Posted by SLS on September 15, 2014, at 19:43:15
In reply to Re: TRK-b agonists for BDNF knockouts, posted by linkadge on September 15, 2014, at 17:56:18
> Hi SLS,
>
> I know that the antidepressant effect of certain AD's requires the enhancement of BDNF production or binding or the like.
>
> I know that BDNF binds to the trk-b receptor. Certain agents (i.e. amitriptyline) are direct trk-b agonists. In other words, they mimic the effects of BDNF in the absence of BDNF.
>
> I wonder if trk-b agonists might benefit individuals with the low functioning version of the BDNF gene.
>
> Linakdge
Great thinking!I was unaware of the Trk receptors.
I excerpted several passages from the following article:
- Scott-----------------------------------------------------
http://www.jci.org/articles/view/41356
Brain-derived neurotrophic factor (BDNF) activates the receptor tropomyosin-related kinase B (TrkB) with high potency and specificity, promoting neuronal survival, differentiation, and synaptic function. Correlations between altered BDNF expression and/or function and mechanism(s) underlying numerous neurodegenerative conditions, including Alzheimer disease and traumatic brain injury, suggest that TrkB agonists might have therapeutic potential.
The findings that TrkB is important for long-term survival, differentiation, and function of newborn neurons in the adult hippocampus (1618), and that neurogenesis plays a fundamental role in depression, suggest that discovery of TrkB ligands might open new treatment avenues for this disorder.
A number of properties limit the therapeutic application of BDNF. Its plasma half-life in rats is less than 1 minute, and it has poor blood brain barrier penetration (21) and poor brain intraparenchymal penetration (22). In addition, BDNF interaction with p75NTR might contribute to its ability to promote pain (23) and other undesired effects. Thus, a long-sought goal has been the development of non-peptide, small molecule ligands capable of activating TrkB signaling with high potency and specificity.
LM22A compounds interact with and act through TrkB.
In preliminary assays, 5 compounds emulating the loop II region of BDNF were considered to have activity significantly above baseline as defined as a percentage of BDNF maximal efficacy. Four compounds with the highest activity (LM22A-1 to -4) were selected for further characterization. Each of these 4 compounds exhibits a distinct chemotype; LM22A-1 is a tripeptide (Pro-His-Trp), and compounds LM22A-2, LM22A-3, and LM22A-4 contain no peptide bonds (Figure 1B).
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Some see things as they are and ask why.
I dream of things that never were and ask why not.- George Bernard Shaw
poster:SLS
thread:1071129
URL: http://www.dr-bob.org/babble/20140914/msgs/1071186.html