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peroxynitrite scavengers treat Alzheimer's disease
Lane Simonian
Posted: Saturday, December 29, 2012 10:25 AM
Joined: 12/12/2011
Posts: 4063


Peroxynitrite scavengers will treat Alzheimer's disease in the earliest stages and peroxynitrite scavengers will treat Alzheimer's disease in the latest stages.  Everything from mice studies to case studies to small clinical trials indicate that this is true.  It is not a matter that mice studies and case studies are often unreliable and that the human clinical trials were small.  It is a matter that the results are the same time and time again.  The following is just a small sample. 

 

Conclusion

Geniposide [in the fruit of Gardenia jasminoides Ellis] can improve cognitive function of the double transgenic mouse model at early and late-stage of Alzheimer’s disease, with a possible mechanism related with neuroprotective and anti-inflammatory activities. The study suggested that oral supplementation of geniposide might be a potential therapeutic strategy for the treatment of early- and late-stage of Alzheimer’s disease.

 

Rosemary for Alzheimer's treatment  


 

My mother is in the final stages of Alzheimer's and was given a rough estimate of only 6 more months of life back in November. As is very common, her condition can change from day to day but still in a general direction for the worse. She reached the point where, if she was even awake at all, she couldn't communicate anymore and hardly showed the sign of being aware of my presence. I've been using alternative medicine for a few years now to treat my depression, anxiety, and also for general health. I've since discovered the overlooked value of the herb Rosemary and now use it to treat the symptoms of my depression. I've also noticed better clarity of thought along with an improved short term memory. I was able to get the doctor's permission to give this herb to my mother and we figured at least it couldn't hurt. Much to my surprise, there's been a noticable change. There have been quite a few day now where my mom has been more focused and alert than she's been in a long time. I even got some news from one of her nurses who said my mother had a brief conversation with her. Its been at least a year or two since I can remember anything like that. This change has also been noticed by others on the nursing staff as well as her doctor, who is very surprised. Now I'm not suggesting this is any kind of a "cure" for Alzheimer's but the improvement in my mother's condition is something to be said about Rosemary and it's given me some more quality time with her that I thought had been thing of the past.........Gary
 

If the rosemary given was in the form of an herb, the critical compound would be rosmarinic acid. 

 

2007 Jun 18;180(2):139-45. Epub 2007 Mar 12.

A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).

Source

Department of Neuropsychopharmacology & Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.

 

 

These results demonstrated that the memory protective effects of RA in the neurotoxicity of Abeta(25-35) is due to its scavenging of ONOO(-), and that daily consumption of RA may protect against memory impairments observed in AD.

 

http://www.ncbi.nlm.nih.gov/pubmed/17420060 

 

If the rosemary was given via aromatherapy the critical compound is eugenol. 

 

Eugenol inhibits Aβ-induced excessive influx of calcium ion into neurons that causes neuronal death.

 

http://www.ingentaconnect.com/content/ben/cbc/2006/00000002/00000001/art00005 

 

The results of clinical trials in which peroxynitrite scavengers were used to treat Alzheimer's disease. 

 

Objective: Recently, the importance of non-pharmacological therapies for dementia has come to the fore. In the present study, we examined the curative effects of aromatherpay in dementia in 28 elderly people, 17 of whom had Alzheimer's disease (AD).

Methods: After a control period of 28 days, aromatherapy was performed over the following 28 days, with a wash out period of another 28 days. Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening. To determine the effects of aromatherpay, patients were evaluated using the Japanese version of the Gottfries, Brane, Steen scale (GBSS-J), Functional Assessment Staging of Alzheimer's disease (FAST), a revised version of Hasegawa's Dementia Scale (HDS-R), and the Touch Panel-type Dementia Assessment Scale (TDAS) four times: before the control period, after the control period, after aromatherpay, and after the washout period.

Results: All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.

Conclusions: In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.

 

http://onlinelibrary.wiley.com/doi/10.1111/j.1479-8301.2009.00299.x/abstract 

 

Conclusions: Melissa officinalis [lemon balm] extract is of value in the management of mild to moderate Alzheimer's disease and has a positive effect on agitation in such patients.

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1738567/ 

 

CONCLUSIONS:

The results of this study indicate the efficacy of S. officinalis [sage] extract in the management of mild to moderate Alzheimer's disease. Moreover, S. officinalis may well reduce agitation of patients but this needs to be confirmed.

 
 

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.

 
 
Conclusion: The results of our clinical trial show that Bacopa monnieri standardized extract (Bacognize® 300 mg twice a day orally) for 6 months results in improvement in some aspects of cognitive functions in geriatric patients suffering from Alzheimer’s disease. While the above results are encouraging given the improvement in cognitive functions in geriatric Alzheimer’s disease patients, further studies that include a control group are required to validate these results.
 
 
And the conclusion drawn from someone who has reviewed the studies on the use of peroxynitrite scavengers in the treatment of Alzheimer's disease. 
 
[Clinical trials with over-the-counter supplements have concentrated either on
items which suppress inflammation, or on antioxidants which scavenge oxygen
derived free radicals. Most of these items have proved to be worthless in the
treatment of Alzheimer's disease. Similarly most drugs used to treat Alzheimer's
disease do little to slow the deterioration, but instead offer a mild temporary
symptom relief. However, evidence has been accumulating that the primary driver
of Alzheimer's disease is a nitrogen derived free radical called peroxynitrite,
which may mediate both amyloid and tau accumulation as well as their toxicity.
Excellent results have been obtained with peroxynitrite scavengers, with
reversals of Alzheimer's disease in human clinical trials being repeatedly
demonstrated. IMHO, the only thing which may be  preventing the abolition of
Alzheimer's disease is the mental inertia of scientists, as well as the
bureaucrats who fund them. Unfortunately, most bureaucrats keep throwing money into repeatedly testing discredited interventions, while ignoring successful
ones. Common sense is anything but...]
 
Peroxynitrite scavengers will not currently cure Alzheimer's disease.  Some peroxynitrite scavengers, such as those found in some essential oils, can in some cases increase anxiety either on their own or in combination with other medications.  Some essential oils can trigger allergic reactions including headaches,  nausea,and breathing problems. 
The long-term use of Bacopa monnieri is not recommended because of possible damage to the liver.  Essential oils used as tinctures can cause similar problems and should not be attempted without the help of a licensed aromatherapist (if it should be attempted at all). 
 
My larger point is this, the evidence that peroxynitrite scavengers can be used to treat Alzheimer's disease at any stage is large and impressive.  The fact that researchers and Alzheimer's organizations in the United States are ignoring this information is a tragedy.  The path forward is there, but the powers that be don't seem to want to take it (God knows that I have tried).  
 

 


Lane Simonian
Posted: Saturday, December 29, 2012 11:58 PM
Joined: 12/12/2011
Posts: 4063


Peroxynitrite scavengers may also have some use in the treatment of vascular dementia, lewy body dementia, and frontotemporal lobe dementia. 

 

http://en.cnki.com.cn/Article_en/CJFDTOTAL-AHYY201203008.htm 

 

https://docs.google.com/viewer?a=v&q=cache:Qbjcvl5_dkUJ:catalyticlongevity.org/prepub_archive/Lewy%2520body%2520diseases.pdf+peroxynitrite+scavengers+dementia+mccarty&hl=en&gl=us&pid=bl&srcid=ADGEESiDQ4Dx2VYoNApSfXTC6Wbb7NCL1bpemqKsoIue598IVU1YdtdUGUIcmc51uanEHl22ylaU2XZSxsi_SBZ6RXVjdD6P7TYSJDnU-feb-h09hYEQitnSovzLdMj6Q8Z0F9sKW4GQ&sig=AHIEtbRHr07UV5AvJFNUTQB_JdWNToVgXQ 

 

http://www.ncbi.nlm.nih.gov/pubmed/21272180 


Serenoa
Posted: Sunday, December 30, 2012 4:43 AM
Joined: 4/24/2012
Posts: 482


Impressive evidence! Thanks for posting this summary.
Serenoa
Posted: Wednesday, January 2, 2013 2:36 AM
Joined: 4/24/2012
Posts: 482


Lane, what do you think of Minocycline as a peroxynitrite scavenger?

 

 

Neuroprotection by minocycline caused by direct and specific scavenging of peroxynitrite.

 

 

Abstract

Minocycline prevents oxidative protein modifications and damage in disease models associated with inflammatory glial activation and oxidative stress. Although the drug has been assumed to act by preventing the up-regulation of proinflammatory enzymes, we probed here its direct chemical interaction with reactive oxygen species. The antibiotic did not react with superoxide or (•)NO radicals, but peroxynitrite (PON) was scavenged in the range of ∼1 μm minocycline and below. The interaction of pharmacologically relevant minocycline concentrations with PON was corroborated in several assay systems and significantly exceeded the efficacy of other antibiotics. Minocycline was degraded during the reaction with PON, and the resultant products lacked antioxidant properties. The antioxidant activity of minocycline extended to cellular systems, because it prevented neuronal mitochondrial DNA damage and glutathione depletion. Maintenance of neuronal viability under PON stress was shown to be solely dependent on direct chemical scavenging by minocycline. We chose α-synuclein (ASYN), known from Parkinsonian pathology as a biologically relevant target in chemical and cellular nitration reactions. Submicromolar concentrations of minocycline prevented tyrosine nitration of ASYN by PON. Mass spectrometric analysis revealed that minocycline impeded nitrations more effectively than methionine oxidations and dimerizations of ASYN, which are secondary reactions under PON stress. Thus, PON scavenging at low concentrations is a novel feature of minocycline and may help to explain its pharmacological activity.

 

 

 http://www.ncbi.nlm.nih.gov/pubmed/21081502 

 

 

I have read before that antibiotics have helped with AD. But, it worries me that their effect on healthy gut flora is devastating, and I believe restoring diversity and quality of these symbiotic microorganisms is critical to improving immune system functioning.

 

 


Lane Simonian
Posted: Wednesday, January 2, 2013 3:27 PM
Joined: 12/12/2011
Posts: 4063


Minocycline and other tetracylcine antibiotics are indeed peroxynitrite scavengers and have been shown to have some beneficial effects for people with Alzheimer's disease, but just like you I am leery of this approach in part because of the potential damage done to good bacteria. 

 

http://antibioticsfor.com/alzheimer.phtml 

http://www.ncbi.nlm.nih.gov/pubmed/9018471 


Lane Simonian
Posted: Sunday, January 6, 2013 5:29 PM
Joined: 12/12/2011
Posts: 4063


This is another article in which the authors basically say that peroxynitrites are responsible for Alzheimer's disease. 

 

2013 Jan;28(1):43-51.

The pathophysiology of triose phosphate isomerase dysfunction in Alzheimer's disease.

Source

Molecular Physiology and Channelopathy Laboratory, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), Barcelona, Spain. marta.tajes@upf.edu.

Abstract

Alzheimer's disease (AD), the most prevalent neurodegenerative disease worldwide, has two main hallmarks: extracellular deposits of amyloid β-peptide (Aβ) and intracellular neurofibrillary tangles composed by tau protein. Most AD cases are sporadic and are not dependent on known genetic causes; aging is the major risk factor for AD. Therefore, the oxidative stress has been proposed to initiate the uncontrolled increase in Aβ production and also to mediate the Aβ's deleterious effects on brain cells, especially on neurons from the cortex and hippocampus. The production of free radicals in the presence of nitric oxide (NO) yields to the peroxynitrite generation, a very reactive agent that nitrotyrosinates the proteins irreversibly. The nitrotyrosination produces a loss of protein physiological functions, contributing to accelerate AD progression.

 

http://www.ncbi.nlm.nih.gov/pubmed/23233058 

 

 

Oxidation can be reversed; whether nitration is irreversible is still an open question.  More importantly, if since the mid-1990s, scientists have known that peroxynitrite-mediated damage is widespread in Alzheimer's disease, how come almost no U.S.-born scientists has studied the use of peroxynitrite scavengers to treat the disease, and if peroxynitrites are not central to the pathogenesis of Alzheimer's disease, how come foreign scientists have been successful at one level or another (in vitro, in mice, in human beings) in partially reversing Alzheimer's disease with peroxynitrite scavengers? 

 

 


Lane Simonian
Posted: Sunday, January 6, 2013 5:52 PM
Joined: 12/12/2011
Posts: 4063


More proof in the pudding (or in the garlic sauce). 

 

Description

L-Deoxyalliin is a water soluble organosulfur compound derived from garlic and is the most abundant constituent of aged garlic extracts. It has neuroprotective and antioxidative activities, reducing edema formation in the ischemic brain by inhibiting free radical-mediated lipid peroxidation and preventing neuronal cell death in cerebral ischemic insult by specifically scavenging peroxynitrite at concentrations up to 100 μM.1 L-Deoxyalliin also demonstrates various anti-amyloidogenic properties in experimental models of Alzheimer’s disease.2  
 

L-Deoxyalliin New

Cayman Chemical Item Number 14014

NSC 96449; S-Allyl-L-cysteine (CAS 21593-77-1)

L-Deoxyalliin (CAS 21593-77-1)

 
See more  

 

 

 

 

 

Review Article

The Antioxidant Mechanisms Underlying the Aged Garlic Extract- and S-Allylcysteine-Induced Protection

1Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Insurgentes Sur 3877, 14269 México, DF, Mexico
2Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Insurgentes Sur 3877, 14269 México, DF, Mexico

 

 

The aforementioned evidence serves to suggest that SAC might prevent the progression of AD by multiple mechanisms: antioxidant, antiamyloidogenic, anti-inflammatory, antitangle, and antiglycative activities (Figure 6). However, further studies are essential to determine if SAC is capable of displaying all these proprieties in humans.

 

Figure 6: S-allylcysteine (SAC) prevents the progression of Alzheimer’s disease (AD) by multiple mechanisms: (1) antioxidant, SAC scavenges free radicals and oxidant specie (direct antioxidant) and restores glutathione peroxidase, glutathione reductase, and superoxide dismutase levels (indirect antioxidant). Consequently, SAC diminishes lipid peroxidation, DNA fragmentation, protein oxidation, and endoplasmic reticulum (ER) stress. The decrease in endoplasmic reticulum stress attenuates Ca2+ release and the subsequent activation of calpain and the caspase-12-dependent pathway, which altogether decrease the cell death; (2) antiamyloidogenic, SAC decreases Aβ formation and/or increases Aβ clearance. SAC lowers amyloid precursor protein (APP) mRNA expression, BACE (β-site APP cleavage enzyme 1) expression and activity and restores PKC activity under AD-like condition, which benefits APP cleavage and decreases the available APP for Aβ. In addition, SAC can bind to Aβ-inhibiting Aβ fibrillation and destabilizing preformed Aβ-peptide fibrils; (3) anti-inflammatory, SAC decreases IL-1β and TNF-α levels and IL-1β-positive plaque-associated microglia; (4) antitangle, SAC reduces tau2 reactivity and its phosphorylation; this reduction in tau appears to involve GSK-3β protein; (5) anti-glycative; SAC declines both activity and mRNA expression of aldose reductase (AR), which subsequently decreases the production of sorbitol and prevents advanced glycation end products (AGEs) formation, such as carboxymethyllysine (CML) and pentosidine, decreasing glycative stress.
 

 


Lane Simonian
Posted: Sunday, January 6, 2013 6:03 PM
Joined: 12/12/2011
Posts: 4063


I like these ones even better. 

 

S-Allyl-l-cysteine (SAC) has been shown to reduce ischemic injury [stroke] due to its antioxidant activity. However, the antioxidant property of SAC has been controversial. The present study investigated the neuroprotective mechanism of SAC in cerebral ischemic insults. SAC decreased the size of infarction after transient or global ischemic insults. While it did not alter the N-methyl-d-aspartate excitotoxicity, SAC significantly scavenged the endogenously or exogenously produced ONOO− [peroxynitrite] and reduced ONOO−  cytotoxicity.


Read More: http://informahealthcare.com/doi/abs/10.1080/10715760600719540?journalCode=fra
 

 

 

 

2011;18(22):3306-13.

The "aged garlic extract:" (AGE) and one of its active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for Alzheimer's disease (AD).

Source

Department of Psychiatry, Indiana University School of Medicine, 791Union Drive, Indianapolis IN 46202, USA.

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the older people and 7(th) leading cause of death in the United States. Deposition of amyloid-beta (Aβ) plaques, hyperphosphorylation of microtubule associated protein tau (MAPT), neuroinflammation and cholinergic neuron loss are the major hallmarks of AD. Deposition of Aβ peptides, which takes place years before the clinical onset of the disease can trigger hyperphophorylation of tau proteins and neuroinflammation, and the latter is thought to be primarily involved in neuronal and synaptic damage seen in AD. To date, four cholinesterase inhibitors or ChEI (tacrine, rivastigmine, donepezil and galantamine) and a partial NMDA receptor antagonist (memantine) are the only approved treatment options for AD. However, these drugs fail to completely cure the disease, which warrants a search for newer class of targets that would eventually lead to effective drugs for the treatment of AD. In addition to selected pharmacological agents, botanical and medicinal plant extracts are also being investigated. Apart from its culinary use, garlic (Allium sativum) is being used to treat several ailments like cancer and diabetes. Herein we have discussed the effects of a specific 'Aged Garlic Extract' (AGE) and one of its active ingredients, S-allyl-L-cysteine (SAC) in restricting several pathological cascades related to the synaptic degeneration and neuroinflammatory pathways associated with AD. Thus, based on the reported positive preliminary results reviewed herein, further research is required to develop the full potential of AGE and/or SAC into an effective preventative strategy for AD.

 

 

It is just a matter of which of the peroxynitrite scavengers make it to the brain the best. 


Lane Simonian
Posted: Sunday, January 6, 2013 9:22 PM
Joined: 12/12/2011
Posts: 4063


Maybe time to revisit ginger for a second. 

 

2005 Sep 21;53(19):7617-22.

Zingerone as an antioxidant against peroxynitrite.

Source

Department of Internal Medicine, College of Oriental Medicine, Dong-Guk University, Pusan National University, Busan, Korea.

Abstract

Peroxynitrite (ONOO(-)), formed from the reaction of superoxide ((*)O(2)(-)) and nitric oxide ((*)NO), induces cellular and tissue injury, resulting in several human diseases such as stroke, Alzheimer's disease, and atherosclerosis...

 

The present study suggests that zingerone has an efficient ONOO(-) scavenging ability, which may be a potent ONOO(-) scavenger for the protection of the cellular defense activity against ONOO(-)- involved diseases.

 

http://www.ncbi.nlm.nih.gov/pubmed/16159194 

 

 

ALZHEIMER'S DISEASE Two of ginger's most important antioxidants, curcumin and gingerol, have been shown to inhibit and even reverse the deposition in the brain of the amyloid plaques that are associated with Alzheimer's disease. Moreover, zingerone, another of ginger's antioxidants, neutralizes the powerful oxidant, peroxynitrite, which has also been implicated as an aggravating factor in Alzheimer's and other neurodegenerative diseases.

 

http://healthandnaturalcure.blogspot.com/2012/09/ginger-powerful-antioxidant-for.html 

 


Lane Simonian
Posted: Tuesday, January 8, 2013 11:33 PM
Joined: 12/12/2011
Posts: 4063


I am not sure if certain compounds in spices and essential oils prevent genetic mutations or inhibit the deleterious effects of those mutation, but this "finding" is interesting, nevertheless. 

 

Genes that are responsible for genetic AD are APP, PSEN1, and PSEN2. Antimutagenic study of phytochemicals has been carried out with the common AD causing APP gene mutation. By our computational analysis, phytochemicals like curcumin, eugenol, and limonene have been identified as "molecular switch" devices to prevent mutation of AD gene. All these chemicals are found to be strongly interacted with the AD gene without making changes to the remaining part of the sequence. Among the analyzed chemicals, curcumin is found to be most interacting with AD gene protecting it from mutation. Hence, inclusion of curcumin-containing food items in our menu would prevent Alzheimer's disease to a large extent.


Read More: http://www.worldscientific.com/doi/abs/10.1142/S0219581X11008010
 
 
Limonene (which is found in various citrus essential oils, for instance), eugenol (in rosemary, bay laurel, basil, clove, cinnamon, nutmeg, and other essential oils), and curcumin in the spice tumeric all inhibit the formation of peroxynitrites. 
 
 
Eugenol and curcumin are peroxynitrite scavengers. 
 
 
How long would it take the greatest medical minds in the world to identify effective peroxynitrite scavengers to partially reverse Alzheimer's disease?  In a perfect world, in which the only interest was humanitarian, a more effective treatment for Alzheimer's disease would really be close at hand.   

 


Lane Simonian
Posted: Wednesday, January 9, 2013 11:13 AM
Joined: 12/12/2011
Posts: 4063


Fortunately for me there is not a lot of chemistry behind Alzheimer's disease, but it has taken me a long time to understand what there is.   The following article shows the chemical structures of some of the compounds suggested for the treatment of Alzheimer's disease.   

 

http://www.sciencedirect.com/science/article/pii/S009130570300128X 

 

 

All of the current medications for Alzheimer's disease contain methyl groups (CH3 or H3C).  Methyl groups inhibit acetylcholinesterase activity thus inhibiting the breakdown of acetylcholine early in the disease (acetylcholine is a compound critical for short-term memory), but they don't inhibit the enzymes (phospholipase C gamma and beta) which lead to the release of acetylcholinesterases, the production of amyloid plaques, and peroxynitrites.  On the other hand, phenolic compounds (containing an OH group) will inhibit phospholipase C gamma and will inhibit the ability of both phospholipase C gamma and beta to produce peroxynitrites. 

 

Namenda and huperzine A in addition to a methyl group contain an amine group (NH2 or H2N) which inhibits the peroxynitrite-mediated activation of the NMDA receptor and the release of glutamate and the influx of calcium which kills brain cells. 

 

Methyl groups donate one electron which weakly scavenges peroxynitrites.  Methoxy groups (CH3O or H3CO) donate two electrons.  Better yet, they enhance the hydrogen donating capacity of phenols.  So methoxyphenols, effectively scavenge peroxynitrites in the following way: ONOO- + 2H+ + 2 electrons=H20 + NO2-.   

 

The most effective way to treat Alzheimer's disease is with methoxyphenols.  This includes eugenol in various essential oils (bay laurel, clove, rosemary, basil, nutmeg, cinnamon leaf, lemon balm, etc.) and ferulic acid, coumaric acid, syringic acid, and vanillic acid in heat-processed ginseng.    

 

http://onlinelibrary.wiley.com/doi/10.1111/j.1479-8301.2009.00299.x/full 

http://www.ncbi.nlm.nih.gov/pubmed/15941312 

http://www.ingentaconnect.com/content/ben/cbc/2006/00000002/00000001/art00005 

 

http://www.ncbi.nlm.nih.gov/pubmed/22780999 

http://www.ncbi.nlm.nih.gov/pubmed/19298205 


Lane Simonian
Posted: Friday, January 11, 2013 11:07 AM
Joined: 12/12/2011
Posts: 4063


For all its apparent complexity, Alzheimer's turns out to be a simple disease.  Block and scavenge peroxynitrites and you treat the disease.  Here is another natural product--piceatannol--that partially does both (JNK is another MAP kinase).  

 

2008 Jul;19(7):459-66. Epub 2007 Sep 14.

Piceatannol attenuates hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells by blocking down-regulation of Bcl-XL and activation of JNK.

Source

Department of Agricultural Biotechnology and Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921, Republic of Korea.

Abstract

There is mounting evidence implicating the accumulation of intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease. Recently, considerable attention has been focused on identifying naturally occurring antioxidants that are able to reduce excess ROS and RNS, thereby protecting against oxidative stress and neuron death. The present study investigated the possible protective effects of piceatannol (trans-3,4,3',5'-tetrahydroxystilbene), which is present in grapes and other foods, on hydrogen-peroxide- and peroxynitrite-induced oxidative cell death. PC12 rat pheochromocytoma (PC12) cells treated with hydrogen peroxide or SIN-1 (a peroxynitrite-generating compound) exhibited apoptotic death, as determined by nucleus condensation and cleavage of poly(ADP-ribose)polymerase (PARP). Piceatannol treatment attenuated hydrogen-peroxide- and peroxynitrite-induced cytotoxicity, apoptotic features, PARP cleavage and intracellular ROS and RNS accumulation. Treatment of PC12 cells with hydrogen peroxide or SIN-1 led to down-regulation of Bcl-X(L) and activation of caspase-3 and -8, which were also inhibited by piceatannol treatment. Hydrogen peroxide or SIN-1 treatment induced phosphorylation of the c-Jun-N-terminal kinase (JNK), which was inhibited by piceatannol treatment. Moreover, SP600125 (a JNK inhibitor) significantly inhibited hydrogen-peroxide- and peroxynitrite-induced PC12 cell death, revealing inactivation of the JNK pathway as a possible molecular mechanism for the protective effects of piceatannol against hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells. Collectively, these findings suggest that the protective effect of piceatannol against hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells is associated with blocking the activation of JNK and the down-regulation of Bcl-XL.

 

2007 Jan;1095:473-82.

Protective effects of piceatannol against beta-amyloid-induced neuronal cell death.

Source

School of Agricultural Biotechnology and Center for Agricultural Biomaterials, Seoul National University, Korea.

Abstract

Beta-amyloid (Abeta) is a main component of senile plaques in Alzheimer's disease (AD) that induces neuronal cell death. Since reactive oxygen species (ROS) have been implicated in Abeta-induced neurotoxicity, considerable attention has recently been focused on identifying naturally occurring antioxidative phenolic phytochemicals that are able to decrease ROS levels. Piceatannol (trans-3,4,3',5'-tetrahydroxystilbene), which has a structure homologous to resveratrol, is an anti-inflammatory and antiproliferative stilbene compound derived from plants. This article investigated the possible protective effects of piceatannol on Abeta-induced PC12 neuronal cell death, and found that piceatannol exerted much stronger protective effects than did resveratrol. Piceatannol treatment attenuated the intracellular accumulation of ROS induced by treatment of PC12 cells with Abeta, inhibited Abeta-induced apoptotic features including internucleosomal DNA fragmentation, nucleus condensation, cleavage of poly(ADP-ribose) polymerase (PARP), and activation of caspase-3. These results suggest that piceatannol blocks Abeta-induced accumulation of ROS, thereby protecting PC12 cells from oxidative stress.

 

 

If the medical community in this country would simply focus on finding the most effective peroxynitrite scavengers, this disease in its current form would be over. 


ffwife54@yahoo.com
Posted: Friday, January 11, 2013 12:48 PM
Joined: 4/15/2012
Posts: 245


Does the research for the aromatherapy have any value for people with the APOE 3/4 GENE?

Lane Simonian
Posted: Friday, January 11, 2013 1:04 PM
Joined: 12/12/2011
Posts: 4063


Good question and the answer is yes.  Essential oils high in eugenol (bay laurel, clove, basil, rosemary, cinnamon leaf, and nutmeg among others) inhibit the formation of peroxynitrites and scavenge peroxynitrites no matter whether the cause of Alzheimer's disease (or Mild Cognitive Impairment) is genetic or not.  Aromatherapy may also help to a lesser degree in the treatment of other forms of dementia.  The Jimbo study (which used rosemary and lemon for cognition and lavender and orange to reduce anxiety) is the closest that exists to back up these contentions. 

 

Objective: Recently, the importance of non-pharmacological therapies for dementia has come to the fore. In the present study, we examined the curative effects of aromatherpay in dementia in 28 elderly people, 17 of whom had Alzheimer's disease (AD).

 

 

Results: All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.

 

Conclusions: In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.

 

http://onlinelibrary.wiley.com/doi/10.1111/j.1479-8301.2009.00299.x/full 

 

Participants were not screened for the APOE3/4 gene.  It is possible that none of the 17 participants in the study with Alzheimer's disease had the gene, but not too likely.   

 


Tom(ek)
Posted: Friday, January 11, 2013 5:19 PM
Joined: 12/21/2011
Posts: 59


I wonder what could happen after combination of aromatherapy and treating of 
brain insulin resistance or herpesviral encephalitis (caused by herpes simplex virus 1 and 2 - HSV-1 and HSV-2, also known as Human herpes virus 1 and 2 - HHV-1 and -2)... Generally, it's a pity that scientists don't try combinations of different possible treatments with using of peroxynitrite scavengers.

 

Every company is looking for one magic pill which could be sold.


Lane Simonian
Posted: Friday, January 11, 2013 5:52 PM
Joined: 12/12/2011
Posts: 4063


This is a particularly interesting insight as herpes simplex virus generates peroxynitrites and aside from that peroxynitrites play a critical role in insulin resistance/type 2 diabetes.  And the herpes simplex virus and type 2 diabetes may increase the risk for Alzheimer's disease. 

 

http://www.northcellpharma.com/news-ClinStud.html 

http://www.ncbi.nlm.nih.gov/pubmed/21110800 

 

I have been looking for some time now for a complementary peroxynitrite scavenger to be used along side of aromatherapy to treat Alzheimer's disease.  Taking several peroxynitrite scavenging herbs may help. The best one that I know of is heat-processed ginseng which like some essential oils contains methoxyphenols. 

 

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

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

Source

Institute of Natural Medicine, University of Toyama, Toyama, Japan.

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 Jul 9. [Epub ahead of print]
 
 
 

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.

 

http://www.ncbi.nlm.nih.gov/pubmed/22780999 

 

Thanks to Myriam, I was able to locate the U.S. distributor for heat-processed ginseng.  The cost of a month's supply was about $700.  I read on one site that steaming ginseng for four hours increased the antioxidant capacity of the ginseng.  Not sure, though, if it would have the same effect as heat-processed ginseng (the process for which is patented). An increase in blood pressure appears to be the main side effect from ginseng, although other studies suggest that blood pressure may actually decrease over time with the use of ginseng. 

 

My larger thought is if you combine a series of methoxyphenols together, you produce a better outcome, so perhaps aromatherapy and heat-processed ginseng--which both proved beneficial in small-scale clinical trials in the treatment of Alzheimer's disease--might have produced even better results when used in conjunction with each other (although then again the potential side effects might increase as well). 

 

I forgot to thank you earlier, Tom(ek), for all the scientific knowledge, background, and insight you have brought to this site.   

 


reporter21
Posted: Saturday, January 12, 2013 9:48 AM
Joined: 12/4/2012
Posts: 5


Lane,

 

How would you go about steaming ginseng, and is there one you would recommend?

Thank you.

Sherry )


Lane Simonian
Posted: Saturday, January 12, 2013 10:28 AM
Joined: 12/12/2011
Posts: 4063


I just found this useful article on the steaming of ginseng this morning. 

 

http://www.sciencedaily.com/releases/2000/11/001130074250.htm 

 

The type of ginseng to use is Panax ginseng, sometimes called Korean ginseng.  White Panax ginseng is dried and peeled whereas red ginseng is unpeeled and steamed. The above article says if you steam ginseng (I am not sure if it makes a difference whether it is white or red ginseng) above boiling temperatures you produce sun ginseng and that no special equipment is needed (a pressure cooker, pehaps). 

 

 

There are some side effects associated with ginseng. 

 

http://altmedicine.about.com/od/ginseng/a/ginseng.htm 

 

The initial evidence for its use to treat Alzheimer's disease is positive. And while I am not certain, perhaps you could achieve the same or similar results without having to spend $700 a month.


Geo
Posted: Saturday, January 12, 2013 3:00 PM
Joined: 6/20/2012
Posts: 34


I posted a link a few weeks a go in the Mediterranean diet thread about using ultrasound to increase the phenols in extra virgin olive oil.

 

It seems the same idea can be applied to ginseng:

 

http://www.ncbi.nlm.nih.gov/pubmed/11510218

 

 

Whether this has the same effects as steaming I just don't know. However ultrasound does create high temperatures at a microscopic level. People out there are using jewellery cleaners for this purpose and to create liposomes. It sound rather crude and outlandish but it does seem to work.

 


Lane Simonian
Posted: Saturday, January 12, 2013 5:06 PM
Joined: 12/12/2011
Posts: 4063


Thanks, Geo.  The answer appears to be yes. 

 

Abstract

The stress metabolic activities of Panax ginseng (P. ginseng) cells induced by low-energy ultrasound (US) were examined. P. ginseng cells in suspension cultures were exposed to 38.5 kHz US at two power levels (power density 13.7 and 61 mW/cm(3)) for 2 min. The US treatment caused rapid increase in the intracellular levels of polyphenol oxidase (PPO), peroxidase (PO), and phenylalanine ammonia lyase (PAL) and the production of polyphenols (PP) and phenolic compounds.

 

 

http://www.researchgate.net/publication/11230238_Ultrasound-induced_stress_responses_of_Panax_ginseng_cells_enzymatic_browning_and_phenolics_production 

 

I have no idea if a ultrasonic jewelry cleaner or an ultrasonic processor would work better than a pressure cooker, but it is something to consider. 


Geo
Posted: Saturday, January 12, 2013 7:17 PM
Joined: 6/20/2012
Posts: 34


Thank you Lane I missed that article. I experiment with ultrasound using ascorbic acid and curcumin so far and have been concerned about possible de-naturalizing effect of it. That article seems to say it indeed happens yet higher phenols are the result.

BTW how do you get your links to come out as proper hyperlinks? Mine always post as just plain text.


Lane Simonian
Posted: Saturday, January 12, 2013 8:06 PM
Joined: 12/12/2011
Posts: 4063


This concerns me sometimes, as well, but I suppose, too, when the phenolic content is increased it is generally a good thing.   

 

JAB--a former member of the site--who had extensive scientific and computer knowledge taught me how to do the hyperlinks: Right click on the url at the very top of the computer of the article you want to link, then left click on copy, right click in the post, and then left click on paste.  A box may come up asking if you want to allow access.  If so, click allow access.  


Geo
Posted: Sunday, January 13, 2013 10:34 PM
Joined: 6/20/2012
Posts: 34


Thanks, that's the way I've been doing it. It must be something to do with my browser settings stripping out the HTML.

 

Thanks for the link. I now think that steaming is the better choice. The abstract Lane posted says:

 

"The US treatment caused rapid increase in the intracellular levels of polyphenol oxidase (PPO), peroxidase (PO)" 


 

From the great research Lane has done on Peroxynitrite, that set alarm bells ringing.

 

This article 

 

 

http://www.rxpgnews.com/alzheimersdisease/Excessive_peroxidase_of_amyloid-beta-_understandin_3665_3665.shtml

 

 

says

 "....When they examined the heme/ amyloid-beta compound researchers in the Atamna laboratory were surprised to discover it was a peroxidase--a type of enzyme that reacts harmfully with biological materials essential for proper brain function such as serotonin and L-DOPA. Dr. Atamna believes that the combination of functional heme deficiency, which harms mitochondria needed to produce energy, together with the increase in oxidative damage caused by the peroxidase, is what eventually kills the cell. " 


 


 

So the previous article found subjecting ginseng to ultrasound increased peroxidase. Not something we want. I'll stick to steaming which it at least tried and trusted. 


 


 


 

 


 


 


 


 


 


Tom(ek)
Posted: Monday, January 14, 2013 9:25 AM
Joined: 12/21/2011
Posts: 59


 

 

Lane, I should thank you for everythig you wrote here.

 

I mentioned about brain insulin resistance because of:

 

Brain Insulin Resistance Contributes to Cognitive Decline in Alzheimer's Disease 

 

http://www.sciencedaily.com/releases/2012/03/120323134908.htm 

 

 

and I wrote about herpes because of publications:

 

Antivirals Reduce the Formation of Key Alzheimer's Disease Molecules in Cell Cultures Acutely Infected with Herpes Simplex Virus Type 1 

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189195/ 

 

Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques. 

 

http://www.ncbi.nlm.nih.gov/pubmed/18973185 

 

Herpes simplex virus type 1 in Alzheimer's disease: the enemy within. 

 

http://www.ncbi.nlm.nih.gov/pubmed/18487848 

 

(you can read there about herpes and amyloid, ApoE)

 

also in the topic "Rare and unusual dementias":

 

http://www.alzconnected.org/discussion.aspx?g=posts&t=2147492024 

 

you can find:

 

INFECTIOUS DISEASES 51

 

16. HERPES ENCEPHALITIS BY KURT JELLINGER

 

It's proof that herpes really can affect human central nervous system (http://en.wikipedia.org/wiki/Herpesviral_encephalitis) and you’ve found link between this virus and peroxynitrite.

 

Of course not every person with AD has got symptoms of herpes infection.... but maybe it is related somehow with some of cases of people with AD.... we will see in the future... I hope.

Maybe in other cases diabetes is the main problem or something else...

 


Lane Simonian
Posted: Monday, January 14, 2013 10:27 AM
Joined: 12/12/2011
Posts: 4063


Thank you, Tom(ek) both for your thank you and especially for your research.   

 

Chronic infections such as Herpes Simplex Virus 1 can indeed contribute to Alzheimer's disease and to other forms of brain damage.  Antiviral and antibiotics may help to prevent or delay this damage.  And peroxynitrite scavengers (which include several antibiotics) may help treat part of the damage. 

 

http://www.eurekaselect.com/92112/article/oxidative-brain-damage-peroxynitrite-bacterial-meningitis-target-adjunctive-therapy 

 

The link between diabetes and Alzheimer's disease is a quite complicated one.  As a result of insulin resistance outside of the brain, more glucose enters into the brain.  Here it is converted to myo-inositol the precursor to amyloid plaques and to peroxynitrites. 

 

The Biosynthesis of Free and Phosphatide Myo-inositol from Glucose by Mammalian Tissue Slices*. GEORGE HAUSER AND VINCENT N. FINELLI ... 

 

Two other factors which contribute to high levels of myo-inositol and increase the risk for Alzheimer's disease are high blood pressure due to high sodium levels and Down syndrome because individuals with Down syndrome carry an extra chromosome that has the sodium/myo-inositol co-transporter.   

 

http://www.ncbi.nlm.nih.gov/pubmed/12366626 

 

http://www.ncbi.nlm.nih.gov/pubmed/16330724 

 

There is a debate as to whether insulin resistance in the brain inhibits the entrance of glucose into the brain.  Even if it does not, peroxynitrites contribute to a scarcity of glucose in the brain via lipid peroxidation. 

 

http://www.ncbi.nlm.nih.gov/pubmed/9202320 

 

The lack of glucose in the brain may contribute to lack of focus and energy, and perhaps to delusions and wandering. 

 

All of the risk factors for Alzheimer's disease appear to lead to peroxynitrite formation and peroxynitrite scavengers can at least partially reverse the damage done by peroxynitrites in the brain. 


Lane Simonian
Posted: Monday, January 14, 2013 11:27 AM
Joined: 12/12/2011
Posts: 4063


My guess is that it is the browser, too.  I wonder if someone might know of a work around the problem. 

 

I did not know of the connection between peroxidases in Alzheimer's disease and cell death.  This may be a particular problem in conjunction with heme deficiency (further evidence from the author you cited).  

 

http://www.pnas.org/content/103/9/3381.abstract 

 

Ginseng, curcumin, and other herbs and spices may help in this regard too by chelating heme (which contains an iron ion--Fe2+) out of amyloid plaques. 

 

http://www.faqs.org/patents/app/20080292733   

http://www.ncbi.nlm.nih.gov/pubmed/16545682 

 

Once the heme is taken out of the plaques, heme based peroxidases may help to lower peroxynitrite levels and contribute to cell survival. 

 

Reactions of heme peroxidases with peroxynitrite.

Source

Institute of Applied Radiation Chemistry, Technical University of Lódź, Poland. lgebicka@mitr.p.lodz.pl

Abstract

The interaction of peroxynitrite, produced by ozonation of azide, with two heme peroxidases (horseradish peroxidase and lactoperoxidase) was studied. Enzymes retained full activity after incubation with peroxynitrite at neutral pH. Lactoperoxidase alone was found to catalyze peroxynitrite decomposition, whereas horseradish peroxidase accelerated peroxynitrite decomposition only in the presence of certain substrates. For example, in the presence of guaiacol the catalyzing effect was clear, but in the presence of trolox was only noticeable.

 

http://www.ncbi.nlm.nih.gov/pubmed/10772335 

 

An interesting thing here is that guaiacol is a methoxyphenol found in roasted coffee.  The combination of various phenolic compounds with various peroxidases appears to be useful in dealing with peroxynitrite-mediated damage.   

 

http://www.sciencedirect.com/science/article/pii/S0014579398002981 

 

The presence of heme in amyloid plaques appears to trigger a negative peroxidase while the chelation of heme out of amyloid plaques appear to trigger beneficial peroxidases. 

 

I would still stick with the steamed ginseng. 

 


Lane Simonian
Posted: Monday, January 14, 2013 10:13 PM
Joined: 12/12/2011
Posts: 4063


Heme within amyloid plaques may interact with nitric oxide to produce peroxynitrites and stimulate peroxidase activity that leads to cell death. 

 

 

Conclusion and Perspectives

The analysis presented herein shows that biological protein tyrosine nitration†† mainly occurs through free radical pathways, and that there is an interplay involving excess •NO, oxidants, and transition metal centers. The individual or combined contribution of the peroxynitrite and hemeperoxidase/transition metal-dependent pathways to biological nitration, the detection of nitrated proteins with altered function in vivo, and the data arising from pharmacological and genetic approaches support the significance of nitration as a biochemical process linked to •NO-dependent pathophysiology. Approaches directed at inhibiting the oxidative modifications caused by reactive nitrogen species, including protein tyrosine nitration, open new avenues for the treatment of inflammatory, vascular, and neurodegenerative diseases.

 

 

http://www.ncbi.nlm.nih.gov/pubmed/20666389 

 

The chelation of iron out of the plaques by curcumin, ginseng, and other phenolic compounds appears to contribute to their antioxidant effects, perhaps including the decomposition of peroxynitrites. 

 

 

 

 


Lane Simonian
Posted: Tuesday, January 15, 2013 12:00 PM
Joined: 12/12/2011
Posts: 4063


 I found this interesting entry on Wikipedia on reactive nitrogen species of which peroxynitrite is one.  I will cut and paste the most relevant sections. 

 

http://en.wikipedia.org/wiki/Reactive_nitrogen_species 

 

Reactive nitrogen species (RNS) are a family of antimicrobial molecules derived from nitric oxide (·NO) and superoxide (O2·−) produced via the enzymatic activity of inducible nitric oxide synthase 2 (NOS2) and NADPH oxidase respectively. NOS2 is expressed primarily in macrophages after induction by cytokines and microbial products, notably interferon-gamma (IFN-γ) and lipopolysaccharide (LPS).[2] 

Reactive nitrogen species act together with reactive oxygen species (ROS) to damage cells, causing nitrosative stress. Therefore, these two species are often collectively referred to as ROS/RNS.

 

 

RNS are produced in animals starting with the reaction of nitric oxide (·NO) with superoxide (O2·−) to form peroxynitrite (ONOO−):[4][5] 

  • ·NO (nitric oxide) + O2·− (superoxide) → ONOO− (peroxynitrite)

Superoxide anion (O2-) is a reactive oxygen species that reacts quickly with nitric oxide (NO) in the vasculature. The reaction produces peroxynitrite and depletes the bioactivity of NO. This is important because NO is a key mediator in many important vascular functions including regulation of smooth muscle tone and blood pressure, platelet activation, and vascular cell signaling.[6] 

Peroxynitrite itself is a highly reactive species which can directly react with various biological targets and components of the cell including lipids, thiols, amino acid residues, DNA bases, and low-molecular weight antioxidants.[7] However, these reactions happen at a relatively slow rate. This slow reaction rate allows it to react more selectively throughout the cell. Peroxynitrite is able to get across cell membranes to some extent through anion channels.[8] Additionally peroxynitrite can react with other molecules to form additional types of RNS including nitrogen dioxide (·NO2) and dinitrogen trioxide (N2O3) as well as other types of chemically reactive free radicals.

 

[edit] Biological targets

Peroxynitrite can react directly with proteins that contain transition metal centers. Therefore, it can modify proteins such as hemoglobin, myoglobin, and cytochrone c by oxidizing ferrous heme into its corresponding ferric forms. Peroxynitrite may also be able to change protein structure through the reaction with various amino acids in the peptide chain. The most common reaction with amino acids is cysteine oxidation. Another reaction is tyrosine nitration; however peroxynitrite does not react directly with tyrosine. Tyrosine reacts with other RNS that are produced by peroxynitrite. All of these reactions affect protein structure and function and thus have the potential to cause changes in the catalytic activity of enzymes, altered cytoskeletal organization, and impaired cell signal transduction.[8] 

 

 

 

 

Oxygenated heme reacts with nitric oxide to produce peroxynitrites and peroxynitrites prevent the degradation of heme.  One more vicious circle in which peroxynitrite perpetuate themselves. 

 

If you removed plaques or chelated the heme out of the plaques you would lower the production of peroxynitrites and slow down the progression of Alzheimer's disease at least early on.  However, independent of the plaques, peroxynitrites activates the p38 MAP kinase and the p38 MAP kinase perpetuates the production of peroxynitrites.  The only way to effectively treat the disease is with peroxynitrite scavengers. 


Lane Simonian
Posted: Tuesday, January 15, 2013 2:16 PM
Joined: 12/12/2011
Posts: 4063


A bit closer but still not there. 

 

Peroxidases (EC number 1.11.1.x) are a large family of enzymes that typically catalyze a reaction of the form:

ROOR' + electron donor (2 e-) + 2H+ → ROH + R'OH

http://en.wikipedia.org/wiki/Peroxidase 

 

When a plant is under stress (from heat or ultrasound) it appears to be able to produce more phenols and peroxidases to defend itself.  The reaction above is just the one that methoxyphenols produce to scavenge peroxynitrites ONOO- + electron donor (2e-) from the methoxy group + 2H+ (from the phenol group)=H20+NO2-.  But when heme is in the amyloid plaque it causes nitration and appears to contribute to the formation of peroxynitrites.   When it is chleated out perhaps it contributes to a peroxidase/phenolic system that scavenges/decomposes peroxynitrites. 

 

 


Geo
Posted: Friday, January 18, 2013 1:34 PM
Joined: 6/20/2012
Posts: 34


So peroxidases can help scavenge except when they meet heme and amyloid, then they can become pro-oxidant.
Have I got that right?

Lane Simonian
Posted: Friday, January 18, 2013 7:30 PM
Joined: 12/12/2011
Posts: 4063


Yes, I think this is the case, Geo.  Heme peroxidases can become prooxidants in the presence of hydrogen peroxide (which can be generated by peroxynitrites).  A methoxyphenol, such as curcumin, can counteract the oxidant effects of heme and heme peroxidases by chelating iron out of amyloid plaques. 

 

We suggest that the oxidation of serotonin by Aβ–heme in the presence of H2O2, ...is a possible molecular link between Aβ and the abnormal neurotransmitters and oxidative damage seen in AD brain. Peroxidases usually oxidize several organic substrates with minimal selectivity. Therefore, we predict that additional biomolecules also are oxidized by the peroxidase activity of excessive Aβ–heme complexes. Consistently, serotonin and DOPA can be oxidized by myeloperoxidase (), further supporting the finding that both neurotransmitters are substrates for the Aβ–heme-dependent peroxidase. The peroxidase activity of Aβ–heme was inhibited by curcumin (Fig. 5); curcumin lowers oxidative damage in the brain of a mouse model for AD (), possibly by chelating Cu and iron (). Redox-active iron was proposed to play a role in the oxidative damage of AD (, ). We propose that inhibiting Aβ–heme peroxidase with curcumin may prevent part of the oxidative damage in AD.

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413946/ 

 

By scavenging and counteracting the damage done peroxynitrites, curcumin increases the breakdown of heme to non-toxic levels and lowers hydrogen peroxide levels via glutathione peroxidase. 

 

Glutathione Peroxidase Protects against Peroxynitrite-mediated Oxidations

A NEW FUNCTION FOR SELENOPROTEINS AS PEROXYNITRITE REDUCTASE*

http://www.jbc.org/content/272/44/27812 

 

 

Inactivation of Glutathione Peroxidase by Peroxynitrite. Sarojini Padmaja,  

 

Other peroxidases, such as myeloperoxidase, lactoperoxidase,

and horseradish peroxidase, had been found to react rapidly with peroxynitrite (20), but these are all heme-containing peroxidases, in contrast with GSH-Px which does not contain a heme but instead a selenocysteine residue in the active site. 

 

   

The high levels of heme in amyloid plaques help increase the formation of peroxynitrites and hydrogen peroxide and heme peroxidase in the presence of hydrogen peroxide becomes an additional oxidant.  This is likely how heme and heme peroxidase contribute to oxidative stress in Alzheimer's disease.  When heme levels are lowered and heme peroxidases act in conjunction with methoxyphenols such as curcumin that lower peroxynitrite and hydrogen peroxide levels, a prooxidant process becomes an antioxidant process.

 

 

 

 

 
 

Lane Simonian
Posted: Saturday, January 19, 2013 8:47 AM
Joined: 12/12/2011
Posts: 4063


One more critical step in understanding how to treat Alzheimer's disease. Now the role of heme peroxidases in the disease makes sense. 

  

Hydrogen peroxide inactivates heme peroxidases, and hydrogen peroxide causes the degradation of heme into oxidizing agents.  Methoxyphenols such as guaicol or curcumin inhibit this process.   

 

https://docs.google.com/a/wnc.edu/viewer?a=v&q=cache:nBal1-NMcekJ:www.sciencepub.net/life/life0301/life-0301-10.pdf+&hl=en&gl=us&pid=bl&srcid=ADGEESgS2Bxwh-n8bfjQwdD9widilYWn07Gixv_HYGrM2b7wZjm22wjUfRQFXGeHhuJD50Lv_IbC4cxMCvFXtNTlJbO2MjkGfZC2-bHSeCOf5rFrm6-h75rpnEwE598YfpwmzTefW0Be&sig=AHIEtbTb1hIsnZZPlTypE2gMPOCHWXBHtw 

 

 

One way in which methoxyphenols inhibit this process is by partially reversing the peroxynitrite oxidation of glutathione peroxidase and the peroxynitrite-mediated depletion of glutathione.  This is important because glutathione peroxidase and glutathione convert hydrogen peroxide into water.   Furthermore, the combination of gluathione and glutathione peroxidase results in the scavenging peroxynitrites.  The combination of methoxyphenols with heme peroxidases also results in the scavenging of peroxynitrites. 

 

Methoxyphenols such as eugenol, curcumin, guaicol, vanillic acid, ferulic acid, sinapic acid, syringic acid, and coumaric acid are the key to treating Alzheimer's disease.  Perhaps, the only remaining question is how to deliver them to the brain in large enough concentrations to inhibit and reverse the damage done by peroxynitrites in the brain. 

 

 


Lane Simonian
Posted: Wednesday, January 23, 2013 11:55 AM
Joined: 12/12/2011
Posts: 4063


A further explanation of how peroxidases under certain circumstances can contribute to the formation of peroxynitrites and nitration damage in Alzheimer's disease.   

 

Abstract

The peroxidase-catalyzed nitration of tyrosine derivatives by nitrite and hydrogen peroxide has been studied in detail using the enzymes lactoperoxidase (LPO) from bovine milk and horseradish peroxidase (HRP). The results indicate the existence of two competing pathways, in which the nitrating species is either nitrogen dioxide or peroxynitrite. The first pathway involves one-electron oxidation of nitrite by the classical peroxidase intermediates compound I and compound II, whereas in the second pathway peroxynitrite is generated by reaction between enzyme-bound nitrite and hydrogen peroxide. The two mechanisms can be simultaneously operative, and their relative importance depends on the reagent concentrations. With HRP the peroxynitrite pathway contributes significantly only at relatively high nitrite concentrations, but for LPO this represents the main pathway even at relatively low (pathophysiological) nitrite concentrations and explains the high efficiency of the enzyme in the nitration. Myoglobin and hemoglobin are also active in the nitration of phenolic compounds, albeit with lower efficiency compared with peroxidases.

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1241230/ 

 

 

 

The nitration of phenolic compounds likely prevents them from interacting with heme peroxidases to scavenge peroxynitrites.  The addition of external phenols inhibits nitration of compounds containing phenols (like tyrosine), helps scavenge peroxynitrites, and partially reverses the oxidation of glutathione peroxidase and increases glutathione levels which allows for the breakdown of hydrogen peroxide and the further scavenging of peroxynitrites.   

 

 

 

 


Lane Simonian
Posted: Wednesday, January 23, 2013 12:36 PM
Joined: 12/12/2011
Posts: 4063


These studies on isoeugenol and eugenol (found in various essential oils, for instance) are for other diseases (diabetes--not too positive; cancer--more positive), but the have relevance for Alzheimer's disease. 

 

Liver, kidney, brain, and heart were assayed for degree of lipid peroxidation, reduced and oxidized glutathione content, and activities of the free radical-detoxifying enzymes catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. All tissues from diabetic animals exhibited disturbances in antioxidant defense when compared with normal controls. Treatment with isoeugenol reversed diabetic effects on hepatic glutathione peroxidase activity and on oxidized glutathione concentration in brain.

 

http://www.ncbi.nlm.nih.gov/pubmed/11424226 

 

 

Eugenol with antioxidant activity inhibits MMP-9 related to metastasis in human fibrosarcoma cells.

Hyang Nam and Moon-Moo Kim
Food Chem Toxicol (2013), PMID 23313798  

The oxidative damage of lipid, protein and DNA is known to be involved in chronic inflammation as well as metastasis. It has been highlighted for searching natural compounds without toxicity to prevent development of these diseases. Thus, it was investigated whether eugenol can inhibit matrix metalloproteinase (MMP) expression and activity as well as antioxidant effect. Eugenol was contained as a major ingredient in herbs such as clove and Magnoliae Flos. The direct scavenging effects of eugenol on DPPH radical, hydrogen peroxide, reducing power, lipid peroxidation and genomic DNA damage related to oxidative stress were evaluated in cell free system. It was observed that eugenol specifically exhibited higher inhibitory effect on hydrogen peroxide than other reactive oxygen species, and also blocked DNA oxidation and lipid peroxidation induced by hydroxyl radical. In addition, the inhibitory effects of eugenol on the activity and expression of MMP-9 activity related to metastasis were determined using gelatin zymography and western-blot. The data showed that it inhibited MMP-9 activities in PMA-stimulated HT1080 cells. Furthermore, it was found that eugenol exerts inhibitory effects on MMP-9 via inactivation of ERK. Therefore, these results suggest that eugenol could be available as an excellent agent for prevention of metasasis related to oxidative stress.

 

http://pubget.com/paper/23313798/Eugenol_with_antioxidant_activity_inhibits_MMP_9_related_to_metastasis_in_human_fibrosarcoma_cells 

 

And of course eugenol (and isoeugenol) is a peroxynitrite scavenger. 

 

2005 Jun 15;53(12):4762-5.

In vitro activity of the essential oil of Cinnamomum zeylanicum and eugenol in peroxynitrite-induced oxidative processes.

Source

Dipartimento di Chimica Bioorganica e Biofarmacia, Università di Pisa, via Bonanno 33, 56126 Pisa, Italy.

Abstract

The essential oil obtained from the bark of Cinnamomum zeylanicum Blume (Lauraceae) and three of its main components, eugenol, (E)-cinnamaldehyde, and linalool (representing 82.5% of the total composition), were tested in two in vitro models of peroxynitrite-induced nitration and lipid peroxidation. The essential oil and eugenol showed very powerful activities, decreasing 3-nitrotyrosine formation with IC50 values of 18.4 microg/mL and 46.7 microM, respectively (reference compound, ascorbic acid, 71.3 microg/mL and 405.0 microM) and also inhibiting the peroxynitrite-induced lipid peroxidation showing an IC50 of 2.0 microg/mL and 13.1 microM, respectively, against 59.0 microg/mL (235.5 microM) of the reference compound Trolox. On the contrary, (E)-cinnamaldehyde and linalool were completely inactive.

 

 

Not only do methoxyphenols such as eugenol, curcumin, and those found in heat-processed ginseng act as direct scavengers they restore part of the brain's own antioxidant system.  Not all the pieces have fallen into place, but enough of them so that in an ideal world an effective treatment for Alzheimer's disease would not be far away. 


Lane Simonian
Posted: Friday, January 25, 2013 12:14 AM
Joined: 12/12/2011
Posts: 4063


This one is for curcumin and Parkinson's but it also applies to Alzheimer's disease. 

 

Results:

Curcumin directly detoxified peroxynitrite and protected brain mitochondria against protein nitration and mitochondrial damage.  Curcumin also protected against GSH [glutathione] depletion mediated oxidative stress.

 

http://www.mdsabstracts.com/abstract.asp?MeetingID=787&id=99234 

 

And a good article on curcumin and Alzheimer's disease. 

 

http://cen.acs.org/articles/90/i31/Tumeric-Derived-Compound-Curcumin-Treat.html 

 

Dr. Gregory Cole is one of a handful of scientists in the United States working on ways to effectively deliver phenolic compounds such as curcumin to the brain to treat Alzheimer's disease.   

 


 
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