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New molecules reverse memory loss linked to depression, aging

aging memory depression reversion

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#1 Engadin

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Posted 14 February 2019 - 09:46 PM


Date: February 14, 2019   Source: Centre for Addiction and Mental Health   Summary: New therapeutic molecules show promise in reversing the memory loss linked to depression and aging. These molecules not only rapidly improve symptoms, but remarkably, also appear to renew the underlying brain impairments causing memory loss in preclinical models.    

New therapeutic molecules developed at Toronto's Centre for Addiction and Mental Health (CAMH) show promise in reversing the memory loss linked to depression and aging.

 

These molecules not only rapidly improve symptoms, but remarkably, also appear to renew the underlying brain impairments causing memory loss in preclinical models.

 

"Currently there are no medications to treat cognitive symptoms such as memory loss that occur in depression, other mental illnesses and aging," says Dr. Etienne Sibille, Deputy Director of the Campbell Family Mental Health Research Institute at CAMH and lead scientist on the study.

 

What's unique and promising about these findings, in the face of many failures in drug development for mental illness, is that the compounds are highly targeted to activate the impaired brain receptors that are causing memory loss, he says.

 

It took a series of studies -- the most recent appearing in January 2019 in Molecular Neuropsychiatry -- to reach this stage. First, Dr. Sibille and his team identified the specific impairments to brain cell receptors in the GABA neurotransmitter system. Then they showed that these impairments likely caused mood and memory symptoms in depression and in aging.

The new small molecules were invented to bind to and activate this receptor target. The idea was that they would exert a therapeutic effect by "fixing" the impairment, resulting in an improvement in symptoms. The molecules are chemical tweaks of benzodiazepines, a class of anti-anxiety and sedative medications that also activate the GABA system, but are not highly targeted.

 

A single dose of these new molecules was administered in preclinical models of stress-induced memory loss. Thirty minutes later, memory performance returned to normal levels, an experiment that was reproduced more than 15 times. In another experiment involving preclinical models of aging, memory declines were rapidly reversed and performance increased to 80 per cent after administration, essentially reaching levels seen in youth or earlier stages of adulthood. This improvement lasted over two months with daily treatment.

 

"The aged cells regrew to appear the same as young brain cells, showing that our novel molecules can modify the brain in addition to improving symptoms," says Dr. Sibille. He expects to start testing the molecules in clinical research in two years. "We've shown that our molecules enter the brain, are safe, activate the target cells and reverse the cognitive deficit of memory loss."

 

If successful, the potential applications are broad. Not only is there a lack of treatment for cognitive deficits in mental illness, but the brain improvements suggest the molecules could help to prevent the memory loss at the beginning of Alzheimer's disease, potentially delaying its onset.

 

These findings were presented today at the American Association for the Advancement of Science (AAAS) Annual Meeting in Washington DC.

 


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#2 toonamy

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Posted 15 February 2019 - 07:49 AM

I came looking today just to find out if there was any talk about this at longecity. Does anyone know what molecules they are talking about? This is very interesting research. Look forward to hearing wiser peoples take on it. 



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#3 Engadin

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Posted 15 February 2019 - 02:22 PM

Guess, by the way they 'unmention' those compounds's names in the article, they are in their way to file a patent. So until the protect their knowledge with it, they won't throw any more info than that until they start testing procedures. Just wait and see.

 

 


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#4 lrdmelchett

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Posted 10 March 2019 - 12:58 AM

Modified benzodiazepine to be more selective?

 

 

I'm going to guess they've got a decent GABA a5R antagonist/inverse agonist.  Ala AI5A  https://en.wikipedia...nverse_agonists

 

 

edit:

 

If their claims of remodeling / increased plasticity is true, well....that's just awesome.  Lot of speculation around GABAA5R improving that type of thing for awhile now.

 

Here's a link to the referenced study

 

https://www.karger.c...Abstract/496086

 

And, out of the numerous references cited, this comes up

 

Piantadosi SC, French BJ, Poe MM, Timić T, Marković BD, Pabba M, et al. Sex-Dependent Anti-Stress Effect of an α5 Subunit Containing GABAA Receptor Positive Allosteric Modulator. Front Pharmacol. 2016 Nov;7:446.

 

Good bet it's GABA a5.  Now, understanding why this new drug is a a5 PAM versus an inverse agonist is the interesting part.  a5 inverse agonists are reported to have nootropic properties (and some studies say antidepressant effects).  


Edited by lrdmelchett, 10 March 2019 - 01:34 AM.

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#5 Phoebus

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Posted 10 March 2019 - 02:12 AM

 


Edited by Phoebus, 10 March 2019 - 02:13 AM.


#6 lrdmelchett

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Posted 13 March 2019 - 01:46 AM

If anyone feels adventurous, there are other, albeit less selective and/or direct, ways to PAM GABA a5 receptor.

 

A couple of the easier options

 

- Ketamine

Upregulates GABRA5 (gene) expression with chronic dosing

This is a very indirect method - who knows what would happen

 

- Rilmazafone

https://www.mimaki-f...item_branch=001

Commercially available GABA a5 preferential PAM.  Minor effects on a2, a3.

Based on the receptor effect profile, I liken this to something like Alprazolam (Xanax).  

However, Alprazolam receptor affinity is reversed - prefers a2/a3 and less so on a5.

 

 

 

Starting at this page one can dig deeper in to all of the possibilities.  

https://en.wikipedia.org/wiki/GABRA5



#7 Mind

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Posted 13 March 2019 - 05:03 PM

Guess, by the way they 'unmention' those compounds's names in the article, they are in their way to file a patent. So until the protect their knowledge with it, they won't throw any more info than that until they start testing procedures. Just wait and see.

 

That is what I was thinking as well. They would like to keep it a guarded secret in order to market the compounds. Hopefully it will make it to market quickly. Regulations can sometimes slow things down.



#8 psilot

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Posted 29 March 2019 - 06:32 AM

I found the wiki page and its patent

 

https://en.wikipedia.org/wiki/GL-II-73

https://patents.goog...ent/CA3016491A1

 

Is it possible to do a custom synth?

 


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#9 Oinen

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Posted 30 March 2019 - 07:47 PM

'Is it possible to do a custom synth?'

Depends, some things are harder and have more room for error to synth than others

The fact that it is so targeted is quite insane though. Interesting stuff.... just shows how complex all this stuff is. You heal one thing, but that just stops further issues - you also have to heal the damage...



#10 lrdmelchett

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Posted 02 April 2019 - 12:19 PM

If anyone feels adventurous, there are other, albeit less selective and/or direct, ways to PAM GABA a5 receptor.

 

A couple of the easier options

 

- Ketamine

Upregulates GABRA5 (gene) expression with chronic dosing

This is a very indirect method - who knows what would happen

 

- Rilmazafone

https://www.mimaki-f...item_branch=001

Commercially available GABA a5 preferential PAM.  Minor effects on a2, a3.

Based on the receptor effect profile, I liken this to something like Alprazolam (Xanax).  

However, Alprazolam receptor affinity is reversed - prefers a2/a3 and less so on a5.

 

 

 

Starting at this page one can dig deeper in to all of the possibilities.  

https://en.wikipedia.org/wiki/GABRA5

 

 

I found the wiki page and its patent

 

https://en.wikipedia.org/wiki/GL-II-73

https://patents.goog...ent/CA3016491A1

 

Is it possible to do a custom synth?

 

 

 

 

FYI, Rilmazafone is a prodrug (metabolized to) GL-II-73.  It's commercially available, as linked above, but with warning below.

 

Unfortunately, GL-II-73, is not completely a5 selective.  It hits a2, a3 at about 50% that of a5.  This means taking Rilmazafone or GL-II-73 carries similar physical dependence risk as classical benzos.

 

Reformed-Redan, on this forum, is having a custom synth done of an a5 selective partial agonist (not sure if one would need full agonism at a5 to get the reported effect).   

 

I'm doing both cause I'm impatient - and have had experience with benzo dependence.  So, I'm wading in very slowly with Rilmazafone so to not get myself in to too much trouble.

 

 

I just need to find cognitive tests that would measure the reported effect objectively.  Ideas?



#11 psilot

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Posted 04 April 2019 - 01:06 AM

You mean Imidazenil?

If it really helps with memory issues I think you can tell it. I have never seen nootropics reviews that come with test scores.

 

FYI, Rilmazafone is a prodrug (metabolized to) GL-II-73.  It's commercially available, as linked above, but with warning below.

 

Unfortunately, GL-II-73, is not completely a5 selective.  It hits a2, a3 at about 50% that of a5.  This means taking Rilmazafone or GL-II-73 carries similar physical dependence risk as classical benzos.

 

Reformed-Redan, on this forum, is having a custom synth done of an a5 selective partial agonist (not sure if one would need full agonism at a5 to get the reported effect).   

 

I'm doing both cause I'm impatient - and have had experience with benzo dependence.  So, I'm wading in very slowly with Rilmazafone so to not get myself in to too much trouble.

 

 

I just need to find cognitive tests that would measure the reported effect objectively.  Ideas?

 



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#12 Rorororo

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Posted 11 April 2019 - 03:13 AM

Area1255 Can you have this synthesized?!? 


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