29 replies to this topic

[formergenius]

• The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's disease mice
• A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer's Disease

The second paper is quite detailed.

Claims/findings thereof:

• J147 is Broadly Neuroprotective
• J147 Enhances Long-Term Potentiation and Memory
• J147 Prevents Memory Deficits in an Alzheimer's Disease Animal Model
• J147 Reduces Soluble Aβ Levels in the Hippocampus
• J147 Reduces Oxidative Stress and the Inflammatory Response
• J147 Reduces Heat-Shock Proteins and Increases Synaptic Protein Expression
• J147 Up-Regulates BDNF

Conclusions:

The above data demonstrate the potential of a new drug discovery paradigm for AD that is based upon the requirement that drug candidates be highly effective in multiple, distinct cell culture models of neurodegeneration. This approach yielded a very potent, orally active drug candidate that targets several different pathways that decline in AD. A large number of potential pharmaceutical, nutritional, and immunological therapies have been tested in clinical trials for AD, but to date they have not altered cognitive decline in humans. In contrast, over 200 compounds appear to reduce plaque loads or behavioral deficits in AD transgenic mice and several compounds increase the amount of BDNF in rodent brain . However, none of these compounds nor any of the drugs that are in clinical trials for AD have the combination of activities of J147 in cell culture and in animals. J147 is unique in its ability to enhance LTP, potentiate learning and memory in both normal and AD transgenic animals, and maintain synaptic proteins while at the same time reducing biochemical markers of inflammation and soluble Aβ levels in AD transgenic mice. Therefore, the range of biological activities of J147 relevant to human AD is also much more extensive than any of the compounds that have failed in clinical trials. In addition, J147 is very potent, has good medicinal chemical properties for a CNS drug, is apparently safe, and is orally active. Finally, unlike the current drugs approved for AD, J147 is neither an acetylcholine esterase inhibitor, an NMDA receptor antagonist, nor a phosphodiesterase inhibitor, yet it enhances cognition with a short-term treatment. Thus J147 is an exciting new compound with the potential to be an AD therapeutic by slowing disease progression through neuroprotection as well as providing immediate cognition benefits. These dual attributes improve the chances for success as a disease-modifying drug as well as in short-term AD clinical trials that use currently accepted approvable measures of outcome.

Currently, self-proclaimed "guerilla biotech" SciOpen Research Group (SRG) is investigating the substance for using it in ALS. They actually have an IndieGoGo campaign:

Eric and the SRG team created this crowdfunding campaign to fund the histopathology (microscopic tissue examination) lab work needed to better analyze the results of our already-ongoing study at the Salk Institute. Through this work, which will be published in a public Open-Access journal, SRG can bring J147 closer to the clinic for ALS patients.

Definitely worth checking out I find.

Anyway, just posted this because I thought it didn't get the attention it deserves when it was posted in /r/Nootropics.
I haven't read too deeply in to it myself, so I'm wondering: what do you guys think about this? Worth a group buy?

Edited by formergenius, 29 March 2014 - 12:31 PM.

[VERITAS INCORRUPTUS]

Certainly an interesting substrate.
Have you had chance to determine any viable therapeutic dose range/protocol from the studies?

[Dazzcat]

I've been following this curcumin derived compound for some time now, has some intriguing properties, from memory J147 is the combination of two molecules right?

Definitely worth a group buy in my opinion, I would like to help out if there is any interest.

Edited by Dazzcat, 29 March 2014 - 08:41 PM.

[Dazzcat]

Certainly an interesting substrate.
Have you had chance to determine any viable therapeutic dose range/protocol from the studies?

For the spatial memory performance tests, the mice were fed 10mg/kg/day of J147 in food for three months prior to tests and were aged to 23months.


Human dose = 10mg/kg/day X (3[mouse]/37[human]) = 0.81mg/kg/day


So average human of 70kg, this is 56mg per day, so relatively potent and the results of the two-day water maze seem impressive, the escape latency time was halved when compared to AD controls for the hidden platform trial.

Source: http://www.ncbi.nlm...._alzrt179-1.jpg

Edited by Dazzcat, 29 March 2014 - 09:36 PM.

[VERITAS INCORRUPTUS]

Thanks Dazzcat
Curious if there are effects of immediacy. ...?
They only tested one dose it seems...?...just a quick review so may have missed things...one dose is not the best way to assess an optimal dosing of course, but it is a start
As well, would have liked a study comparing i.p. to oral as well, just always interested in some level of bioavailability comparison.

[BigPapaChakra]

Have to do an essay, so I can't really look right now - any studies on the safety profile (I know curcumin/turmeric itself is very safe)? If it appears safe, I'm up for any potential group buy.

[Dazzcat]

Thanks Dazzcat
Curious if there are effects of immediacy. ...?
They only tested one dose it seems...?...just a quick review so may have missed things...one dose is not the best way to assess an optimal dosing of course, but it is a start

None of the tests were after only one dose from what I can see, you might be confusing it with scopolamine which was administered about 30mins prior to some tests. The Y maze, water maze and fear conditioning under the influence of scopolamine was performed when the mice had already consumed J147 each day for two weeks in their food, also the same tests were performed with AD mice model and J147 was consumed for each day for 3 months, so it's 14 doses vs 84 doses respectively. At least for the AD model, one of the proposed mechanism of action was through reducing levels of soluble amyloid beta proteins, therefore it would be expected for this to take some time, this would explain why the AD test group of mice had a much longer regime before trials. Unfortunately, none of the tests that I can see were performed on healthy mice, so this is yet another unknown when it comes to translating to the effects on healthy humans.

As well, would have liked a study comparing i.p. to oral as well, just always interested in some level of bioavailability comparison.

In vivo it was only tested via oral consumption which is the most relevant anyhow right? It had a half life of 1.5 hours in plasma and 2.5hours in the brain and 28% bioavailability in mice. My question would be, can this be translated to human pharmakenetics?

Edited by Dazzcat, 30 March 2014 - 07:43 PM.

[VERITAS INCORRUPTUS]

Thanks again Dazzcat...

There is no pure translation to human pharmokinetics, but murine models are generally a very good indicator for probability toward a similar pharmokinetic profile in humans.

I see they did assess bioavailability from what you noted. I did note it appeared there was not notation on any effects of 'immediacy', but I only noticed the 3 month assay in that again I only glanced the study.

I am always just curious as to that aspect of bioavailability, dosing protocols, et. al. In the end, as it is generally of practical viability for oral dosing, it certainly is always preferred to have the majority of the assays be on a per oral basis. However, again, one dose is a very limited assay, quite sub-optimal for gaining a keener insight into aspects of dosing.

As well, healthy murine model would of course be preferred for the purposes of most here. Take what you can get though, lol...hopefully they follow-up soon with some strong studies indicating some variable that would be of benefit to our interests

[niner]

J147 is only vaguely similar to curcumin. It's so highly modified that I really wouldn't even call it a curcumin derivative. You won't be able to say anything about its safety or PK based on what we know about curcumin. It's too chemically different.

[VERITAS INCORRUPTUS]

^^^^
I wholly concur; to even refer to it as a derivative seems odd. perhaps opportunistic within taking advantage of the high regard, perceived safety, and general overall familiarity of curcumin (and tumeric) itself

[Jeoshua]

Well, it's no stranger than people considering Sunifiram a Racetam, even tho it only has the vaguest resemblance to Piracetam, and even then only in the placement of the Oxygen groups. From what I've read on J147, it is one of the latest in a long line of research chemicals that originally started with actual Curcumin, reguardless of how far it's diverged from it's parent molecule.

[normalizing]

for the people who claim J147 is not even closely related to curcumin, how do you know exactly what this substance is ? and how is it produced to begin with ? from what i read, people who created it refered to it as more potent BBB form of curcumin with better bioavailability and permeability. so niner and whoever else mentioned this, how did you come to the conclusion this one is a completely different type of synthetic compound ?

[VERITAS INCORRUPTUS]

^^^^
Does this help you out?
http://www.tocris.co...26#.U0G1uPldWT8
http://en.wikipedia.org/wiki/Curcumin

[Dazzcat]

J147 is only vaguely similar to curcumin. It's so highly modified that I really wouldn't even call it a curcumin derivative. You won't be able to say anything about its safety or PK based on what we know about curcumin. It's too chemically different.

At least we can say that J147 may not impair the tumor suppressor P53 protein compared to curcumin as it lacks the alpha, beta-unsaturated ketone substituent, which is a good start. Though this is not to say it doesn't lack pro-cancer effects through other pathways, for example, while the main mechanism of action of J147 through up-regulating CREB has therapeutic effects on LTP, according to wiki it's also been associated with the growth of certain cancers.

Also there may be pro-oxidant effects similar to curcumin, but this is pure speculation on my part.

https://www.ncbi.nlm...pubmed/15090465

[formergenius]

the main mechanism of action of J147 through up-regulating CREB has therapeutic effects on LTP

Oh, is it? Which study is that? It's the first one I posted. No longer interested in the substance.

edit: Is there any way to induce neurogenesis without activating CREB? It seems even TrkB agonism (e.g. via 7,8-DHF) activates CREB.

Edited by formergenius, 06 April 2014 - 10:33 PM.

[VERITAS INCORRUPTUS]

the main mechanism of action of J147 through up-regulating CREB has therapeutic effects on LTP

Oh, is it? Which study is that? It's the first one I posted. No longer interested in the substance.

edit: Is there any way to induce neurogenesis without activating CREB? It seems even TrkB agonism (e.g. via 7,8-DHF) activates CREB.

I believe they go hand in hand; though as you pointed out in the other thread it is the regional expression that seems significant.

of relevance:
http://www.ncbi.nlm....pubmed/20569094
http://www.ncbi.nlm....pubmed/17876779
scientopia.org/blogs/scicurious/2010/05/19/the-neurogenesis-theory-of-depression-and-a-little-guy-called-creb/

With CREB induction there may be a heightened degree of learned patterning which can reinforce and promote negative patterning for those in prone states...? It would by the same token as well have a negative effect on fostering extinctions wherein such is a relevant concern.

Edited by VERITAS INCORRUPTUS, 06 April 2014 - 10:51 PM.

[Dazzcat]

the main mechanism of action of J147 through up-regulating CREB has therapeutic effects on LTP

Oh, is it? Which study is that? It's the first one I posted. No longer interested in the substance.

edit: Is there any way to induce neurogenesis without activating CREB? It seems even TrkB agonism (e.g. via 7,8-DHF) activates CREB.

Why is it that you have lost interest in J147 in favour of 7,8-DHF? I know next to nothing about 7,8-DHF, but there may be advantages with J147 in that it upregulates synthesis of both BDNF and NGF which translates to a more boarder activity given that NGF binds to TrKA receptors. No idea if 7,8-DHF has much effect on NGF, but if it activates CREB, then I would suspect so?

Also wouldn't direct agonism of TrkB potentially have some issues surrounding over stimulation or desensitization of that receptor?

Edited by Dazzcat, 06 April 2014 - 11:22 PM.

[formergenius]

Why is it that you have lost interest in J147 in favour of 7,8-DHF? I know next to nothing about 7,8-DHF, but there may be advantages in J147 in that it upregulates synthesis of both BDNF and NGF which translates to a more boarder activity given that NGF binds to TrKA receptors. No idea if 7,8-DHF has much effect on NGF, but if it activates CREB, then I would suspect so?

Also wouldn't direct agonism of TrkB potentially have some issues surrounding over stimulation or desensitization of that receptor?

Not in favour of either per se. I just don't want CREB activation, which, as discussed from here, doesn't always have positive effects. I already put down the money for 7,8-DHF, so that's why I'm still going to try it. As for TrkB agonism; yes I would suppose desensitization could pose a problem, however I'd think it to be be minimal on the short-term. Consider Cerebrolysin; there haven't been any adverse effects reported with long-term use as far as I know, yet it contains BDNF which is a TrkB agonist. Maybe I'm too quick to judge, but I would like to see a method of neurogenesis that doesn't involve CREB activation.

[Dazzcat]

Hey just out of interest I obtained a quote for J147 at 99% purity by the same respectable lab that synthesized EVP-6124, price includes HMNR and HPLC assays.

 

 

50g $2500us

100g $3860us

 

50gram price = $50/gram and ruffly $3.00 per dose of 60mg.*

 

100gram price = $38.60/gram and ruffly $2.30 per dose of 60mg.*

 

*One dose per day

 

 

 

 

 

What do you guys think? Still worth a shot?

 

Edited by Dazzcat, 15 April 2014 - 08:38 AM.

[formergenius]

Considering a minimum usage of 4 weeks, that would be $75. $100 to test it for 6 weeks, $150 for more than 2 months, the latter being a proper trial to determine efficacy (considering the observation that neurogenic substances generally take 4-6 weeks to become apparent in their effects). I think that is pretty fair price for initial exploratory purposes. Should feedback come in that it is a proper substance, I'm sure suppliers (looking at you, Ceretropic!) would catch up on it and offer it for an affordable price.

[Dazzcat]

I have a feeling we may not have enough interest to support a group buy at this stage. If we go with the 100g option at 3 grams each, then that's around 30 people. I could always inquire about a minimum order, if only a few of us are interested.

Regarding CREB and how it relates to depression and memory, it's pretty complex, a little beyond me. From what I gather, CREB activation in the hippocampus maybe beneficial for memory and depression, while in other brain areas such as nucleus accumbens seems detrimental to emotional health, but no idea how this would impact memory.

What would be helpful to know is if J147 has a global effect on CREB within the brain or whether it is specific to the hippocampus? Also if it does have global effects, then would the net result of increased CREB across different brain regions results in a positive change on emotional well being? 

 

Then we have the situation where when they remove CREB, anti-depressants have a faster onset of action, so perhaps we have to treat memory improvement and emotional improvement as separate beasts.

Edited by Dazzcat, 16 April 2014 - 09:26 PM.

[VERITAS INCORRUPTUS]

My apologies if this is not as well written or substantiated as i am just relating thoughts on the matter that i have culled over deliberating over this issue now and again over the past couple of weeks. Hopefully it makes some sense

 

It is perhaps best to put aside overly focusing on CREB for a moment as targeting specific focus on one protein will potentially cloud your understanding. It all comes down to the role of neuronal plasticity. Those prone to depression and/or have been debilitated via 'situationally induced' chronic depression have deficits within neuronal plasticity; such requires a restoration of the deficient and/or defective signalling pathways via enhanced neuronal plasticity. All agents that show a significant effect on alleviating depression will in some manner promote pathways that enhanced neurogenesis, synaptogenesis, and that which is related to correcting impairment of neuronal plasticity. Those that appear to promote such most directly and substantially will have the most rapid and pronounced effect.

 

Chronic depression atrophies the brain which needs to be restored via a normalization of defective mechanisms that sustain the impairment of neuronal plasticity within the psychoneurochemical environment present within depression, especially MDD.

 

Simply as well, enhancement of functional neuronal plasticity will have some effect to enhance cognitive functioning. Notably, the body always has a greater ability to reset to level that normalize as opposed to those that enhance supraphysiologically, however, all neurogenic/synaptogenic enhancement will display some fundamental cognitive enhancement to some level. Such can generally only be promoted to such a degree before feedback mechanisms will halt such progress.

 

Neurotrophic enhancers, that which enhances neuronal plasticity, improve fundamental underlying cognitive functional networks which both relates to improved cognitive ability and 'emotional' ability (the ability for the brain to better process response to 'emotional conditions'/'coping/situational adaptive mechanisms'). Nootropics generally improve signalling in some form, largely via neurotransmission enhancement in some manner, above the fundamental underlying neuronal network. Obviously as well, when such is directed in a manner that promotes mood enhancement related neurotransmission, there can be some temporary positive effect on mood, though this generally carries the potentiation of 'non-physical' withdrawal symptomatological expression (not specifically relating to that which characterizes classical drug-abuse withdrawal).

 

As such, getting back to a basic matter of regional specific matters, the NAc will only experience enhancement via the induction of different neuronal signalling that correlates with reward and substances that stimulates reward paradigms and underlying neuronal reward circuitry; that which is most pronounced within substances of abuse. The neurogenic substances that improve mood and tolerance toward 'emotional stressors' are the same that as well enhance underlying core cognitive functioning is my hypothesis (improve underlying functional brain circuitry so to speak); such are innately regionally specific to regions that do not encompass stimulation of neurogensis of significance within the Nac (though certainly I would recommend avoidance of using such with any drugs of abuse as such may promote an enhanced state of dependence/regional dysregulation).

 

J147 is potentially one of the 'paradigm substrates' for such class of substances that have a wholly positive effect as so described on promotion of 'brain repair/enhancement' and neuronal plasticity. Some references that have pertinence and that more fully elaborate:

 

http://bbcd.bio.unir...idepressant.pdf http://www.ncbi.nlm.nih.gov/pubmed/17049922 http://www.ncbi.nlm.nih.gov/pubmed/17876779 http://www.ncbi.nlm.nih.gov/pubmed/17634380 http://www.ncbi.nlm.nih.gov/pubmed/18497094 http://www.ncbi.nlm.nih.gov/pubmed/19541429 http://www.ncbi.nlm.nih.gov/pubmed/20186711 http://www.jneurosci.org/content/33/34/13673 https://www.sciencemag.org/content/338/6103/72 (very specific to the 'neurogenic interactome' as so termed) http://www.jmolecularpsychiatry.com/content/1/1/17 (regarding Nac/reward neurogensis) http://www.stembook.org/node/1128

Edited by VERITAS INCORRUPTUS, 17 April 2014 - 03:58 PM.

[ceridwen]

Desperate for a group buy

[ceridwen]

Desperate for a group buy

[Dazzcat]

^ Very unlikely it's going to happen due to lack of interest and concern over side effects from CREB up-regulation. I'd say it may take someone ordering a sample and then testing to spark some interest.

 

Edited by Dazzcat, 05 June 2014 - 10:01 PM.

[medicineman]

group buy!

[chris106]

A group buy MAY not be necessary - TLR will soon carry a trial stock of this.

However, the Jury still kinda seems to be out on if they are legit or not...

[medicineman]

A group buy MAY not be necessary - TLR will soon carry a trial stock of this.

However, the Jury still kinda seems to be out on if they are legit or not...

I don't see why teamtlr is held under so much more scrutiny than other vendors. I have had the most pleasant experience with them. They held on to my order (quite a large one) for over four months, and they have been nothing but accommodating. They have not hesitated to help, and have been extremely generous. They have not hesitated to provide papers, certification, etc. I am quite pleased, they have filled a gap in the nootropic community. Maybe I am blind to their evil ways, I don't know. I don't understand why they have been ostracized in here and reddit almost immediately upon mention of teamtlr.

All to their own I guess. Regarding the J147, I inquired about the delay, and this is the reply that I got:

The delay with J147 has occurred to this degree unexpectedly as the literature available for the synthesis was totally invalid for production.  We had three of our chemists try this method, and as well variations within the given method, and all with the same conclusion of total inefficacy.  This is highly irregular that the given literature for a synthesis is not in any way viable.  Notably, the original literature was a quite relatively uncomplicated synthesis and should have afforded our rapid production of the compound if such was at all viable, however, being that it is totally not viable we have to come up with an original and effective route.  This has proved very challenging as true effective routes for this are proving difficult as well.  However, we have had our chemists working diligently attempting to formulate viable routes to get to move to a production.

Though unfortunately we are in this position due to the given literature being totally invalid, costing us severe expense, effort, and loss in time, we still will be looking to afford some form of compensatory situation.  We wish to always afford as best to those who support Project TLR and to enable progressive research to best flourish.
We do anticipate word on what the status of the J147 is very shortly, and we will inform accordingly.

[chris106]

I don't see why teamtlr is held under so much more scrutiny than other vendors. I have had the most pleasant experience with them.

 

I didn't mean to scrutinize them in any way. I guess what I meant to say is that there aren't too many experience reports with them from users who have been around for a longer time. Yours is one more and I'm glad to hear you had good experiences with them.

I guess one point of critique was that they have a lot of products they don't exactly show the ingredients of, because of proprietary formulas.
For some this might be a no-go, for others not so much.

However, I plan to order from them in the future, so I'm glad you can vouch for them!

[thedarkbobo]

I for one am somewhere between getting Cerebr/Dihexa and waiting for this one. Prices are still quiet high for continuos dosing.

 

100% for 1g makes no sense for me unless it makes my memory /nearly/ photographic

 

I hope somebody with deeper pockets will try this one.