Saturday, February 6, 2010

7,8-Dihydroxyflavone (a selective TrkB agonist) as new class of brain protecting drugs ?

In recent days, I have seen many groups working on the diverse activities of  flavonoid family of chemicals. In my earlier blog, have mentioned about Quercetin   (quercetin a flavonoid has been reported for diverse activities). Now interestingly  investigators at Emory University School of Medicine,  have reported that '7,8-Dihydroxyflavone' (see structure - also a  member of the flavonoid family of chemicals, abundant in fruits and vegetables-cherries to soybeans)   can partially prevent the death of neurons in experimental models of three neurological diseases" and  this  selective effect suggest that it could be  a new class of brain-protecting drugs.

Investigators at Emory University School of Medicine, led by Dr. Keqiang Ye, (Associate professor of pathology and laboratory medicine), were searching for a way to mimic a protein found in the brain called BDNF (brain-derived neurotrophic factor).

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, one of the authors 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". 

Researchers tried a a library of chemicals to find those that could stimulate one of the proteins on the surfaces of neurons that BDNF binds to. They could show that, 7,8-dihydroxyflavone sends survival signals to brain cells by pulling together two TrkB receiver-dish molecules, just like BDNF does. Interesting part of this research is that, 7,8-Dihydroxyflavone is active in the brain when injected into the body cavity (meaning that it can cross the blood-brain barrier). As claimed by the co-author Ye, many experimental "neuroprotectant" drugs have been unsuccessful in clinical trials for diseases such as stroke and Parkinson's over the last decade and 7,8-Dihydroxyflavone is the first molecule that specifically triggers TrkB. To show the effects of 7,8-dihydroxyflavone depended on TrkB,  authors used mice with a modified TrkB gene and were successful in doing so. Detailed animal studies to substantiate the claim  are essential , still  in my opinion its a good achievement... (details...)

1 comment:

T said...

You're right, this paper is a big deal - so far the only TrkB agonists have been partial agonists, and even then they're generally peptides or peptide mimetics, and none of them have really made it past animal testing. You can imagine that you'd need a fairly longer molecule, probably a dimer, and definitely one like a peptide, to pull the "receiver" dishes together, so it's so fascinating that they were able to use such a small molecule sans nitrogens to achieve this. I'm going to check out the paper to see how exactly they're sure the molecule is doing it - it's not upregulating BDNF?