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7,8-Dihydroxyflavone - BDNF receptor agonist improves memory consolidation in mice and increases AMPA gene expression

dihydroxyflavone bdnf nootropics

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#1 boowasabi

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Posted 02 August 2015 - 12:48 AM


7,8-Dihydroxyflavone improves memory consolidation processes in rats and mice.

 

Brain-derived neurotrophic factor (BDNF) is a crucial regulator of neuronal survival and neuroplasticity in the central nervous system (CNS). As a result, there has been a growing interest in the role of BDNF in neuropsychiatric disorders associated with neurodegeneration, including depression and dementia. However, until now, BDNF-targeting therapies have yielded disappointing results. BDNF is thought to exert its beneficial effects on synaptic and neuronal plasticity mainly through binding to the tyrosine kinase B (TrkB) receptor. Recently, 7,8-dihydroxyflavone (7,8-DHF) was identified as the first selective TrkB agonist. In the present study the effect of 7,8-DHF on memory consolidation processes was evaluated. In healthy rats, 7,8-DHF improved object memory formation in the object recognition task when administered both immediately and 3h after learning. In a transgenic mouse model of Alzheimer's disease, i.e. APPswe/PS1dE9 mice, spatial memory as measured in the object location task was improved after administration of 7,8-DHF. A similar memory improvement was found when their wild-type littermates were treated with 7,8-DHF. The acute beneficial effects in healthy mice suggest that effects might be symptomatic rather than curing. Nevertheless, this study suggests that 7,8-DHF might be a promising therapeutic target for dementia.

 

http://www.ncbi.nlm....pubmed/24070857

 

7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome.

 

Fragile X syndrome (FXS) is characterized by immature dendritic spine architectures and cognitive impairment. 7, 8-Dihydroxyflavone (7, 8-DHF) has recently been identified as a high affinity tropomyosin receptor kinase B (TrkB) agonist. The purpose of this paper was to examine the utility of 7, 8-DHF as an effective pharmacotherapeutic agent that targets dendritic pathology and cognitive impairments in FXS mutant. We synthesized pharmacologic, behavioral, and biochemical approaches to examine the effects of 7, 8-DHF on spatial and fear memory functions, and morphological spine abnormalities in fragile X mental retardation 1 (Fmr1) gene knock-out mice. The study found that 4 weeks of treatment with 7, 8-DHF improved spatial and fear memory, and ameliorated morphological spine abnormalities including the number and elongation of spines in the hippocampus and amygdala. Further mechanism analysis revealed that 7, 8-DHF enhanced the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor, but reduced the normal levels of GluA2 at the synapses in Fmr1. Potentially related to drug-induced changes in AMPA receptor subunits, 7, 8-DHF at the synapses led to phosphorylation of specific serine sites on subunits Ser818 and Ser813 of GluA1, and Ser880 of GluA2, as well as phosphorylation of TrkB, calcium/calmodulin-dependent protein kinase II, and protein kinase C. However, 7, 8-DHF neither affected behavioral performance nor increased TrkB phosphorylation in WT mice, which suggested that it had FXS-specific correcting effect. Altogether, these results demonstrated that 7, 8-DHF improved learning and memory, and reduced abnormalities in spine morphology, thus providing a potential pharmacotherapeutic strategy for FXS.

 

http://www.ncbi.nlm....pubmed/25229717

 

A Synthetic 7,8-Dihydroxyflavone Derivative Promotes Neurogenesis and Exhibits Potent Antidepressant Effect

7,8-Dihydroxyflavone is a recently identified small molecular tropomyosin-receptor-kinase B (TrkB) agonist. Our preliminary structural activity relationship (SAR) study showed that the 7,8-dihydroxy groups are essential for the agonistic effect. To improve the lead compound's agonistic activity, we have conducted an extensive SAR study and synthesized numerous derivatives. We have successfully identified 4'-dimethylamino-7,8-dihydroxyflavone that displays higher TrkB agonistic activity than the lead. This novel compound also exhibits a more robust and longer TrkB activation effect in animals. Consequently, this new compound reveals more potent anti-apoptotic activity. Interestingly, chronic oral administration of 4'-dimethylamino-7,8-dihydroxyflavone and its lead strongly promotes neurogenesis in dentate gyrus and demonstrates marked antidepressant effects. Hence, our data support that the synthetic 4'-dimethylamino-7,8-dihydroxyflavone and its lead both are orally bioavailable TrkB agonists and possess potent antidepressant effects.

 

7,8-Dihydroxyflavone Infographic 

 

See thumbnail for a chart showing 7,8-dhf (as well as a 7,8-dhf derivative) elicited increases in neurogenesis. 

 

Questions

  1. Does 7,8-Dihydroxyflavone cross the BBB?
  2. Has this been tested in humans?
  3. What do subjective reports suggest? 

Attached Files


Edited by boowasabi, 02 August 2015 - 12:49 AM.

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#2 resveratrol_guy

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Posted 02 August 2015 - 04:01 PM

Do you have a link to the full text which is not paywalled?

 

In any event, do they provide units for that graph (e.g. 10^5 neurons or whatever)? It's not that I believe they would base their results on the difference between 7 neurons and 3 neurons; it's that I'm looking for a level of professionalism to at least suggest that this is reliable research. This is no small consideration because it would appear that they've discovered a structural ("anabolic") nootropic, as opposed to a receptor tweak which merely enhances efficiency in a failing ecosystem. And what are they "positive" for, e.g. BrdU or what?

 

An unverified summary of the benefits is here and the initial Longecity report is here.

 

If anyone wants to try it on their rats, it's readily available from Alibaba.

 

What do you know, there's already a group buy for this; see aphex's experience report, for example.


Edited by resveratrol_guy, 02 August 2015 - 04:06 PM.


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#3 rikelme

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Posted 03 August 2015 - 06:44 PM

There is 7,8-DHF topic:

http://www.longecity...ihydroxyflavone



#4 boowasabi

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Posted 04 August 2015 - 05:51 PM

Do you have a link to the full text which is not paywalled?

 

In any event, do they provide units for that graph (e.g. 10^5 neurons or whatever)? It's not that I believe they would base their results on the difference between 7 neurons and 3 neurons; it's that I'm looking for a level of professionalism to at least suggest that this is reliable research. This is no small consideration because it would appear that they've discovered a structural ("anabolic") nootropic, as opposed to a receptor tweak which merely enhances efficiency in a failing ecosystem. And what are they "positive" for, e.g. BrdU or what?

 

An unverified summary of the benefits is here and the initial Longecity report is here.

 

If anyone wants to try it on their rats, it's readily available from Alibaba.

 

What do you know, there's already a group buy for this; see aphex's experience report, for example.

 

Thanks for the helpful links. You are correct in thinking that the y axis of the attached graph corresponds to positivity for BrdU. I did not realize there was a group buy in the works, I'll have to check that out. 

 

Here are the links to the PDFs:

 

7,8-Dihydroxyflavone improves memory consolidation processes in rats and mice.

pdf: https://drive.google...iew?usp=sharing

 

7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome.

pdf: https://drive.google...iew?usp=sharing

 

A Synthetic 7,8-Dihydroxyflavone Derivative Promotes Neurogenesis and Exhibits Potent Antidepressant Effect

pdf: https://drive.google...iew?usp=sharing

 

Here's the full figure description:

Figure 5. 40 -Dimethylamino-7,8-dihydroxyflavone and 7,8-dihydroxyflavone promote neurogenesis. (A) Neurogenesis assay. Male C57BL/6J mice were orally administrated with 5 mg/kg 40 -DMA-7,8-DHF and 7,8-DHF and vehicle solvent for 21 days and followed by 50 mg/kg BrdU ip injection. In 2 h, the mice were perfused and brain sections were immunostained with anti-BrdU and DAPI. The positive cells in dentate gyrus were highlighted by arrow (left panels). Quantitative analysis of the BrdU positive cells in dentate gyrus (right panel). (B) 7,8-DHF and its derivative upregulate TrkB activation in dentate gyrus. Paraffin section were deparaffinized in xylene and rehydrated gradient ethanol solution. Samples were boiled in 10 mM sodium citrate buffer for 20 min for antigen retrieval purpose. Brain sections were incubated with anti-TrkB (BD biosciences, San Jose, CA) 1:50, and anti-p-TrkB Y816 was used at 1:300 dilution. Secondary antibody were applied using antirabbitAlexa 594 (red), antimouse-FITC (green). DAPI (blue) was used for nuclear staining.

 

 


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#5 resveratrol_guy

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Posted 06 August 2015 - 03:18 AM

 

Do you have a link to the full text which is not paywalled?

 

In any event, do they provide units for that graph (e.g. 10^5 neurons or whatever)? It's not that I believe they would base their results on the difference between 7 neurons and 3 neurons; it's that I'm looking for a level of professionalism to at least suggest that this is reliable research. This is no small consideration because it would appear that they've discovered a structural ("anabolic") nootropic, as opposed to a receptor tweak which merely enhances efficiency in a failing ecosystem. And what are they "positive" for, e.g. BrdU or what?

 

An unverified summary of the benefits is here and the initial Longecity report is here.

 

If anyone wants to try it on their rats, it's readily available from Alibaba.

 

What do you know, there's already a group buy for this; see aphex's experience report, for example.

 

Thanks for the helpful links. You are correct in thinking that the y axis of the attached graph corresponds to positivity for BrdU. I did not realize there was a group buy in the works, I'll have to check that out. 

 

Here are the links to the PDFs:

 

7,8-Dihydroxyflavone improves memory consolidation processes in rats and mice.

pdf: https://drive.google...iew?usp=sharing

 

7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome.

pdf: https://drive.google...iew?usp=sharing

 

A Synthetic 7,8-Dihydroxyflavone Derivative Promotes Neurogenesis and Exhibits Potent Antidepressant Effect

pdf: https://drive.google...iew?usp=sharing

 

Here's the full figure description:

Figure 5. 40 -Dimethylamino-7,8-dihydroxyflavone and 7,8-dihydroxyflavone promote neurogenesis. (A) Neurogenesis assay. Male C57BL/6J mice were orally administrated with 5 mg/kg 40 -DMA-7,8-DHF and 7,8-DHF and vehicle solvent for 21 days and followed by 50 mg/kg BrdU ip injection. In 2 h, the mice were perfused and brain sections were immunostained with anti-BrdU and DAPI. The positive cells in dentate gyrus were highlighted by arrow (left panels). Quantitative analysis of the BrdU positive cells in dentate gyrus (right panel). (B) 7,8-DHF and its derivative upregulate TrkB activation in dentate gyrus. Paraffin section were deparaffinized in xylene and rehydrated gradient ethanol solution. Samples were boiled in 10 mM sodium citrate buffer for 20 min for antigen retrieval purpose. Brain sections were incubated with anti-TrkB (BD biosciences, San Jose, CA) 1:50, and anti-p-TrkB Y816 was used at 1:300 dilution. Secondary antibody were applied using antirabbitAlexa 594 (red), antimouse-FITC (green). DAPI (blue) was used for nuclear staining.

 

 

 

 

 

Thanks for those studies. But oh boy, those BrdU+ counts were literal. As in, they're subject to horrendous quantization error because they're less than 10. Fortunately, on account of the group buy reports above, we have a good reason to continue an investigation of its human benefits.
 



#6 Ark

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Posted 06 August 2015 - 04:41 AM

How's the group buy coming? Any room for more participants?

Thanks,

#7 boowasabi

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Posted 12 August 2015 - 02:20 PM

How's the group buy coming? Any room for more participants?

Thanks,

 

It looks like the 7,8-dhf group buy thread is old; no updates since 2014. Are there any legitimate sources of 7,8-dhf with COAs?



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#8 pure

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Posted 15 August 2015 - 03:48 AM

Sure, I can type you up a COA in Word for my 7,8-
It's 110% pure, its H-NMR conforms, its MW conforms, its Heavy Metals, Pesticides, etc. are within limits, etc.
Only problem is, it tastes suspiciously like GABA. But the COA says it's 7,8-, so it must be, right?
I know we're all amateurs, but really...
When is everyone going to 'get it' that COA's are as worthless as the paper they're not printed on?
UNLESS... you also have the test reports printed by the testing equipment, from which the data was sourced to fabricate I mean prepare the COA.
Just think how many dramas/sagas that have played out in this forum because original test reports were not available and COA's were relied upon.
The reality is that most research chemicals come from China, and if you think for a minute you can trust Chinese manufacturers, then you're delusional.
Apart from the scamming, lying, cheating which is endemic in China, the issue is further compounded by the fact that by nature they are careless, lack attention to detail, imprecise, and have not got a clue that credibility, reliability, competence, are of the utmost importance especially in relation to chemicals production.
Of course, there are the 1% or so of Chinese in China who 'get it', but 'trusting' is not worth the risk IMO.
In my view you at least need to see a minimum of the following test reports printed by the testing equipment:
- H-NMR for identity, assuming there is a Reference Standard test report available
- MS (MW) for identity
- HPLC for purity
- toxic Metals (Lead, Mercury, Arsenic, Cadmium, Aluminium), if relevant subject to ingredients
- Pesticides, if relevant subject to ingredients
- Residual Organic Solvents, if relevant subject to production process
- Endotoxins, if being injected

Edited by pure, 15 August 2015 - 04:18 AM.

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