February 8, 2010

Brain protein work indicates new protection drugs

Pathologist Keqiang Ye has made a series of discoveries recently, arising from his investigations of substances that can mimic the growth factor BDNF (brain-derived neurotrophic factor).

BDNF is a protein produced by the brain that pushes neurons to withstand stress and make new connections.

“BDNF has been studied extensively for its ability to protect neurons vulnerable to degeneration in several diseases, such as ALS, Parkinson’s and Alzheimer’s disease,” Ye says. “The trouble with BDNF is one of delivery. It’s a protein, so it can’t cross the blood-brain barrier and degrades quickly.”

Working with Ye, postdoctoral fellow Sung-Wuk Jang identified a compound called 7,8-dihydroxyflavone that can duplicate BDNF’s effects on neurons and can protect them against damage in animal models of seizure, stroke and Parkinson’s disease. The compound’s selective effects suggest that it could be the founder of a new class of brain-protecting drugs.

7,8-dihydroxyflavone is a member of a family of antioxidant compounds naturally found in foods ranging from cherries to soybeans. Ye says his laboratory has already identified compounds that are several times more active. The next step is more animal studies to choose compounds likely to have the best drug profiles: stable and non-toxic.

“It is likely that many people take in small amounts of 7,8-dihydroxyflavone in their diets,” he says. “But drinking green tea or eating apples doesn’t give you enough for a sustained effect.”

Along the way to finding 7,8-dihydroxyflavone, Jang and Ye have also identified other molecules, both natural and artificial, which can mimic BDNF. For example, the tricyclic antidepressant amitryptiline activates the same signaling molecules as BDNF in neurons. This provides an alternative mechanism for how some antidepressants may exert their effects.

A description of 7,8-dihydroxyflavone’s properties was published online Jan. 25 by the Proceedings of the National Academy of Sciences (PNAS).

An article from neuroscientist Kerry Ressler’s laboratory describing how 7,8-dihydroxyflavone and genetic manipulation of BDNF can be used to probe fear memory formation was also published in PNAS on Jan. 25. Ye’s studies on amitriptyline were published in the June 2009 issue of the journal Chemistry & Biology.

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