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Study Suggests Chronic Inflammation Triggers Alzheimer's
Myriam
Posted: Thursday, December 20, 2012 5:19 PM
Joined: 12/6/2011
Posts: 3326


(Source: PsychCentral) - A team of scientists under the guidance of the University of Bonn and University of Massachusetts have discovered a new signaling pathway in mice associated with the death of brain nerve cells from chronic inflammation.


"Many years before the initial symptoms of Alzheimer's disease occur, so-called plaques, which consist of incorrectly folded beta-amyloid peptides, form in the brain of affected persons," said lead author Dr. Michael T. Heneka. In addition, there are abnormal tau protein deposits in the brain cells of the patients. "As a result of a signal cascade, there is a chronic inflammatory reaction and the progressive loss of nerve cells," said Dr. Eicke Latz.

 

Go to full story:
http://psychcentral.com


Lane Simonian
Posted: Thursday, December 20, 2012 8:31 PM
Joined: 12/12/2011
Posts: 4855


Serenoa and I have been trying to determine the role of inflammation in Alzheimer's disease on the thread on TREM2.  I think it more or less comes down to this: peroxynitrites contribute to tissue damage and the death of neurons which leads to inflammation and inflammation can lead to the further production of peroxynitrites.  Peroxynitrite scavengers will limit tissue damage, neuronal cell death, and inflammation.  

 

http://www.fasebj.org/content/14/5/691.full 

 

 

One of the best peroxynitrite scavengers is eugnol which is found in various essential oils (clove, bay laurel, rosemary, basil, nutmeg, etc.). 

 

https://docs.google.com/viewer?a=v&q=cache:GXUZvMR-ndEJ:www.mdpi.com/1420-3049/15/12/9252/pdf+anti-oxidant+anti-inflammatory+essential+oils&hl=en&gl=us&pid=bl&srcid=ADGEESgZADz4sd8Ij_JKcN0c7CO6VxaphGP3--_SlkY_VYgKc5Sh_Cy-zwrmDLCunevFY9jXNPmduRlXpZULfTsgo-aOAPvWtkeESypEXfvoT6WxN2Hkf_jwPIAJ7m5y0yr-NueFtGN9&sig=AHIEtbS3hvD9BzImNtA5Ga5aLQTdFk8k4g 

 

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

 

 


Lane Simonian
Posted: Friday, December 21, 2012 12:16 AM
Joined: 12/12/2011
Posts: 4855


Good. good, good! Scavenge peroxynitrites and you prevent cell death and inflammation in Alzheimer's disease.  This article comes very close to making this point. 

 

2012;13(9):12113-29. doi: 10.3390/ijms130912113. Epub 2012 Sep 24.

Gelam honey scavenges peroxynitrite during the immune response.

Source

Department of Anesthesiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; E-Mails: marzida@gmail.com (M.M.); gracieo@um.edu.my (G.O.).

Abstract

Monocytes and macrophages are part of the first-line defense against bacterial, fungal, and viral infections during host immune responses; they express high levels of proinflammatory cytokines and cytotoxic molecules, including nitric oxide, reactive oxygen species, and their reaction product peroxynitrite. Peroxynitrite is a short-lived oxidant and a potent inducer of cell death. Honey, in addition to its well-known sweetening properties, is a natural antioxidant that has been used since ancient times in traditional medicine. We examined the ability of Gelam honey, derived from the Gelam tree (Melaleuca spp.), to scavenge peroxynitrite during immune responses mounted in the murine macrophage cell line RAW 264.7 when stimulated with lipopolysaccharide/interferon-γ (LPS/IFN-γ) and in LPS-treated rats. Gelam honey significantly improved the viability of LPS/IFN-γ-treated RAW 264.7 cells and inhibited nitric oxide production-similar to the effects observed with an inhibitor of inducible nitric oxide synthase (1400W).... Thus, honey may attenuate inflammatory responses that lead to cell damage and death, suggesting its therapeutic uses for several inflammatory disorders.

 

 


Lane Simonian
Posted: Friday, December 21, 2012 12:26 AM
Joined: 12/12/2011
Posts: 4855


And two that I have cited before: 

 

  • ARTICLE
    • Cellular/Molecular
     

Peroxynitrite Mediates Neurotoxicity of Amyloid β-Peptide1–42- and Lipopolysaccharide-Activated Microglia

  1. Valter D. Longo1, *  

+ Author Affiliations

  1. 1 Division of Biogerontology, Andrus Gerontology Center, and Department of Biological Sciences, and
     
  2. 2 Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90089
     
 

Abstract

The amyloid β-peptide (Aβ) activates microglia and promotes the generation of cytokines and oxygen species, including nitric oxide (NO) and tumor necrosis factor α (TNF-α), which can be either neurotoxic or neuroprotective. We show that neuron death in cocultures of rat cortical microglia and neurons activated by lipopolysaccharide (LPS) or Aβ1–42 plus interferon γ (IFNγ) is caused by short-lived diffusible molecules and follows the generation of superoxide and/or peroxynitrite as determined by electron paramagnetic spectroscopy. Neurotoxicity induced by LPS or Aβ1–42 plus IFNγ is blocked by inhibitors of NO synthesis and by the peroxynitrite (ONOO−) decomposition catalysts FeTMPyP [5,10,15,20-tetrakis(n-methyl-4′-pyridyl)porphinato iron (III) chloride] and FeTPPS [5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride] but not by the TNF-α inhibitor pentoxifylline. The specificity of FeTMPyP for ONOO− was confirmed by its ability to block the toxicity of a peroxynitrite donor but not of NO donors or of high levels of superoxide in a yeast mutant lacking superoxide dismutase 1. These results implicate peroxynitrite as a mediator of the toxicity of activated microglia, which may play a major role in Aβ1–42 neurotoxicity and Alzheimer's disease.

 

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.

Abstract

Peroxynitrite (ONOO(-))-mediated damage is regarded to be responsible for the cognitive dysfunction induced by amyloid beta protein (Abeta) in Alzheimer's disease (AD). In the present study, we examined the protective effects of rosmarinic acid (RA), a natural scavenger of ONOO(-), on the memory impairment in a mouse model induced by acute i.c.v. injection of Abeta(25-35). Mice daily received i.p. several doses of RA after the injection of Abeta(25-35). RA prevented the memory impairments induced by Abeta(25-35) in the Y maze test and novel object recognition task. RA, at the effective lowest dose (0.25mg/kg), prevented Abeta(25-35)-induced nitration of proteins, an indirect indicator of ONOO(-) damage, in the hippocampus. At this dose, RA also prevented nitration of proteins and impairment of recognition memory induced by ONOO(-)-i.c.v.-injection. Co-injection of the non-memory-impairing dose of ONOO(-) with Abeta(25-35) blocked the protective effects of RA (0.25mg/kg). 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.

 
Find the right peroxynitrite scavenger or scavengers and you not only stop the progression of Alzheimer's disease, you partially reverse it. 
 

 


Myriam
Posted: Saturday, December 22, 2012 2:07 PM
Joined: 12/6/2011
Posts: 3326


Thanks, Lane!!! Ummm, I am great at reading/understanding legalese, but go cross-eyed reading medical terms, but got that peroxynitrites are the problem...right?
Lane Simonian
Posted: Saturday, December 22, 2012 3:44 PM
Joined: 12/12/2011
Posts: 4855


That is right, Myriam!  The same pathway that leads to the formation of peroxynitrites leads to inflammation.  It may be the peroxynitrites themselves by damaging tissue and killing neurons cause most of the inflammation.  In any case if you block peroxynitrite formation, you also block inflammation, and more importantly you prevent the death of neurons.  That is why eugenol in various essential oils by acting as peroxynitrite scavengers help prevent the death of neurons. 

 

 

Eugenol (4-allyl-2-methoxyphenol) is a fragrant compound that is commonly contained in various sorts of plants, especially in spices and medicinal herbs. Eugenol has been used for dental analgesic, which also has anticonvulsive and anti-microbial activities. Besides, anti-inflammatory and antioxidative activities of eugenol are known...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 

 

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.

 

And from one of the best early studies on peroxynitrites: 

 

Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease

  1. George Perry1  

+ Author Affiliations

  1. 1 Institute of Pathology and
     
  2. 2 Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, and
     
  3. 3 Department of Anesthesiology, School of Medicine, University of Alabama, Birmingham, Alabama 35233
     
 

Abstract

Increasing evidence suggests that oxidative damage to proteins and other macromolecules is a salient feature of the pathology of Alzheimer’s disease. Establishing the source of oxidants is key to understanding what role they play in the pathogenesis of Alzheimer’s disease, and one way to examine this issue is to determine which oxidants are involved in damage.

In this study, we examine whether peroxynitrite, a powerful oxidant produced from the reaction of superoxide with nitric oxide, is involved in Alzheimer’s disease. Peroxynitrite is a source of hydroxyl radical-like reactivity, and it directly oxidizes proteins and other macromolecules with resultant carbonyl formation from side-chain and peptide-bond cleavage. Although carbonyl formation is a major oxidative modification induced by peroxynitrite, nitration of tyrosine residues is an indicator of peroxynitrite involvement. In brain tissue from cases of Alzheimer’s disease, we found increased protein nitration in neurons, including but certainly not restricted to those containing neurofibrillary tangles (NFTs). Conversely, nitrotyrosine was undetectable in the cerebral cortex of age-matched control brains. This distribution is essentially identical to that of free carbonyls.

These findings provide strong evidence that peroxynitrite is involved in oxidative damage of Alzheimer’s disease. Moreover, the widespread occurrence of nitrotyrosine in neurons suggests that oxidative damage is not restricted to long-lived polymers such as NFTs, but instead reflects a generalized oxidative stress that is important in disease pathogenesis.

 

http://www.jneurosci.org/content/17/8/2653.full 

 

And one of the best conclusions in regards to 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...]

 

http://www.cryonet.org/cgi-bin/dsp.cgi?msg=32233
 

 

 

 

 


Lane Simonian
Posted: Thursday, December 27, 2012 9:25 PM
Joined: 12/12/2011
Posts: 4855


Further evidence that peroxynitrites are the principal cause of and should be the prinicipal target in the treatment of Alzheimer's disease. 

 

Peroxynitrite, the coupling product of superoxides and nitric oxide, is a potent oxidant that induces an array of deleterious events including peroxidation of membrane lipids (Rubbo et al., 1994), depletion of glutathione (Salgo et al., 1995), DNA single strand breakage (Szabó & Ohshima, 1997), mitochondrial dysfunction (Brown, 1999) and cell death (Cookson et al., 1998; Pieper et al., 1999). All these events are thought to be directly mediated by peroxynitrite.

In the present study, we report experimental evidence consistent with the possibility that peroxynitrite may also act as a signalling molecule. In particular, endogenous as well as exogenous peroxynitrite promotes a release of arachidonic acid (AA) most likely attributable to stimulation of phospholipase A2 (PLA2).

 

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1572026/ 

 

In the chart below it is phospholipse C activation that causes the activation of protein kinase C and MAPK which results in the production of peroxynitrites.   So now I understand why most anti-inflammatories, such as aspirin and ibuprofen, don't work in the treatment of Alzheimer's disease: they work to control inflammation long after peroxynitrites have already formed.  I become more certain of the mantra every day.  Stop the formation of peroxynitrites and you prevent Alzheimer's disease.  Scavenge and repair the damage done by peroxynitrites, and you not only stop the progression of Alzheimer's disease you partially reverse it.  I know fairly specifically which compounds do both, but armed with this knowledge some researcher who was truly interested in treating this disease could likely find even more effective treatments in very short order. 

 

 


brutus
Posted: Friday, December 28, 2012 9:38 PM
Joined: 12/3/2012
Posts: 3


My neurologist recommended that I consider trying this diet to help with the plaque in my brain that seems to be the cause of my frontaltemporal dememetia and vascular dementia. 

   The Anti-Inflammatory diet may help with the dementia it is worth a try. http://www.drweil.com/drw/u/ART02012/anti-inflammatory-diet


Lane Simonian
Posted: Saturday, December 29, 2012 10:59 AM
Joined: 12/12/2011
Posts: 4855


A belated welcome, Brutus.  I am glad that your neurologist recommended that you consider trying Dr. Weil's anti-inflammatory diet.  I contacted Dr. Weil's institute in Arizona but they are not currently doing any research on dementia.  Nevertheless this type of diet may help in the treatment of dementia.