Coronavirus, Alzheimer's Disease, and Peroxynitrite

Lane Simonian

I don't want to hijack Crushed's thread so I will start a new one.

The coronavirus can cause damage to the brain.  The mechanisms, if not the exact results, are the same as Alzheimer's disease.  In both cases, the brain's main defense against oxidative damage are depleted.  

Researchers at Baylor College of Medicine have investigated the effect of infection with COVID-19 on the levels of oxidative stress, oxidant damage and glutathione, the most abundant physiological antioxidant. Compared to healthy age-matched individuals whose samples were taken before the pandemic started in 2019, patients hospitalized with COVID-19 had significantly increased levels of oxidative stress and oxidant damage, and markedly reduced levels of glutathione. 

The hippocampi – the brain centres for learning and memory – are one of the earliest regions to be sabotaged by Alzheimer’s pathology. Our data revealed that GSH levels plummet in the hippocampi of patients with Alzheimer’s as well as those with MCI. The frontal cortices – brain CEOs responsible for a variety of executive functions – are chronologically affected later in Alzheimer’s. GSH levels mimic this chronology with no changes in the cortices of MCI patients, but significant reduction in those of Alzheimer’s patients. Interestingly, GSH remains unaffected in the cerebellum – a brain region unaffected by Alzheimer’s till late stages. It appears GSH decline is not ubiquitous but rather a region-specific phenomenon that appears to precisely map the progression of Alzheimer’s in our brains.

The decline in gluathione levels allows hydrogen peroxide and peroxynitrite to damage various receptors, transport systems, and enzymes in the brain which among other things lead to the depletion of acetylcholine which is needed for the retrieval of short-term memories.

Glutathione supplementation has been suggested as a treatment for Alzheimer's disease and Covid-19 but glutathione is not directly taken up by cells.

A better option is to use are very strong peroxynitrite scavengers such as panax ginseng/Korean red ginseg (studies on ginseng as a treatment for the coronavirus are very preliminary).

A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer’s disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer’s Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer’s disease.

Crushed

Sorry Lane but OPEN  LABEL  just screams worthless garbage

Lane Simonian

I want to try to hammer home the main parts of the argument, for what is true for the coronavirus is also very likely true for Alzheimer's disease:

Participation of nitrogen oxide and its metabolites in the genesis of hyperimmune inflammation in COVID-19

Despite the success in the tactics of treating COVID-19, there are many unexplored issues related to the development and progression of the process in the lungs, brain, and other organs, as well as the role of individual elements, in particular, nitric oxide (NO), and in the pathogenesis of organ damage. Based on the analyzed literature data, we considered a possible pathophysiological mechanism of action of NO and its derivatives in COVID-19. It can be noted that hyperimmune systemic inflammation and "cytokine storm" are enhanced by the production of NO, products of its oxidation ("nitrosative stress"). It is noted in the work that as a result of the oxidation of NO, a large amount of the toxic compound peroxynitrite is formed, which is a powerful proinflammatory agent. Its presence significantly damages the endothelium of the vascular walls and also oxidizes lipids, hemoglobin, myoglobin, and cytochrome, binds SH-groups of proteins [such as glutathione], and damages DNA in the target cells. This is confirmed by the picture of the vessels of the lungs on computed tomography and the data of biochemical studies. In case of peroxynitrite overproduction, inhibition of the synthesis of NO and its metabolic products seems to be justified. Another aspect considered in this work is the mechanism of damage by the virus to the central and peripheral nervous system, which remains poorly understood but may be important in understanding the consequences, as well as predicting brain functions in persons who have undergone COVID-19. According to the analyzed literature, it can be concluded that brain damage is possible due to the direct effect of the virus on the peripheral nerves and central structures, and indirectly through the effect on the endothelium of cerebral vessels. Disturbances in the central nervous regulation of immune responses may be associated with the insufficient function of the acetylcholine anti-inflammatory system. It is proposed to further study several approaches to influence various links of NO exchange, which are of interest for theoretical and practical medicine.

So all the same problems as Alzheimer's disease: declining levels of acetylcholine, declining levels of glutathione, damage to blood vessels, DNA damage, mitochondrial dysfunction, over-inflammation, and death of cells.

Larrytherunner

Lane, if Korean red ginseng was effective in treating Alzheimers, don't you think sellers of this product would want to do a FDA clinical trial. Then if it were successful, they could legally advertise it as a treatment for Alzheimers. Why hasn't a pharmaceutical company isolated the theraputic chemicals in Korean red ginseng and conducted an FDA clinical trial. If a trial is successful, then they could market it as a drug.

Korean red ginseng may contain some kind of stimulant that helps patients feel better and perhaps perform slightly better on tests, but so does caffeine in coffee. I don't think coffee or ginseng will slow down mental decline in Alzheimers.

Can ginseng trials done with no government supervision be trusted? There are lot of easy ways to get patients to perform better on tests, like helping with the answers or changing the answers later. Getting the preferred results is easy when no one is watching.

Lane Simonian

Inferences are among the most inaccurate forms of reasoning.  The expensive of running a large clinical trial versus the uncertain payoff of doing so is a trade off that not many companies are willing to do. 

I understand the limitations of open label trials, but with the exception of Korean red ginseng and Anavex 2-73 (blarcamesine) no drug or natural treatment has led to improvements in cognition in Alzheimer's disease over an 18 month to two year period (blarcamesine largely stabilized Alzheimer's disease for 148 weeks).

Here are some key components of Korean red ginseng and their effects.

Saponins

Accumulated evidence suggests that saponins have significant neuroprotective effects on attenuation of central nervous system disorders, such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease. However, our understanding of the mechanisms underlying the observed effects remains incomplete. Based on recently reported data from basic and clinical studies, this review highlights the proposed mechanisms of their neuroprotective function including antioxidant, modulation of neurotransmitters, anti-apoptosis, anti-inflammation, attenuating Ca(2+) influx, modulating neurotrophic factors, inhibiting tau phosphorylation, and regeneration of neural networks.

Polysaccahrides

In addition, NFP [non-saponin fraction from rich polysaccharide rich of Korean red ginseng] treatment ameliorated mitochondrial deficits in Aβ-treated HT22 cells. Moreover, NFP treatment significantly increased the AHN [adult hippocampal neurogenesis] and neuritogenesis of neural stem cells in both healthy and AD brains. Furthermore, NFP significantly increased cell proliferation in the HT22 cells. Finally, NFP administration significantly enhanced and restored the cognitive function of healthy and AD mice, respectively. Taken together, NFP treatment demonstrated changes in proteins involved in central nervous system organization/maintenance in aged brain and ameliorates AD pathology. Collectively, our findings suggest that NFP from KRG could be a potential therapeutic candidate for aging and AD treatments.

Saponins and Polysaccharides

Our analysis revealed that KRGE not only inhibited tau aggregation but also promoted the dissociation of tau aggregates. In addition, the KRGE fractions, such as saponin, nonsaponin, and nonsaponin fraction with rich polysaccharide, also inhibited tau aggregation and promoted the dissociation of tau aggregates. Our observations suggest that RG could be a potential therapeutic agent for the treatment of neurodegenerative diseases associated with tauopathy.

Polyphenols

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.

So the components in Korean red ginseng do everything that you would wish for in the treatment of Alzheimer's disease: scavenge peroxynitrite, inhibit tau aggregation, reverse tau aggregation, ameliorate mitochondrial dysfunction, reduce inflammation, promote the regeneration of neurons, and limit the death of neurons. And in doing so, it has lead to improvements in cognition in human beings with Alzheimer's disease.

Marta

You haven’t answered Larry’s question.

Lane Simonian

If something does not work as we expect it to, then it has to be fraud.  If it worked, everyone would have heard of it.  If it worked why isn't the company  pouring money into a phase three clinical trial.  Again, all inferences.

Coffee and ginseng are both stimulants, but the compounds in ginseng are more effective at treating Alzheimer's disease than those in coffee.  If you understand the pathways that lead to Alzheimer's disease and how different compounds work on those pathways, then the results make sense.  It does not mean there are not problems with the trials, but it probably means that what you see is actually what you see.

Marta

None of us understand the processes that lead to AD, as they have not yet been elucidated.

Lane Simonian

We actually do know a great deal of the pathways that lead to Alzheimer's disease.

https://www.genome.jp/pathway/hsa05010

https://www.frontiersin.org/files/Articles/131867/fncel-09-00091-HTML/image_m/fncel-09-00091-g003.jpg

Particular attention should be paid to the consequences following excessive peroxynitrite (ONOO-) formation, for example the depletion of the brain's main antioxidant glutathione (GSH), cell death (apoptosis), protein oxidation, DNA damage, inflammation, and mitochondrial dysfunction (left out is tyrosine nitration which inhibits neurogenesis in the hippocampus and which contributes to tau aggregation).  Now read above that ginseng contains several compounds that are peroxynitrite scavengers and then read about its effects on nearly everyone of the problems described above, and put the pieces together (or not if one prefers).

Marta

Lane:  these are the common denominators which induce apoptosis; not unique to AD. 

When will you understand this?

Lane Simonian

The first one is specifically for Alzheimer's disease; the second one applies to a series of neurodegenerative diseases including Alzheimer's disease

Marta

These are the same processes that are part of the common denominators that lead to cell death from many other diseases.  When will you recognize this?

Iris L.

What are we supposed to eat?  I eat a lot of antioxidants and green tea and pomegranate juice.

Iris

Crushed

Lane said

And in doing so, it has lead to improvements in cognition in human beings with Alzheimer's disease.

Lane also said

It does not mean there are not problems with the trials, but it probably means that what you see is actually what you see.
 

Its not a "problem"  you are putting lipstick on a pig, whatever you do it is still a pig.  Open label trials of  DEMENTIA drugs are garbage.   They don't have "problems"  They are worthless    You need double blind trials so you know what you see is real
  
 Here is what such a study looks like   

Randomized Controlled Trial. 2017 Sep;15(9):1111-1120.  

doi: 10.6004/jnccn.2017.0149.  

A Double-Blind, Randomized, Placebo-Controlled Trial of Panax Ginseng for Cancer-Related Fatigue in Patients With Advanced Cancer

Abstract

Background: Despite the high frequency, severity, and effects of cancer-related fatigue (CRF) on the quality of life (QoL) of patients with cancer, limited treatment options are available. The primary objective of this study was to compare the effects of oral Panax ginseng extract (PG) and placebo on CRF. Secondary objectives were to determine the effects of PG on QoL, mood, and function. Methods: In this randomized, double-blind, placebo-controlled study, patients with CRF ≥4/10 on the Edmonton Symptom Assessment System (ESAS) were eligible. ........
 Conclusions:Both PG and placebo result in significant improvement in CRF. PG was not significantly superior to placebo after 4 weeks of treatment. There is no justification to recommend the use of PG for CRF.

Lane Simonian

Keep eating and drinking these antioxidant, Iris.  You may already be doing so, but berries are very high in antioxidants; so too are many spices.

Here is likely the key to treating Alzheimer's disease and some other forms of dementia as well:

Defenses against peroxynitrite: selenocompounds and flavonoids

The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite...

Further, flavonoids, such as (-)-epicatechin, which occurs in green tea or cocoa as monomer or in the form of oligomers, can contribute to cellular defense against peroxynitrite.

The problem with many treatments for Alzheimer's disease is that they focus on triggers for the diseases or on points leading to the formation of peroxynitrite.  Amyloid is a secondary trigger so its removal has almost no effect on the progression of the disease.  Primary triggers such as oral bacterial infection or asthma can be targets but help only those with these primary triggers.  Since there are so many triggers and they are often combined (for example air pollution combined with pre-diabetes) focusing on one trigger is usually not very productive.

Several factors that increase oxidative stress in the brain also deplete antioxidants in the brain such as glutathione.  External antioxidants then have to be used to fight the disease.  These antioxidants such as those found in panax ginseng or in various essential oils via aromatherapy inhibit processes that lead to peroxynitrite formation, scavenge peroxynitrite, and reverse part of the damage that it does to the brain.

Is this a problem only in Alzheimer's disease?  No it is not.  This is indeed a contributor to cell death in many disease.  Different parts of the brain or other parts of the body may be affected and the degree and precise nature of damage may differ, but one type of disease or another is often the result.

Stuck in the middle

Iris, you had the right idea on another thread when you recommended the Mediterranean diet.  The easiest way to learn to eat healthy is to buy a diabetic cookbook.  The recommended diet for diabetes is simply to eat what any human being should eat for health.