Small molecule boosts production of brain cells, protects new cells from dying, UT Southwestern researchers find

Drs. Joseph Ready (from left), Jef De Brabander, Andrew Pieper and Steven McKnight discovered a compound that boosts learning and memory in rodents.
Drs. Joseph Ready (from left), Jef De Brabander, Andrew Pieper and Steven McKnight discovered a compound that boosts learning and memory in rodents.

DALLAS – July 8, 2010 – UT Southwestern Medical Center researchers have found a compound that preserves newly created brain cells and boosts learning and memory in an animal study.

The study of this compound, which appears in the July 9 issue of Cell, springs from a $2.5 million National Institutes of Health Director’s Pioneer Award to Dr. Steven McKnight, chairman of biochemistry at UT Southwestern and senior author of the study.

Over a three-year period, the research team led by Dr. McKnight and Dr. Andrew Pieper, assistant professor of psychiatry and biochemistry at UT Southwestern, screened 1,000 individual molecules to see which ones might enhance the production of neurons in the adult mouse hippocampus, a region of the brain critical to learning and memory. The scientists found that one of the compounds, called P7C3, achieved this by protecting newborn neurons from dying.

The researchers then administered P7C3 to “knockout” mice lacking a gene that controls the generation of new neurons in the hippocampus. Humans who lack this gene have a variety of learning disabilities, and the “knockout” rodents show related abnormalities as well as a poorly formed hippocampus. When the “knockout” mouse received P7C3, however, normal structure and function of the hippocampus were restored.

In elderly rats, which characteristically show a decline in the birth and formation of hippocampal neurons, the researchers found that P7C3 increased both the birth and survival of new neurons, and the memory and learning capability of the aged rats.

“It’s been a wonderful experience,” Dr. Pieper said. “At first there was a lot of doubt, because we could have gone through the whole screen and found nothing.”

The researchers currently are studying the mechanism by which P7C3 protects cells from dying, and whether it might have any protective effect in other models of neurodegenerative disease.

“We don’t know yet whether P7C3 can block the death of mature nerve cells, which is what occurs in humans with these conditions,” Dr. McKnight said.

Dr. McKnight was one of the first 12 recipients of the NIH Director’s Pioneer Award, which is designed to allow researchers to pursue risky experiments that have the potential for producing highly innovative results.

“When I received the award, I thought ‘I’m not going to waste it on something safe – I’m going to go for it. That’s what the NIH expected of me and my team,’ ” Dr. McKnight said. “I’d like to give the NIH credit for betting on ‘cowboy’ science. If this pans out, it will be the most useful contribution of my career.”

Dr. Francis Collins, director of the NIH, said Dr. McKnight’s results exactly fit the award’s purpose.

“The NIH Director’s Pioneer Award gives highly innovative investigators the freedom to pursue bold new avenues of research. Such approaches can yield substantial payoffs, as in the case of the exciting clinical implications of Professor McKnight’s basic neurobiological research discovery,” Dr. Collins said.

Other UT Southwestern researchers involved in the study were Dr. Jeffrey Long and Shanhai Xie, both research scientists in biochemistry; graduate students Ginger Becker, Emanuela Capota, Ching-Han Shen and Kerstin Ure; Sandi Jo Estill, research associate in biochemistry; Jeannie Zhong, research scientist in psychiatry; Paula Huntington, research associate in psychiatry; medical student Shauna Goldman; Maria Capota and Jeremiah Britt, both research technicians in psychiatry; Dr. Tiina Kotti, assistant professor of molecular genetics; Dr. Noelle Williams, associate professor of biochemistry; Dr. Karen MacMillan, assistant instructor of biochemistry; Jacinth Naidoo, research assistant in biochemistry; Lisa Melito, research associate in biochemistry; Dr. Jenny Hsieh, assistant professor of molecular biology; Dr. Jef De Brabander, professor of biochemistry; and Dr. Joseph Ready, associate professor of biochemistry.

Dr. Daniel Brat of Emory University School of Medicine also participated in the study.

In addition to the NIH, the study also was funded by The Hartwell Foundation, NARSAD, the Staglin Family Fund, the UT Southwestern High Risk/High Impact research program, the Morton H. Meyerson Family Tzedakah Fund, the Simons Foundation and an anonymous donor who has supported Dr. McKnight’s research for 15 years.

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Media Contact:
Aline McKenzie
214-648-3404
aline.mckenzie@utsouthwestern.edu

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