Protein PERK

[kjschy]

Hi to everybody, did anyone heard about hyperactivation of the Unfolded Protein Response (PERK )or UPR. and this medications Trazodone e il DBM.

Love Anna

[ncgardener799]

I am in the US and would like more information on your finding regarding trazodone. How can I get the article you mention? Thanks

[kjschy in reply to ncgardener799]

lamedicinainunoscatto.it/20... italian site they are related to unfolding protein PERK

they are the only medication tested on human

if u find other news pls let me know.

in this site:

ncbi.nlm.nih.gov/pmc/articl...

u will find something about Protein Perk in relation to the tau patology.

[kjschy in reply to kjschy]

lamedicinainunoscatto.it/20...

[kjschy in reply to ncgardener799]

click on second txt to ridirect in right site

[ncgardener799]

Thank you. I will need to ask someone to translate for me. IS this a medication that helps slow the folding of tau protein?

[kjschy in reply to ncgardener799]

Two new drugs to treat neurodegenerative diseases

BY SIMONE SALEMME -May 4, 201710425

What do diseases such as Alzheimer's disease, Parkinson's disease and the rarer prion diseases have in common? These debilitating and deadly neurological conditions, in addition to sharing a lack of drugs that can halt their progression, have at their base a process of neurodegeneration.

In a study published in Brain, Giovanna Mallucci and her team demonstrated how two drugs, Trazodone and DBM, already tested in humans for other diseases, are effective in interrupting the neurodegenerative process in a mouse model.

Rationale for the study

There are many factors involved in inducing and sustaining a neurodegenerative process, but recently one has emerged as a major player: hyperactivation of the Unfolded Protein Response or UPR.

This is a well-preserved response in mammals to a cellular stress situation such as the accumulation of misfolded proteins within the Endoplasmic Reticulum. When this occurs, the cell attempts to defend itself by blocking protein synthesis and increasing molecular chaperones in an attempt to remove the accumulation. If this is not achieved, the cell has no choice but to activate a process of self-destruction.

This would appear to contribute to the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), Fronto-Temporal Dementia (FTD), Progressive Supranuclear Palsy (PSP) and Creutzfeld-Jacob Disease (CJD).

In these diseases, one branch of the UPR is abnormally active, specifically the one in which an enzyme called PERK is involved, which, when phosphorylated, acts on its substrate eIFa2, in turn phosphorylating it.

High levels of PERK-p and eIFa2-p are temporally and spatially associated with the deposition of disease-specific misfolded proteins. It is on this branch that Dr Mallucci's team has focused its attention for the development of possible drugs.

The first drugs

To validate the hypothesis that inhibiting or reducing the activation of the UPR could interrupt the neurodegeneration process, the researchers developed and tested several drugs in a mouse model, including two that stood out for their effectiveness: GSK2606414 and ISRIB.

Both drugs, which act on the PERK/eIFa2 pathway, demonstrated a substantial neuroprotective action, leading to a beneficial effect regardless of the misfolded proteins involved. This is a remarkable result given its possible application to the wide range of neurodegenerative diseases.

Unfortunately, however, neither GSK2606414 nor ISRIB can be used in humans due to the pancreatic toxicity of the former compound and the insolubility of the latter.

This limitation, together with the encouraging results obtained from the UPR intervention, prompted researchers to search for drugs that could be used effectively and safely in humans.

In the search for a possible drug, two main strategies can be adopted: on the one hand, the long and complex production and testing of a new drug, and on the other, the search in the pharmacopoeia for a drug already approved for a specific condition, but whose action also extends to the therapeutic target under study. It is precisely this latter strategy that the team of researchers has undertaken.

The study

Firstly, the researchers opted for C. elegans as a model for studying this pathway, as exposure to tunicamycin causes the nematode to activate the UPR with an easily observable effect, i.e. growth inhibition. Any drug that acts by inhibiting the UPR leads to unblocking and allows the nematode to grow and enlarge.

Of the 1040 drugs in the NINDS Custom Collection 2, a large database of drugs currently available in neurology, 20 enabled the nematode to overcome the blockade of tunicamycin. From these 20 candidates, the researchers narrowed it down to two compounds: Trazodone and Dibenzoylmethane (DBM).

In in vitro tests, the two drugs were shown to restore protein synthesis by only partially inhibiting the UPR, which is beneficial as complete blockade was the basis of GSK2606414's toxicity.

Having established the efficacy of the compounds in vitro, the researchers then moved on to the mouse model, calculating equivalent doses for the mice and administering the compounds via food. Two in vivo models were used: one in which prion disease was induced and one in which taupathy (a category that includes AD, FTD and PSP) was replicated.

Surprisingly, in the majority of mice with prion disease, both Trazodone and DBM were able to prevent the onset of neurological symptoms: 80% and 71% of mice respectively, compared to 100% of mice in the control group in which the disease manifested itself clinically.

Considering the 20-30% of treated mice that showed signs of prion disease progression, it is possible that they received a lower dose because it was dependent on food intake, which unfortunately varied from mouse to mouse.

Finally, in the taupathy model, a neuroprotective action benefiting the hippocampus was demonstrated, in which the advanced atrophy present in untreated mice was not observed.

In addition, Trazodone showed an unexpected and interesting effect in this model: a reduction in p-tau levels. p-tau is an altered biomarker in taupathies and lowering its levels is of considerable interest as it is one of the main targets of Alzheimer's disease therapies.

Conclusions

In a field of high need for effective drugs such as neurodegenerative diseases, Trazodone and DBM are two promising options that could be tested in human trials in the near future.

[kjschy in reply to kjschy]

all this is dated 2017, i haven't find anything else

[ncgardener799]

Is this the English translation of the link you sent me, if so thank you!!!! It would have taken my friend a lot of time to translate given the scientific nature of the article. She speaks 3 languages, French and English are her strongest and Italian follows . That is really interesting. I am going to pass it on to my husbands movement disorder research neurologist. Also the director of Cure PSP in US. Thank you again.

[kjschy in reply to ncgardener799]

Please keep me inform if they find or have any suggestion.Good night