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Oxidation, Inflammation, and Alzheimer's disesae
Lane Simonian
Posted: Wednesday, May 2, 2018 1:06 PM
Joined: 12/12/2011
Posts: 4830


The understanding of Alzheimer's disease seems to be at a tipping point.  The belief that misfolded proteins (amyloid and tau) are the cause of Alzheimer's disease is now beginning to give way to the broader picture that inflammation and oxidation are critical mediators of the disease.  To that point is a study that just came out:

Potential new treatments for dementia and Alzheimer’s Disease

A study published in the journal Human Molecular Genetics has uncovered why clinical drug trials that aim to reduce proteins in the brain, associated with the onset of Alzheimer’s Disease and dementia have been unsuccessful. The findings are a promising sign for the development of new treatments using currently available drugs.

The research team, comprised of US and Australian scientists, sourced evidence from a broad scope of animal models and human studies of diseases linked to dementia, to demonstrate that inflammation is a significant cause rather than a symptom...

This study was a collaborative effort between Richards, the National Institutes of Health (U.S.) and the University of Adelaide’s Medical School. It has long been acknowledged that inflammation can intensify as dementia-related diseases advance, but establishing it as the cause is a new discovery. It has hitherto been assumed that inflammation merely remove tissue damage sustained due to the protein aggregates.  

https://www.news-medical.net/news/20180502/Potential-new-treatments-for-dementia-and-Alzheimere28099s-Disease.aspx

Protein kinase C is a key enzyme that triggers inflammation and oxidation in Alzheimer's disease.  Amyloid oligomers (and many other toxins) only do damage through activation of protein kinase C.  Or in other words, amyloid oligomers and other risk factors for Alzheimer's disease damage the brain via inflammation and oxidation.

"Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active."

The solutions would seem easy but they are not.  Inhibiting protein kinase C alpha activity early in Alzheimer's disease would seem a great target, but if you inhibit the enzyme too much you negatively affect memory and learning (plus inhibiting the enzyme does not reverse the damage already done).

Anti-inflammatory drugs would seem another easy target.  But whether those drugs work before or after oxidation may be critically important.

The main oxidant in Alzheimer's disease (peroxynitrite) may activate an immune response (via immune cells called microglia) as a result of DNA damage.  The inflammatory response may in turn lead to the production of more peroxynitrite.   Over time, peroxynitrite may also damage microglia.

The critical target then is not so much inflammation (although certain anti-inflammatories may help early on), but peroxynitrite.  As just one of many examples:

Inhibition of nitric oxide synthase expression in activated microglia and peroxynitrite scavenging activity by Opuntia ficus indica var. saboten.

Activated microglia by neuronal injury or inflammatory stimulation overproduce nitric oxide (NO) by inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) such as superoxide anion, resulting in neurodegenerative diseases. The toxic peroxynitrite (ONOO-), the reaction product of NO and superoxide anion further contributes to oxidative neurotoxicity.These results imply that Opuntia ficus indica may have neuroprotective activity through the inhibition of NO production by activated microglial cells and peroxynitrite scavenging activity.

The common name for Optunia ficus indica is nopal cactus or prickly pear (for anyone who might want to research some studies/advertisements).

 Find the right peroxynitrite scavengers and it is highly likely that you find effective treatments for Alzheimer's disease.

 


Lane Simonian
Posted: Friday, May 11, 2018 9:15 AM
Joined: 12/12/2011
Posts: 4830


This is likely the specific route to inflammation in Alzheimer's disease:

NADPH Oxidase–Derived Peroxynitrite Drives Inflammation in Mice and Human Nonalcoholic Steatohepatitis via TLR4-Lipid Raft Recruitment

Toll-Like Receptors in Central Nervous System Glial Inflammation and Homeostasis

The recent emergence of studies examining TLRs in the central nervous system (CNS) indicates that these receptors not only play a role in innate immunity in response to infectious diseases but may also participate in CNS autoimmunity, neurode-generation, and tissue injury.

Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death

Peroxynitrite is necessary and sufficient for PS [phosphatidylserine exposure] and neuronal loss

We have previously shown that coapplication of the inducible NO synthase inhibitor 1400W, the SOD mimetic MnTBAP, or the peroxynitrite scavenger FeTPPS with LTA prevented neuronal loss.

The key to preventing neuronal cell death in Alzheimer's disease is to remove peroxynitrite.


Lane Simonian
Posted: Saturday, May 12, 2018 9:34 AM
Joined: 12/12/2011
Posts: 4830


A once muddled picture is finally getting much clearer in my mind.

Several factors contribute to oxidation and those same factors usually but not always lead to the overproduction of amyloid.  So it is possible to have Alzheimer's disease without much or any amyloid.  Amyloid oligomers then further increase the production of oxidants.  But amyloid is rarely if ever the sole cause of oxidative stress.  Thus removing it does very little good.

Secondly the nitro-oxidant peroxynitrite causes inflammation by activating microglia and activated microglia in turn add to the production of peroxynitrite.  Amyloid oligomers and activated microglia are thus add on insults, they are not the sole causes of the disease.


Lane Simonian
Posted: Monday, May 28, 2018 10:35 AM
Joined: 12/12/2011
Posts: 4830


Here is some evidence that oxidative stress is the main trigger for cognitive impairment:

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: Friday, July 6, 2018 12:26 AM
Joined: 12/12/2011
Posts: 4830


This is what I have been saying for years:

 2002 Dec;21(6):506-22.

Risk factors for Alzheimer's disease: role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment.

Abstract

The etiology of Alzheimer's disease (AD) is not well understood. Etiologic factors, chronic inflammatory reactions, oxidative and nitrosylative stresses and high cholesterol levels are thought to be important for initiating and promoting neurodegenerative changes commonly found in AD brains. Even in familial AD, oxidative stress plays an important role in the early onset of the disease. Mitochondrial damage and proteasome inhibition represent early events in the pathogenesis of AD, whereas increased processing of amyloid precursor protein (APP) to beta-amyloid (Abeta) fragments (Abeta(40) and Abeta(42)) and formation of senile plaques and neurofibrillary tangles (NFTs) represent late events. We propose a hypothesis that in idiopathic AD, epigenetic components of neurons such as mitochondria, proteasomes and post-translation protein modifications (processing of amyloid precursor protein to beta-amyloid and hyperphosphorylation of tau), rather than nuclear genes, are the primary targets for the action of diverse groups of neurotoxins. Based on epidemiologic, laboratory and limited clinical studies, we propose that a combination of non steroidal anti-inflammatory drugs (NSAIDs) and appropriate levels and types of multiple micronutrients, including antioxidants, may be more effective than the individual agents in the prevention, and they, in combination with a cholinergic agent, may be more effective in the treatment of AD than the individual agents alone. In addition, agents, which can prevent formation of plaques or dissolve these plaques [oligomers instead] may further enhance the efficacy of our proposed treatment strategy.

Without peroxynitrite formation there are few oligomers and little inflammation.  So while reducing oligomers or inflammation may have some affect early on, it is anti-oxidants that need to be part of any treatment of Alzheimer's disease. 

As one example, peroxynitrite increases lipoxygenase activity and leukotrienes which in turn increase peroxynitrte formation  That is part of the reasons why drugs designed to limit leukotrienes or the receptors through which the operate (such as Montelukast) may have some early effect on the disease.  


12/15-Lipoxygenase Is Increased in Alzheimer’s Disease

Possible Involvement in Brain Oxidative Stress 

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1615676/

https://apps.childrenshospital.org/clinical/research/rosenberg/brain.html

 

 

 


Lane Simonian
Posted: Monday, June 29, 2020 7:16 PM
Joined: 12/12/2011
Posts: 4830


Three important findings from a recent study on antioxidants in the prevention and treatment of Alzheimer's disease.

A combination of antioxidants at increasing doses was more beneficial at preventing the debilitating disease than any other treatment currently available.

Evidence is also accumulating that combinations of antioxidants may be more effective, taking advantage of synergistic effects of appropriate antioxidants as well as a nutrient-rich diet to prevent and reverse AD.

This review focuses on nutritional, nutraceutical and antioxidant treatments of AD, although they can also be used in other chronic degenerative and neurodegenerative diseases.

https://medicalxpress.com/news/2020-06-antioxidant-cocktail-key-alzheimer.html

https://royalsocietypublishing.org/doi/10.1098/rsob.200084


Lane Simonian
Posted: Thursday, July 2, 2020 10:02 AM
Joined: 12/12/2011
Posts: 4830


Another study along similar lines:

Antioxidant treatment in acute ischemic stroke may delay the onset of Alzheimer's dementia

 

With normal ageing oxidative stress increases and is involved in causing degenerative diseases like Alzheimer's disease. An ischemic stroke significantly increases oxidative stress in the brain, and this may increase the rate of neuronal degeneration. The authors hypothesize that antioxidant treatment in acute ischemic stroke, by diminishing this oxidative imbalance, may delay the onset of clinically overt dementia...

To date there is growing evidence of the association of vascular risk factors like hypertension, high cholesterol levels or diabetes mellitus with cognitive impairment and Alzheimer's disease. Unfortunately, simply managing these risk factors had little effect in reducing the incidence of dementia. These factors, however, strongly increase the risk of a patient to suffer an ischemic stroke and incident stroke approximately doubles the risk of dementia. From the study of Saver published in 2006 we know that "each hour in which treatment fails to occur the brain loses as many neurons as it does in 3.6 years of normal aging"...

There is a considerable overlap between the oxidative stress-induced pathogenesis in ischemic stroke and Alzheimer's disease including mitochondrial dysfunction (the mitochondria being the main generators of energy in the cells), calcium overload of the cells, activation of different destructive enzymes by the excess intracellular calcium, aberrant gene transcription and expression, induction of autophagy (a process by which cells degrade their own cytoplasmic proteins and organelles) and activation of inflammatory responses...

In view of the implication of oxidative stress in the genesis of AD pathology, the authors hypothesize that with aging, in the presence of well-established vascular risk factors, and possibly with a genetic contribution, AD pathology develops slowly without clinically overt cognitive impairment. However, after a stroke there is a sudden burst in oxidative stress which accelerates the pathogenesis of dementia and leads to clinically obvious cognitive impairment. If this hypothesis would be proven the reason for reaching antioxidant treatment in acute ischemic stroke would be reinforced. Further studies in this direction with long follow-up periods would be needed. Nonetheless, in view of the high incidence and prevalence of the disease, the results could be rewarding.

 

https://www.eurekalert.org/pub_releases/2020-07/bsp-ati070220.php


HowDoYouDeal
Posted: Sunday, July 5, 2020 8:37 PM
Joined: 2/17/2019
Posts: 347


Nice work Lane!  So glad you are here, keeping us all current on what is going on and explaining it. Monti, your study postings are also quite impressive. For the Boards,Thank you!
HowDoYouDeal
Posted: Sunday, July 5, 2020 8:48 PM
Joined: 2/17/2019
Posts: 347


Hmm, prickly pear huh?

 

Reduces Inflammation

https://www.organicfacts.net/health-benefits/fruit/prickly-pears.htmlIn traditional medicine, the cactus fruit was mashed and applied topically to parts of the body that were inflamed. When consumed, the antioxidants and minerals in prickly pears can lower inflammation, particularly in conditions like arthritis, gout, or muscle strain.

  A Seoul National University study confirmed its anti-inflammatory properties. It can also be topically applied to eliminate the swelling of bug bites, which in fact is a method in use for hundreds of years. [13]


Lane Simonian
Posted: Monday, July 6, 2020 10:46 AM
Joined: 12/12/2011
Posts: 4830


Thank you, HowDoYouDeal.

I have not thought about prickly pear for a few years now.  Three years ago there was an study on prickly pear and brown seaweed for the treatment of Alzheimer's disease and Parkinson's disease  A compound derived from brown seaweed is now used as a drug against Alzheimer's in China, but for some reason not much work has been done on prickly pear.

https://www.sciencedaily.com/releases/2017/01/170109102443.htm

This was the first article that I read about prickly pear (Optimus ficus)

Inhibition of Nitric Oxide Synthase Expression in Activated Microglia and Peroxynitrite Scavenging Activity by Opuntia Ficus Indica Var. Saboten

Activated microglia by neuronal injury or inflammatory stimulation overproduce nitric oxide (NO) by inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) such as superoxide anion, resulting in neurodegenerative diseases. The toxic peroxynitrite (ONOO-), the reaction product of NO and superoxide anion further contributes to oxidative neurotoxicity. A butanol fraction obtained from 50% ethanol extracts of Opuntia ficus indica var. saboten (Cactaceae) stem (SK OFB901) and its hydrolysis product (SK OFB901H) inhibited the production of NO in LPS-activated microglia in a dose dependent manner (IC50 15.9, 4.2 microg/mL, respectively). They also suppressed the expression of protein and mRNA of iNOS in LPS-activated microglial cells at higher than 30 microg/mL as observed by western blot analysis and RT-PCR experiment. They also inhibited the degradation of I-kappaB-alpha in activated microglia. Moreover, they showed strong activity of peroxynitrite scavenging in a cell free bioassay system. These results imply that Opuntia ficus indica may have neuroprotective activity through the inhibition of NO production by activated microglial cells and peroxynitrite scavenging activity.

https://pubmed.ncbi.nlm.nih.gov/16807879/


Llewis
Posted: Sunday, August 2, 2020 8:45 AM
Joined: 2/9/2019
Posts: 13


Lane;

Have you run across any new findings that change your opinions on Anavex? I know PDD/RETT'S  results are due any day. Some really interesting studies for some other conditions it may help with I think.

Thanks much

Larry Lewis


Lane Simonian
Posted: Sunday, August 2, 2020 6:20 PM
Joined: 12/12/2011
Posts: 4830


I am just anxiously awaiting the results of Anavex's trials.  I saw one positive article last month, but I have not seen any new science in recent months.

https://seekingalpha.com/article/4357368-anavex-is-likely-to-report-positive-parkinsons-disease-trial-results-for-a2minus-73

I remain cautiously optimistic, but not based on anything new.


Llewis
Posted: Sunday, August 2, 2020 6:52 PM
Joined: 2/9/2019
Posts: 13


Thanks. I'm really excited to see their results. Have especially high hopes for Rett but think PDD and ALZ may be encouraging too with established dose titration. There's a lab study exploring Barth syndrome  and of course one place looking into possible use as Covid treatment. Mechanism of action may have multiple uses.

Lane Simonian
Posted: Sunday, August 2, 2020 7:52 PM
Joined: 12/12/2011
Posts: 4830


Thank you very much, Larry, for the additional information/applications.  It would be wonderful if Anavex 2-73 helps improve the lives of people with various diseases and conditions.
Llewis
Posted: Wednesday, August 5, 2020 3:30 PM
Joined: 2/9/2019
Posts: 13


Lane; I'm sure you've seen this but I'm very optimistic on early use of this drug.

Anavex got special access scheme approval from TGA.

Families suffering in Australia please research this drug or have your doctor do so. Also have him look if you're suffering from Parkinson's Dementia or have a child with Rett syndrome. Whole new approach.

Good luck



Llewis
Posted: Wednesday, August 5, 2020 5:19 PM
Joined: 2/9/2019
Posts: 13


When I referred to your dr in above post I should have said them not him. Sorry; this old age isn't working out. 8&lt

Lane Simonian
Posted: Wednesday, August 5, 2020 11:40 PM
Joined: 12/12/2011
Posts: 4830


This is very good news, indeed.  Thank you, Larry!