote tissue repair,” added Miller, a senior scientist at SickKids.
The research, published online Thursday in the journal Cell Stem Cell, involved lab-dish experiments using both mouse and human brain stem cells, as well as learning and memory tests performed on live mice given the drug.
Researchers started by adding metformin to stem cells from the brains of mice, then repeated the experiment with human brain stem cells generated in the lab. In both cases, the stem cells gave rise to new brain cells.
They then tested the drug in lab mice and found that those given daily doses of metformin for two or three weeks had increased brain cell growth and outperformed rodents not given the drug in learning and memory tasks.
One standard test involves a water maze in which the mice must swim around until they locate a hidden platform.
“And the remarkable thing is the mice that got the metformin, what they showed was increased flexibility in terms of the way they learned the location of things,” said Miller, explaining that the drug-treated mice had a greater ability to learn and remember.
“If you then, for example, moved the platform some place completely different, the metformin-treated animals were remarkably good at just saying, ‘OK, things have changed’ and learning the new thing and (were) much better than the controls (untreated mice).”
Miller said it was serendipity that led the team to conduct the study. About 18 months ago, they found a pathway known as PKC-CBP that signalled embryonic neural stem cells to make brain cells. At about the same time, some U.S. collaborators at Johns Hopkins University found the same pathway was activated by metformin in liver cells -- the means by which the drug controls glucose levels that go awry in diabetes.
Based on those findings, Miller’s team thought metformin might activate the same pathway in neural stem cells.
“I love this story because it’s a classic example of how very basic research into how things work has led to a potential therapeutic endpoint,” she enthused.
One big bonus for researchers is that metformin has been well-tested and long prescribed for a number of diseases, including metabolic disorders in children. The drug also has been shown to have anti-cancer properties.
“The advantage again is that because metformin has been in people from seven until 107, we have lots of safety data on it, we know exactly what kinds of doses, et cetera, et cetera,” she said. “So that’s a really huge plus with moving forward.”
When it comes to progressive neurodegenerative diseases such as Alzheimer’s, Miller said there is a lot of excitement among scientists about finding a drug that could recruit stem cells to produce healthy neurons, “at least to give people just a bit longer healthier cognition, if you will.”
Metformin might be such a drug, but the difficulty is that stem cells age and diminish as people get older, so it’s unclear whether there would be adequate numbers of healthy brain stem cells to produce new neurons that would have a therapeutic benefit.
Still, it’s a possible and worthwhile line of investigation, she said.
Miller’s team is already in discussions with clinical colleagues about launching a pilot study to test metformin in young patients with acquired brain damage, either as result of treating a childhood brain tumour or from a traumatic head injury.
Such a study would try to determine if the drug could increase brain cell mass -- using a functional MRI scan, for instance -- and measuring any improvement in cognition and behaviour.
If approved, Miller said a pilot study could begin within the next year or so.
For more information
Video: Metformin and Neurogenesis with Freda Miller
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