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interesting research from Lady Davis Institute
markus8174
Posted: Monday, October 8, 2018 9:31 AM
Joined: 1/25/2018
Posts: 135


Just read an article about research done at "Lady Davis Institute" and Dr. Joseph Flores concerning the blocking of Caspace1 thus inhibiting Caspace 6 (Caspace-6 has been implicated in AD) . The result was a reversal of Alzheimer's in mice.- Just what we need, smarter mice!.  As I have posted before, starting my wife on a "fenamate" class NSAID showed a significant improvement in the memory and judgement. The improvement lasted a couple of years for her. I wonder if the NSAID we are using effects the Caspace pathway that is evident in the inflammatory response. Caspace-1 inhibitors have been used in treating some autoimmune inflammatory diseases (according to the article). It will most likely be too late for anyone reading this post, but maybe our grandchildren will not have to endure this tragic disease. The article was on the "sciencedaily" webpage in the category of "health-Alzheimer's"
Lane Simonian
Posted: Monday, October 8, 2018 10:07 AM
Joined: 12/12/2011
Posts: 4359


Here is the link from Birdies post:

https://publications.mcgill.ca/medenews/2018/09/25/promising-novel-treatment-against-alzheimer-disease/

I did not respond to Birdies post because the possible reasons for the value of this treatment are complicated, but may be it is time to take a shot at it.

Fenamates do inhibit caspase 1 activation.

https://www.nature.com/articles/ncomms12504#f2

The inhibition of caspases limits microglia activation (immune cells found in the brain) and subsequent inflammation and oxidation.  However, some of the oxidative damage to the brain precedes caspase activation (and is responsible for that activation in the first place via DNA damage).  For the relative short-term then caspase inhibitors may be of some use in the treatment of Alzheimer's disease, but not likely over the long term.

To add: "Oxidative/nitrosative stress induces peroxynitrite formation that may be a key trigger of caspase1/inflammasome activation."


Lane Simonian
Posted: Monday, October 8, 2018 12:32 PM
Joined: 12/12/2011
Posts: 4359


I thought of one more thing.  You can directly inhibit caspase activation or you can inhibit the receptors that lead to caspase activation.  The problem with the latter is that there are many receptors that can trigger Alzheimer's disease (g protein-coupled receptors, receptor tyrosine kinases, and ionotropic receptors).  If one particular receptor is triggering the disease then perhaps inhibition of that receptor will do some good early on, but otherwise you have to consider the other receptors that may also be playing a role in triggering the disease.

For Fenamates:

Fenamate NSAIDs are inhibitors of cyclooxygenases, antagonists of non-selective cation channels, subtype-selective modulators of GABA(A) receptors, weak inhibitors of glutamate receptors and activators of some potassium channels. These pharmacological actions are all implicated in the pathogenesis of ischemic stroke. 

As Alzheimer's disease progresses, the most important receptor to inhibit is the NMDA glutamate receptor.



Birdies
Posted: Monday, October 8, 2018 12:36 PM
Joined: 7/3/2018
Posts: 19


Hi Marcus,

I posted on this a few days ago.  The drug was previously trialed for epilepsy.  I called the drug maker Vertex (vx-765) to find information, but they had none to offer.

Is your wife still taking Monteleukast?  Any improvement?   I would appreciate a response as soon as possible as we are taking my mom to neurologist tomorrow.

Thanks!


markus8174
Posted: Monday, October 8, 2018 9:17 PM
Joined: 1/25/2018
Posts: 135


Birdies wrote:

Hi Marcus,

I posted on this a few days ago.  The drug was previously trialed for epilepsy.  I called the drug maker Vertex (vx-765) to find information, but they had none to offer.

Is your wife still taking Monteleukast?  Any improvement?   I would appreciate a response as soon as possible as we are taking my mom to neurologist tomorrow.

Thanks!

Yep-still on monteleukast. She is up to 40mg/day--20 in AM 20 before bed. I can't say if there continues to be much improvement, but logic and executive functions seem more functional. Short term memory is very gone.

 



Birdies
Posted: Tuesday, October 9, 2018 8:37 AM
Joined: 7/3/2018
Posts: 19


Thanks for replying Marcus...  who knows maybe the VX-765 caspase-1 Inhibitor will be available thru a trial sooner than later.
Larrytherunner
Posted: Wednesday, October 10, 2018 7:01 AM
Joined: 2/26/2016
Posts: 118


VX-765 has been around for at least 15 years and has gone through many clinical trials for different diseases without success. Since it has never been approved by the FDA for the treatment of any disease, it is not available to the public.

 

It may take many years for this drug or any other anti-inflammatory drug to start in a clinical trial, and many more years for it to be completed. I am glad that researchers and drug companies are looking into treating brain inflammation due to an overactive immune system as a treatment for Alzheimer's. Meanwhile the anti-inflammatory drug montelukast (Singulair) is available now and it is cheap, effective and safe for long term use. It is a drug I have been using for two and a half years.


Lane Simonian
Posted: Wednesday, October 10, 2018 9:44 AM
Joined: 12/12/2011
Posts: 4359


I will at my own risk comment again as this is likely getting close to the heart of the disease.  

Montelukast inhibits caspase-3 activity and ameliorates oxidative damage in the spinal cord and urinary bladder of rats with spinal cord injury.

Spinal cord injury (SCI) leads to an inflammatory response that generates substantial secondary damage within the tissue besides the primary damage. Leukotrienes are biologically active 5-lipoxygenase products of arachidonic acid metabolism that are involved in the mediation of various inflammatory disorders including SCI. In this study, we investigated the possible protective effects of montelukast, a leukotriene receptor blocker, on SCI-induced oxidative damage...In conclusion, SCI caused oxidative tissue injury through the activation of pro-inflammatory mediators and by neutrophil infiltration into tissues, and the neuroprotective and antiapoptotic effects of montelukast are mediated by the inhibition of lipid peroxidation, neutrophil accumulation and pro-inflammatory cytokine release. Moreover, montelukast does not only exert antioxidant and antiapoptotic effects on the spinal cord, but it has a significant impact on the bladder tissue damage secondary to SCI.

Leukotriene receptors are g protein-coupled receptors that are involved in asthma and Alzheimer's disease.  If you have asthma and are taking Montelukast your risk for developing Alzheimer's disease is likely reduced.

Secondly, any overactivation of g protein coupled receptors likely leads to the overproduction of leukotriene which in turn leads to more oxidation and inflammation.

That is the good news.  The bad news is that in patients without asthma, oxidative damage precedes leukotriene formation so some damage has already been done to the brain.  How significant it is to reduce further damage remains to be seen.

Case reports suggest that Montelukast has some positive benefits.  It may be that more substantial benefits could be achieved with higher doses or it could be the limitations of the drug itself.

Case Series Using Montelukast in Patients with Memory Loss and Dementia

Cognitive decline and dementia are a growing problem as the population ages. Effective therapies to prevent and treat these problems are limited. Neuro-inflammation has been suggested as a cause of dementia []. Montelukast is a leukotriene receptor antagonist used to treat seasonal allergies and asthma. It acts as a cysteinyl leukotriene (CysLT1) receptor antagonist blocking the action of leukotrienes and decreasing inflammation []. Animal studies have shown that administering Montelukast improves memory function []. This case series of patients in a private Internal Medicine practice between 2013-2014 used Montelukast in patients with various levels of memory impairment and dementia. Patients were given Montelukast 80 mg daily in 4 divided doses every 2-3 hours. Memory impaired patients had subjective improvement in the memory and recall. Patients with dementia were noted by family members to be less agitated, but had no memory improvement at the doses used. Montelukast may be useful to treat memory impairment and dementia. Long term use might act as a prophylactic to prevent dementia.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420184/


Larrytherunner
Posted: Friday, October 12, 2018 7:07 AM
Joined: 2/26/2016
Posts: 118


Lane, you have a very convincing style of writing that gives readers the impression that you really know a lot about your subject. However you make a lot of statements and assumptions that are just not true or they are misleading. Here are some examples.

1. You say that if you have asthma and you are taking montelukast, your risk for developing Alzheimer's disease is likely reduced. This is misleading because it implies that if you don't have asthma, montelukast would not be effective. Montelukast works by blocking inflammation signaling molecules called leukotrienes from entering cells. It is true that in both diseases, leukotrienes may be a contributing factor. However the immune cells producing leukotrienes in the lungs are not the same as the immune cells producing leukotrienes in the brain, and leukotrienes produced outside the brain can not pass though the blood brain barrier unless there is some kind of brain injury. 

In the case of asthma, excess leukotrienes are produced primarily by neutrophils and mast cells. In the case of Alzheimer's, excess leukotrienes are produced within the brain by microglia and to a smaller extent, by astrocytes. Since leukotrienes within the brain and within the lungs come from different sources, why do you say that you have to have asthma for montelukast to be effective for Alzheimer's. Asthma patients do have a very small greater chance of developing Alzheimer's, but the vast majority of Alzheimer's patients do not have asthma. As for me, I don't have asthma, but montelukast has been very effective these two and a half years in treating my early stage dementia. I am feeling completely normal again.

2. Secondly you have got the inflammation process out of order. You say that G protein coupled receptor activation leads to an over production of leukotrienes. That is not the way it works. It is the over activation of microglia, and to a smaller extent, astrocytes, that produces excess leukotrienes. Receptors don't activate leukotrienes. They are gates that allow leukotrienes to be transported inside the cells.

3. Thirdly you used the mouse spinal cord model as an example. In this model, oxidative damage occures in minutes and hours, and leukotrienes may be a contributing factor in the damage. You say that montelukast may not help in Alzheimer's because the oxidative damage has already been done. Come on, Lane. Do you think this a good example of Alzheimer's? Oxidative damage in Alzheimer's goes on for years and decades. What the mouse model is a good example of is what would happen if someone got hit in the head with a baseball bat. Then oxidative damage would happen in minutes and hours, leukotriene producing neutrophils would infiltrate through the broken blood brain barrier, and it would be definitely too late for montelukast to be of help. 

Lane, you are a very good writer with a large scientific vocabulary. I can tell that you have spent a lot of time reading about Alzheimer's research and about various natural treatments. But your science is often quite bad and you often misinterpret research articles. Further it is often difficult when reading your posts determining whether you are referring to someone else's research or you are coming up with your own conclusions.

I do have to give you credit for one thing - persistence. It seems no matter how many mistakes you make, you never give up. I like that.

 


dolor
Posted: Sunday, October 14, 2018 10:37 PM
Joined: 11/9/2017
Posts: 255


Lane,
I can't get the right link to insert here, but I think you'll want to read NPR's recent articles on the research by Dr E. Ely of Vanderbilt UMC on ICU-caused delirium leading to dementia. 

Lane Simonian
Posted: Monday, October 15, 2018 10:32 AM
Joined: 12/12/2011
Posts: 4359


I thank you Larry for the lengthy, well-thought out response.  I know that you have a background in science, but your response showed even a greater depth of understanding than I expected.  I don't agree with some of your conclusions, but the quality of the analysis itself was first rate. 

To your first point in Alzheimer's disease the blood-brain barrier is damaged which allows a variety of compounds to enter the brain ranging for anti-amyloid drugs to cholesterol. 

https://www.ncbi.nlm.nih.gov/pubmed/29782323

Whether leukotrienes pass through a damaged blood-brain barrier in Alzheimer's disease is unknown.  Due to oxidative stress, leukotriene levels will be higher than normal whether one has asthma or not.

Secondly, overactivation of g protein-coupled receptors due to consequent DNA damage is a leading cause of microglia activation in Alzheimer's disease (and thus the overproduction of leukotrienes).  

https://www.frontiersin.org/articles/10.3389/fncel.2018.00258/full

Efforts to target specific g protein-coupled receptors have not been particularly effective in the treatment of Alzheimer's disease in part because so many of these receptors may play a role in the disease and secondly as the disease progresses both g protein-coupled receptors and microglia are damaged by oxidation. I don't expect Montelukast which is an antagonist of the cysteinyl-leukotriene receptor (a g protein-coupled receptor) to be much different, although perhaps it helps some individuals with mild cognitive impairment.  I would like to be surprised regarding this, though.

Thirdly, oxidative stress can be kept in check for years by glutathione and other antioxidants in the brain.  Eventually though oxidation and nitration damage critical receptors, transport systems, and enzymes in the brain.  This is likely the key to understanding and treating Alzheimer's disease:

Relationship between Inflammation and Oxidative Stress and Cognitive Decline in the Institutionalized Elderly

Objective. Cognitive impairment reduces quality of life and is related to vascular and neurodegenerative disorders. However, there is also a close relationship between these diseases and oxidative stress. Thus, the purpose of this study was to assess whether inflammation and oxidative damage are associated with low cognitive performance in the elderly with different housing conditions. Methods. The study groups consisted of 32 institutionalized and 25 noninstitutionalized Brazilian elderly subjects. Oxidative damage, inflammation markers, and cognitive function were evaluated. Results. The results demonstrated pronounced oxidative stress in the institutionalized elderly group, which also had a lower antioxidant status compared to noninstitutionalized subjects. High levels of proinflammatory cytokines were also observed in the institutionalized elderly. Furthermore, the raised levels of inflammatory markers were correlated with increased oxidative stress, and both were associated with low cognitive performance. However, based on multiple linear regression analysis, oxidative stress appears to be the main factor responsible for the cognitive decline. Conclusions. The findings suggest that individuals with lower antioxidant status are more vulnerable to oxidative stress, which is associated with cognitive function, leading to reduced life quality and expectancy.

https://www.hindawi.com/journals/omcl/2015/804198/



Lane Simonian
Posted: Monday, October 15, 2018 10:49 AM
Joined: 12/12/2011
Posts: 4359


Thanks, Dolor.  Here is a link to the interesting article.

https://www.npr.org/sections/health-shots/2018/10/10/654445929/when-icu-delirium-leads-to-symptoms-of-dementia-after-discharge

There could be a number of explanations for ICU delirium including high levels of stress and certain anesthetics.  Sepsis itself can lead to delirium.


dolor
Posted: Monday, October 15, 2018 2:33 PM
Joined: 11/9/2017
Posts: 255


Lane,
That's the one. Thanks for adding the link. There are embedded links to other articles as well as more info on Dr. Ely's research, as you probably noticed. 

It's just gruesome. But it is another clue in hell's mystery, isn't it. Infections, oxygen, trauma...I'm going to be following those crumbs next. 


Lane Simonian
Posted: Tuesday, October 16, 2018 9:32 AM
Joined: 12/12/2011
Posts: 4359


I noticed that this version of the article posted on the caregiver's forum was more insightful and somewhat more hopeful.

https://www.npr.org/sections/health-shots/2018/10/10/654898309/how-to-prevent-brain-sapping-delirium-in-the-icu

These are good areas to explore, Dolor.


Lane Simonian
Posted: Tuesday, October 16, 2018 10:02 AM
Joined: 12/12/2011
Posts: 4359


The authors of this article make several valuable observations even though they are not writing about Alzheimer's disease.

Oxidative stress plays a key role in the pathogenesis of cancer and many metabolic diseases; therefore, an effective antioxidant therapy would be of great importance in these circumstances. Nevertheless, convincing randomized clinical trials revealed that antioxidant supplementations were not associated with significant reduction in incidence of cancer, chronic diseases and all-cause mortality. As oxidation of essential molecules continues, it turns to nitro-oxidative stress because of the involvement of nitric oxide in pathogenesis processes. Peroxynitrite damages via several distinctive mechanisms; first, it has direct toxic effects on all biomolecules and causes lipid peroxidation, protein oxidation and DNA damage. The second mechanism involves the induction of several transcription factors leading to cytokine-induced chronic inflammation. Finally, it causes epigenetic perturbations that exaggerate nuclear factor kappa-B mediated inflammatory gene expression. Lessons-learned from the treatment of several chronic disorders including pulmonary diseases suggest that, chronic inflammation and glucocorticoid resistance are regulated by prolonged peroxynitrite production.

However, in case of chronic oxidative stress, once iNOS [inducible nitric oxide synthase] is totally activated, ordinary antioxidants provide little protection due to massive ONOO [peroxynitrite] generation. Thus, in case of chronic oxidative stress such as chronic hyperglycemia, dyslipidemia, tobacco smoking, exposure to allergens, prolonged drug use which are known to produce oxidative damage, conventional antioxidants become ineffective.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2984115/


The most effective peroxynitrite scavengers are methoxyphenols such as synapic acid, syringic acid, vanillin, eugenol, curcumin (although enhanced absorption is needed) have shown efficacy against Alzheimer's disease at various levels including clinical trials.  There are problems with a number of these trials, but the chances of them all being wrong is close to zero.

Here is one example:

 2009 Feb;12(1):124-30. doi: 10.1089/jmf.2007.0646.

Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng.

Abstract

To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.

 

 2012 Nov;15(6):278-82. doi: 10.1179/1476830512Y.0000000027.

Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease.

Abstract

OBJECTIVES:

Ginseng has been reported to improve cognitive function in animals and in healthy and cognitively impaired individuals. In this study, we investigated the efficacy of a heat-processed form of ginseng that contains more potent ginsenosides than raw ginseng in the treatment of cognitive impairment in patients with moderately severe Alzheimer's disease (AD).

METHODS:

Forty patients with AD were randomized into one of three different dose groups or the control group as follows: 1.5 g/day (n = 10), 3 g/day (n = 10), and 4.5 g/day (n = 10) groups, or control (n = 10). The Alzheimer's Disease Assessment Scale (ADAS) and Mini-Mental State Examination (MMSE) were used to assess cognitive function for 24 weeks.

RESULTS:

The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.

DISCUSSION:

 

These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.




 
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