Drugs to Grow Your Brain

Compounds that trigger the growth of new brain cells might help treat depression.

Newborn neurons: This image shows a section of the hippocampus, the part of the brain important for learning and memory. Mature neurons are shown in green, while newborn neurons are orange, and neural stem cells are red. Credit: BrainCells Inc.

Drugs that encourage the growth of new neurons in the brain are now headed for clinical trials. The drugs, which have already shown success in alleviating symptoms of depression and boosting memory in animal models, are being developed by BrainCells, a San Diego-based start-up that screens drugs for their brain-growing power. The company hopes the compounds will provide an alternative to existing antidepressants and says they may also prove effective in treating cognitive disorders, such as Alzheimer's.

"The fact that you might be able to take small molecules to stimulate specific cells to regenerate in the brain is paradigm-shifting," says Christopher Eckman, a neuroscientist at the Mayo Clinic in Jacksonville, FL. "[This approach] takes advantage of the body's innate ability to correct itself when given appropriate cues." Eckman studies compounds that boost brain cell growth in models of neurodegenerative disease and is not involved with BrainCells.

In the last ten years, scientists have discovered that new neurons are born in the adult brain and that increases or decreases in this cell growth, known as neurogenesis, may be involved in myriad brain diseases, including depression, schizophrenia and stroke. Subsequent research has shown that existing drugs, including Prozac and other antidepressants, boost neurogenesis. In fact, that property may be an integral component of the drugs' effectiveness--for example; some experiments suggest that new cell growth in the hippocampus is necessary for antidepressants to work.

Scientists at BrainCells aim to exploit that finding by screening drugs expressly for their ability to boost brain cell growth. (While some existing drugs have this effect, they weren't selected for it.) Scientists select drug candidates by assessing their impact on human neural stem cells growing in a dish, examining how many new cells are born and how well they develop into fully differentiated neurons. The company is focusing mainly on drugs that are already on the market or have been tested in humans for other indications and therefore have a good safety profile.

After screening different types of antidepressant compounds that are already on the market, researchers at BrainCells found all the drugs have a similar ability to boost brain cell growth. However, existing antidepressants fail to help 30 to 50 percent of patients and often carry problematic side-effects. So the scientists began searching for other compounds that carry similar benefits but lack the side effects. "It's possibly that some people who don't respond to SSRIs [a common type of antidepressant] would respond to a drug that targets neurogenesis directly," says James Schoeneck, Braincells's chief executive officer.

Clinical trials of the company's lead candidate, known as BCI-540, began earlier this year. The drug, originally developed for Alzheimer's disease, boosts brain cell growth by 20 percent. These results are comparable to Prozac. "Because the drug had already been tested in 700 patients, we knew its safety profile," says Schoeneck. (Clinical trials for Alzheimer's were halted because of a high rate of placebo response.) Schoeneck says the drug has so far shown no signs of gastrointestinal or sexual side effects, two of the most problematic side effects of current antidepressants.

The company also plans to test the drug, which shows anti-anxiety effects in rodents, for Post-Traumatic Stress Disorder (PTSD), an anxiety disorder common in combat veterans and assault victims. But the role of neurogenesis in mood disorders is still controversial. "Not everyone is convinced that neurogenesis is integrally related to the cause of depression," says Arnold Kriegstein, director of the Institute for Regeneration Medicine at the University of California, San Francisco.

Drugs that boost brain cell growth may also aid cognition. Previous research has shown that neurogenesis in the hippocampus, a brain area integral to learning and memory, is important for maintaining plasticity in that part of the brain, which in turn is linked to memory function. "With aging, there's a decrease in neurogenesis," says Kriegstein. "The hypothesis is that if you could boost neurogenesis to compensate for that age-related decline, you might maintain functional levels."

BrainCells is also testing a compound, known as BCI-632, for its cognitive enhancing properties. "It's the most neurogenic compound we've seen," says Schoeneck. While the compound hasn't yet been tested in humans, it appears to boost at least one type of memory in rodents. The company aims to begin clinical trials next year.

Novel drug combinations may also have neurogenesis-boosting power. For example, researchers at Brain cells have found that a respiratory drug and a cardiovascular drug, both already on the market, seem to dramatically boost brain cell growth in cellular tests.

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