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Biological Chemistry

Compound Protects Brain Cells From Explosive Force

Neuroscience: Small molecule preserves memory and motor skills in mice exposed to simulated blast

by Lauren K. Wolf
September 22, 2014 | A version of this story appeared in Volume 92, Issue 38

Credit: Cell Reports
When (–)-P7C3-S243 (shown) is given to a mouse exposed to a blast wave, the compound helps keep the rodent’s nerve cells intact (bottom, cross section of one cell shown). Without treatment, the cells fare poorly (top).
Cross-sectional views of the axons of two nerve cells from mice. On top is a cell after traumatic brain injury. The outer coating of the axon (the myelin) is thin and damaged. The mitochondrium inside is damaged. On bottom is a cell after traumatic brain injury but that has been treated with an experimental compound, (-)-P7C3-S243. This cell is intact.
Credit: Cell Reports
When (–)-P7C3-S243 (shown) is given to a mouse exposed to a blast wave, the compound helps keep the rodent’s nerve cells intact (bottom, cross section of one cell shown). Without treatment, the cells fare poorly (top).

Since 2000, more than 300,000 U.S. soldiers have been diagnosed with traumatic brain injury, which can trigger memory loss and psychiatric disorders. Aside from counseling and rehabilitation, doctors have no way of counteracting the brain damage caused by bomb blasts and other severe impacts.

That might change in the future, thanks to a research team led by Andrew A. Pieper of the University of Iowa Carver College of Medicine. The scientists have demonstrated that a compound, when administered up to 24–36 hours after a blast injury, protects a mouse’s nerve cells from degradation (Cell Rep. 2014, DOI: 10.1016/j.celrep.2014.08.030).

Along with Pieper, team members Steven L. McKnight and Joseph M. Ready of the University of Texas Southwestern Medical Center discovered the family of compounds to which this molecule belongs several years ago. Searching for agents to promote the growth of new nerve cells in the brain, they hit upon an aminopropyl carbazole that they dubbed P7C3. Rather than spurring cell growth, though, this compound increased the survival rate for new neurons, the researchers found. From there, the team synthesized derivatives of P7C3 with improved effects.

The compound tested in the blast experiments, called (–)-P7C3-S243, is a member of this optimized series. When given to mice exposed to a blast wave, not only does it safeguard their neurons, it preserves the rodents’ memory and motor skills for at least a few weeks.

To learn how (–)-P7C3-S243 shields the brain from harm, the Iowa and UT Southwestern researchers modified the compound with a cross-linker followed by a fluorescent tag. Using mass spectrometry and various assays, they then zeroed in on the molecule’s binding partner: NAMPT, an enzyme critical to energy metabolism in living cells. They published this finding in conjunction with their blast study (Cell 2014, DOI: 10.1016/j.cell.2014.07.040).

Ready tells C&EN the team thinks (–)-P7C3-S243 activates NAMPT in nerve cells and accelerates the enzyme’s catalytic activity. Although more tests are needed, he says, “we think it’s helping to maintain the redox activity of the neurons.”

“These are exciting results,” says Lee E. Goldstein, an expert in neurodegenerative diseases at Boston University School of Medicine. “They indicate that traumatic brain injury due to blast is amenable to therapeutic intervention.” He cautions, though, that (–)-P7C3-S243 likely won’t be a “magic bullet.” Traumatic brain injury affects many molecular pathways and will probably require multiple therapies, he says.

On Sept. 11, UT Southwestern announced that Google-backed life sciences firm Calico licensed the P7C3 molecules for an undisclosed up-front fee and milestone and royalty payments. In a press statement, Hal V. Barron, the firm’s president of R&D, said, “We look forward to working with the world-leading scientists who discovered the P7C3 class of molecules to learn whether the remarkable biological effects can be translated to the treatment of human disease.”


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