Scientists from University of Texas Southwestern Medical Center, Dallas, lead by Dr.Steven McKnight, have discovered a compound (see structure) that restores the capacity to form newmemories in aging rats, likely by improving the survival of newborn neurons in the brain's memory hub. The research has turned up clues to a neuroprotective mechanism that could lead to a treatment for Alzheimer's disease.
"This neuroprotective compound, called P7C3, holds special promise because of its medication-friendly properties. It can be taken orally, crosses the blood-brain barrier with long-lasting effects, and is safely tolerated by mice during many stages of development." claims Dr.Steven McKnight
In hopes of finding compounds that might protect such vulnerable neurons during this process, Pieper, McKnight and colleagues tested more than 1000 small molecules in living mice. One of the compounds, designated P7C3 (see structure), corrected deficits in the brains of adult mice engineered to lack a gene required for the survival of newborn neurons in the hippocampus. Giving P7C3 to the mice reduced programmed death of newborn cells, normalizing stunted growth of branch-like neuronal extensions and thickening an abnormally thin layer of cells by 40 percent. Among clues to the mechanism by which P7C3 works, the researchers discovered that it protects the integrity of machinery for maintaining a cell's energy level.
To find out if P7C3 could similarly stem aging-associated neuronal death and cognitive decline, the researchers gave the compound to aged rats. Rodents treated with P7C3 for two months significantly outperformed their placebo-treated peers on a water maze task, a standard assay of hippocampus-dependent learning. This was traced to a three fold higher-than-normal level of newborn neurons in the dentate gyrus of the treated animals. Rats were used instead of mice for this phase of the study because the genetically engineered mice could not swim.
Prolonged treatment of aged rats with P7C3 also enhanced the birth of new neurons. "Aged rats normally show a decline in neurogenesis associated with an inability to form new memories and learn tasks," Pieper explained..
In their study, rats treated with P7C3 each day showed evidence of an increase in the formation of newborn neurons and significant improvements in their ability to swim to the location of a missing platform, s standardized test of larning and memory in rats.
The key to the treatment's success is the protection of newborn neurons, the researchers report. In fact, they explained, the normal process by which newborn neurons are incorporated into the brain as mature cells is a long and perilous one. Notably, they say that two other drugs (Dimebon and Serono compounds) -- both of which bear structural similarities to P7C3 -also encourage the growth of new neurons. It's tempting to think that all three compounds work in the same way the researchers pinpointed a derivative of P7C3, called A20, which is even more protective than the parent compound. They also produced evidence suggesting that two other neuroprotective compounds eyed as possible Alzheimer's cures may work through the same mechanism as P7C3. The A20 derivative proved 300 times more potent than one of these compounds currently in clinical trials for Alzheimer's disease. This suggested that even more potent neuroprotective agents could potentially be discovered using the same methods. Following up on these leads, the researchers are now searching for the molecular target of P7C3 - key to discovering the underlying neuroprotective mechanism.
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