Restoring Neuron Formation

Researchers at the University of Texas Southwestern Medical Center, in Dallas, have identified a compound that prevents learning and memory problems common in aging rodents (Cell 2010, 142, 39).

The work provides a “striking demonstration of a treatment that stems age-related cognitive decline in living animals,” according to Thomas R. Insel, director of the National Institute of Mental Health, which helped fund the research.

Led by biochemists Steven L. McKnight and Andrew A. Pieper, the team found the compound by sifting through the medical center’s chemical library for substances that could restore neuron formation in the hippocampus of genetically engineered mice that almost totally lack this capacity. Neurogenesis in the hippocampus is crucial for learning and memory.

“These mice are bad at making new neurons,” McKnight says. “The question was, Can you fix that?” After testing more than 1,000 compounds in the mice, he adds, he and his coworkers found that “the answer to that was yes. Sure enough, we had evidence that you can actually create new neurons that work.” The most active compound in the library was an aminopropylcarbazole the authors dubbed P7C3.

The UT Southwestern team then tested the compound on rats. “Aged rats normally show a decline in neurogenesis associated with an inability to form new memories and learn tasks,” Pieper says. But aged rats dosed with P7C3 grew more neurons and performed better in a memory test than did control rats.

The researchers believe the compound, which is orally active and caused no apparent harm in the mice tested, not only helps generate neurons but also lessens the likelihood they’ll succumb to the programmed cell death that often strikes newborn neurons before they’re wired into brain circuitry.

Enhancement of neurogenesis in humans could help treat disorders such as depression, while reducing cell death could be useful in treatments for neurodegenerative diseases such as Alzheimer’s, notes William S. Messer Jr., a University of Toledo pharmacologist who studies neurological disorder therapies.

Messer adds that P7C3’s mechanism is presently unclear. McKnight and Pieper suggest it might resemble that of two structurally similar though less effective compounds that nurture neurons, the antihistamine Dimebon and a Serono Pharmaceuticals brominated carbazole.