Experimental Drug Reverses Cognitive Decline

Wishful

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https://newatlas.com/medical/drug-protein-production-reverse-age-related-cognitive-decline/

Not something we can ask our doctors for any time soon, but I thought it was interesting. ME researchers might want to see if the drug has an effect on PWME. Do they have any animals yet that can be used as ME test subjects? I'm pretty sure that there are quite a few PWME who would sign a legal waiver to try an experimental drug that has even a slight chance of helping.

If there are any animals that really do have ME, they'd probably be willing to pawprint a legal waiver too. :)
 

Hip

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Interesting how rapidly this drug ISRIB works (in mice): Drug Reverses Age-Related Mental Decline Within Days.

ISRIB treatment seems quite long-lasting too:
The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.
The safety of ISRIB looks good as well:
One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors, Walter says.

First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state, after which it can still respond normally to problems in individual cells.

Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form – against an aggressive viral infection, for example.
ISRIB stands for Integrated Stress Response (ISR) InhiBitor.



Here is some info I found on the integrated stress response (ISR).

Reading this makes me think an overactive ISR might play a role in ME/CFS, especially since the body activates the ISR in response to viral infection. The IST seems to be a kind of cell danger response, from what I can see.

When the ISR is triggered, it temporarily halts protein synthesis in the cell.

Obviously viruses which have entered a cell require protein synthesis to create copies of themselves, so if the body's ISR response kicks in and halts protein synthesis, then that will tend to stop viral replication.

The integrated stress response protects cells from a variety of harmful stressors by temporarily halting protein synthesis. However, chronic ISR activation has pathological consequences and is linked to several neurological disorders.
Source: here.


The integrated stress response can be triggered within a cell due to certain conditions. These can either be extrinsic or intrinsic factors.

Extrinsic factors include hypoxia, amino acid deprivation, glucose deprivation, viral infection and presence of oxidants.

The main intrinsic factor is endoplasmic reticulum stress due to the accumulation of unfolded proteins.
Source: here.
 

Pyrrhus

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Obviously viruses which have entered a cell require protein synthesis to create copies of themselves, so if the body's ISR response kicks in and halts protein synthesis, then that will tend to stop viral replication.
...Unless if the virus has an IRES or some other mechanism to continue viral protein synthesis despite de-activation of the translation initiation factor eIF2. (e.g. enteroviruses)
 

Hip

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.Unless if the virus has an IRES or some other mechanism to continue viral protein synthesis despite de-activation of the translation initiation factor eIF2. (e.g. enteroviruses)
Yes, I found a paper which said enteroviruses have a mechanism to counter ISR activation, so that they can continue making viral proteins.

However, perhaps enterovirus only partially counters the ISR activation in cells it infects — enough so that it can make its viral proteins, but with still some degree of ISR activation present in the cell, so that the cell has difficulty making its own proteins.



ISRIB has been licensed by Google's anti-aging research company Calico.

ISRIB (whose CAS number is 1597403-47-8) appears to be available at dozens of lab chemical suppliers, 10 mg costing around the $100 mark. And on Alibaba, one wholesaler is selling 1 gram for $100.

In terms of dose, this study injected mice with 0.25 mg/kg of ISRIB. That converts to a human 0.02 mg/kg, which for an 80 kg human is an injectable dose of 1.6 mg.

Though regarding the treatment of neurodegeneration diseases, the study says:
Unfortunately, ISRIB is not itself a candidate for such therapies, given its high insolubility, and new compounds are needed.
I am not sure how they were able to treat mice, but state that solubility issues prevent ISRIB from being used to treat human neurodegeneration diseases.



@mitoMAN might be interested in this.
 
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The insolubility issue might be seen in the posts at longecity forum where people appear to take it daily, but who even knows what they were taking, the thread doesn't end well https://www.longecity.org/forum/topic/68589-isrib-group-buy-new/
That said, who knows, it seems exciting, my brain fog is becoming progressively worse. I know prednisone helps but it's not exactly something one can do long term
 

Hip

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Interesting that people at Longecity were trying out ISRIB back in 2014.

Here are some excerpts from one report in that thread by someone who took ISRIB:
So far I'm very much surprised about the effect on the overall cognition. My personal experiences are, that ISRIB definitely has it's effects on memory consolidation, but in my experience it doesn't only influence the long term memory formation (as JPC suggested), but the short term memory as well.

It mens practicaly, that while reading a text, it is way much easier to remember the words, expression, and contexts as well (after 1-2 days).

I will try the Cambridge test soon, and send you an update, but without that I can say, ISRIB is a lot more potent, than anything, I used so far.

I'm not sure why, but I also feel a squeezing sensation in my forehead, followed by a potent perceptional increasement effect, similar to PRL, but a lot stronger

This report comes from (a presumed) healthy person; potentially the benefits of ISRIB might be greater in those with neurological disease.
 
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junkcrap50

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The insolubility issue might be seen in the posts at longecity forum where people appear to take it daily, but who even knows what they were taking, the thread doesn't end well https://www.longecity.org/forum/topic/68589-isrib-group-buy-new/
That said, who knows, it seems exciting, my brain fog is becoming progressively worse. I know prednisone helps but it's not exactly something one can do long term
Where were they buying their ISRIB? From alibaba?

Edit: Sorry, should have read the thread first. They're custom synthesizing it.
 

Hip

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Potential Dangers of ISRIB

Is ISRIB Dangerous for the Heart?

There is a report of one person who tried just two small doses of ISRIB (total of 15 mg intranasally) passing out and collapsing two days later. This is a young person with no previous history of passing out or having heart issues.

On going to hospital, the cardiologist performed an ECG (electrocardiogram), and found the heart was out of whack. Heart rate was erratic, varying form normal to extremely low (20 bpm). Heart arrhythmias in the form of atrial fibrillation were diagnosed. Electric shock to the heart (cardioversion) was planned, to knock the heart back to a normal rhythm; but then heart returned to normal rhythm on its own. On release from hospital, no further heart problems were observed, and heart enzymes were fine, suggesting no permanent damage.

Another person who took 110 mg of ISRIB over 4 days (partly intranasally, partly orally dissolved in DMSO), reported getting some chest discomfort, modest chest pain, and some shortness of breath lasting several days, which appeared one week after their last dose of ISRIB. This person had no previous heart issues, and and ECG and ultrasound performed by a cardiologist 6 months prior showed a healthy heart.

Other people have reported a slow heart rate while on ISRIB.


Can ISRIB Precipitate Psychosis and Hallucinations?

There is also a report of a high functioning autistic woman who suffered brain injuries as a child experiencing a short period of psychosis and hallucinations episode while taking ISRIB. She had experienced episodes of psychosis previously, but never with hallucinations. She previously had also taken ISRIB previously without such adverse effects.

These above reports come from a Telegram ISRIB group and a Discord ISRIB channel.


ISRIB-Like Compound Shown to Cause Anomalies in Dog Hearts

A compound called 2BAct, which works similarly to ISRIB, was found to cause significant cardiovascular anomalies in dogs.

To quote the paper:
The molecule was well-tolerated in the animal studies described here, and did not elicit any relevant effects in a rat cardiovascular (CV) safety study; however, significant anomalies were observed in a dog CV model. This CV safety liability makes this particular molecule unsuitable for human dosing.
Another paper found that the integrated stress response (ISR, which ISRIB inhibits) affects the heart. The paper states that the ISR regulates the autophagy and apoptosis (cell death) of cardiac progenitor cells. So taking ISRIB will have an affect on these cardiac cells.

And this paper says there is a connection between activating the ISR and arrhythmias. If there were a rebound effect on the ISR when you stop ISRIB, you might get higher levels of ISR after stopping, which might trigger arrhythmias. This rebound might explain why the heart issues experienced by the two people above only appeared some days after they stopped ISRIB.


ISRIB Shown In Vitro to Cause Accelerated Cell Death When ER Stress is Present

In cell culture studies where ER-stress was artificially induced, 24 hours of ISRIB treatment in vitro accelerated cell death (Sidrauski et al, 2013). This suggests that in diseases characterized by increased ER stress, UPR or ISR modulators such as ISRIB might be toxic. Ref: here.

Conditions which involve endoplasmic reticulum (ER) stress include viral infection, type 2 diabetes, atherosclerosis, metabolic syndrome, cardiovascular diseases, obesity and fatty liver disease. Ref: here.



ISRIB has never been tested on humans in any clinical trial, and although it can be bought at some research chemical and peptide suppliers, and is being researched by Google's Calico, to me, after learning more about ISRIB, it does not look like a safe substance to experiment with.

Indeed, ISRIB researcher Professor Susanna Rosi, who is exploring the potential benefits of ISRIB, stated "ISRIB is still far from being used to treat humans".

I was looking into ISRIB to se if it might be useful to help repair the mild brain damage I sustained from the viral encephalitis which triggered my ME/CFS; but after these reports of possible cardiac ill effects, I am not going to risk it.



Other ISRIB Observations and Facts

ISRIB can have potent nootropic effects (improved cognition). Some report these nootropic effects cease to appear after some months of ISRIB use.

More than one person has reported that ISRIB increases brain fog, but if you eat a lot of food, then the brain fog dissipates. So it requires eating a lot to keep brain fog at bay. Strange phenomenon.

Several people have reported blunted emotions while on ISRIB.

One report from a person trying ISRIB is here and here.

ISRIB appears to have a strong anti-cancer effect against aggressive fast-growing prostate cancers (though no effect against normal cancers).

One anecdotal report of a short course of ISRIB permanently fixing some prefrontal cortex brain damage in a Russian guy, caused by a car crash when he was a child. The repair to the brain was confirmed by MRI scans taken before and after the ISRIB treatment.

One report of a person who gave ISRIB to their grandmother who had terminal stage Alzheimer's. She began to remember everyone. But died after 4 months (this may have been from old age and her type 1 diabetes).

Some people have reported the inability to get drunk on ISRIB.

People have reported faster wound healing while using ISRIB.

ISRIB half-life in mice is 8 hours. Ref: here.
 
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