PERK/eIF2α-P activation in neurodegenerative diseases

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FatherOf2
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PERK/eIF2α-P activation in neurodegenerative diseases

Postby FatherOf2 » Sun Apr 23, 2017 11:02 am

I came across this article: http://www.nextbigfuture.com/2017/04/anti-dementia-drugs-will-soon-start-clinical-trials.html
"Scientists hope they have found a drug to stop all neurodegenerative brain diseases, including dementia... When a virus hijacks a brain cell it leads to a build-up of viral proteins. Cells respond by shutting down nearly all protein production in order to halt the virus's spread. Many neurodegenerative diseases involve the production of faulty proteins that activate the same defenses, but with more severe consequences. The brain cells shut down production for so long that they eventually starve themselves to death... Prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival"

Over-activation of PERK/eIF2α-P signalling is also observed in some genetic forms of autism. I quickly searched for natural supplements that would suppress the PERK/eIF2α signaling and found that alpha-linolenic acid does it: https://www.ncbi.nlm.nih.gov/pubmed/26399745. Alpha-linolenic acid should not be confused with alpha-lipoic acid, which is an anti-oxidant and used for chelation. Both acids are typically abbreviated as ALA. Alpha-linolenic acid is an omega-3 fatty acid found in seeds (chia, flaxseed, hemp), nuts (notably walnuts), and many common vegetable oils. Flaxseed oil is probably the most common source of alpha-linolenic acid. This acid is susceptible to oxidation and will become rancid more quickly than many other oils. That is why flaxseed oil is typically refrigerated.

FatherOf2
Posts: 1676
Joined: Mon Mar 11, 2013 1:37 am

Re: PERK/eIF2α-P activation in neurodegenerative diseases

Postby FatherOf2 » Sun Apr 23, 2017 11:31 am

It is interesting that "aluminum activates PERK-EIF2α signaling and inflammatory Proteins": https://www.ncbi.nlm.nih.gov/pubmed/26546554. A life-long accumulation of aluminum could be a probable cause of dementia.

Amother interesting fact that Baclofen, a medication studied for autism and found to improve communication and socialization through activation of GABA_B raceptors, also suppresses the PERK pathway: http://journal.frontiersin.org/article/10.3389/fncel.2016.00255/full

FatherOf2
Posts: 1676
Joined: Mon Mar 11, 2013 1:37 am

Re: PERK/eIF2α-P activation in neurodegenerative diseases

Postby FatherOf2 » Sun Jul 23, 2017 12:48 am

I came across another interesting article: Autism tied to mutations in gene that polices proteins https://spectrumnews.org/news/autism-tied-mutations-gene-polices-proteins/ "The researchers identified more than 40 mutations in three genes that activate EIF2A: GCN2, PERK and PKR". So, it appears that suppression of protein synthesis through phosphorylation of eIF2α is at the core of many autism cases. At the same time, I found the following article: https://corpina.com/extreme-nootropics-big-guns-cognitive-enhancement/. "Another member on the front lines of extreme nootropics is a class of drugs called Protein Kinase RNA-Activated inhibitors, or PKR inhibitors... Researchers at Baylor College of Medicine (BCM) have discovered that when the activity of PKR — a molecule normally elevtated during viral infections — is inhibited in the brain, mice learn and remember dramatically better... After administering a single dose of a PKR inhibitor to the experimental group of mice, they were able to finish the maze after only a single training session. The control group of mice needed several sessions to accomplish this."

So, how can we restore protein synthesis and network formation in the brain?

(1) I already mentioned Alpha Linolenic Acid, which suppresses the PERK/eIF2α signaling. Flaxseed or Ahiflower oils are the best sources of it. Ahiflower oil appears to be more potent.

(2) Gastrodin https://www.ncbi.nlm.nih.gov/pubmed/26987953. Extracted from the root of the exotic orchid, Gastrodia elata, to treat a range of cognitive problems ranging from vertigo and headaches to paralysis and seizures. Gastrodin has regenerative properties that include rebalancing neurotransmitters, increasing blood flow, decreasing memory loss, protecting brain functions during a stroke, and potentially reducing risk of Alzheimer’s and Parkinsons. A lengthy overview about Gastrodin can be found here: http://www.lifeextension.com/Magazine/2013/SS/Broad-Spectrum-Protection-Against-Brain-Aging/Page-01.

(3) Dibenzoylmethane, found in the root extract of Licorice, and an anti-depressant trazodone hydrochloride (Desyrel/Oleptro) reversed eIF2α-P-mediated translational attenuation in vitro and in vivo. Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity https://academic.oup.com/brain/article/140/6/1768/3737867/Repurposed-drugs-targeting-eIF2-P-mediated. New experimental drugs GSK2606414 and ISRIB are also mentioned.

(4) The other interesting supplement is EGCG extract from green tea. It doesn't directly inhibit PKR, but it inhibits secretion of HMGB1, a mediator of systemic inflammation, which is released following PKR activation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363608/. This action of EGCG is an added bonus on top of activation of BDNF and mast cell stabilization.


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