Brain Arachidonic Acid

[Peatit]

Something Ray said in a politics & science interview made me look after an answer to an apparently simple question: Why does the brain concentrate a such percentage of AA and moreover, why does it regenerate it by taking it from the circulating AA in the blood stream?
If it was something harmful, logic leads me to believe that it would not be stored in the most important organ of the body.

That's the extract from the said interview (Politics & Science: Thyroid And Regeneration):
[QUOTE ]
If you look at just arachidonic acid, for example, which makes up a considerable amount of the fat in the brain, that changes and is renewed by the bloodstream about 5% per day.
[/QUOTE]

 

[lollipop]

Interested in this. Following.

 

[ecstatichamster]

is it possible that the brain isn't making AA and that it would make Mead acid instead?

 

[Peatit]

is it possible that the brain isn't making AA and that it would make Mead acid instead?

Well, this is not what I understand from Ray's quote.
He seems to speak specifically about AA

 

[ecstatichamster]

Well, this is not what I understand from Ray's quote.
He seems to speak specifically about AA

well yes, but is it possible that if you don't consume linoleic acid, the body won't use it to make AA, but would instead synthesize Mead acid...

 

[ReSTART]

The metabolism of AA is not to purely inflammatory or harmful compounds.
Lipoxin - Wikipedia
Prostaglandin-endoperoxide synthase 2 - Wikipedia
Resolvin - Wikipedia

While metabolizing arachidonic acid primarily to PGG2, COX-2 also converts this fatty acid to small amounts of a racemic mixture of 15-Hydroxyicosatetraenoic acids (i.e., 15-HETEs) composed of ~22% 15(R)-HETE and ~78% 15(S)-HETE stereoisomers as well as a small amount of 11(R)-HETE. The two 15-HETE stereoisomers have intrinsic biological activities but, perhaps more importantly, can be further metabolized to a major class of agents, the lipoxins. Furthermore, aspirin-treated COX-2 metabolizes arachidonic acid almost exclusively to 15(R)-HETE which product can be further metabolized to epi-lipoxins. The lipoxins and epi-lipoxins are potent anti-inflammatory agents and may contribute to the overall activities of the two COX's as well as to aspirin.

 

[Spokey]

I'd pose a similar question to test that logic. If dioxin is so terrible, why would we accumulate it in our fats?
It seems to me like the composition of our brains just reflect the environmental fats diet, and it won't waste energy making mead acid under conditions where alternative, but less ideal fats, are available.

 

[Peatit]

@Spokey, your demonstration is interesting and makes sense.
But according to Ray, the brain's fat turnover is very high, unlike our subcutaneous fat (one of the places where toxins mainly accumulate). Given those facts and in the hypothesis of an individual's diet limiting the availability of long chain PUFAs, following your logic, the fat composition should change overtime (pretty quickly in fact if 25% of the fats are renewed each day).
Have someone here heard about this actually happening?

 

[lollipop]

OH MY look at this guys:

“It has long been a belief in the scientific field that the building blocks of brain cells, phospholipids, are enriched by polyunsaturated fatty acids. When trying to prove that the brain, like other major organs, are made of polyunsaturated fatty acids, Dr. Kim and his team were surprised by the results.

"We found the opposite of what science has widely believed -- phospholipids containing polyunsaturated fatty acids in the brain are lower than other major organs," said Dr. Kim. "Knowing that there are lower amounts of polyunsaturated fatty acids in the brain, we may need to rethink how this acid impacts brain health and conditions like oxygen deprivation."



https://www.sciencedaily.com/releases/2017/10/171030123345.htm

@haidut @Travis @Amazoniac @Diokine @ecstatichamster you guys might find this interesting.

 

[ecstatichamster]

OH MY look at this guys:

“It has long been a belief in the scientific field that the building blocks of brain cells, phospholipids, are enriched by polyunsaturated fatty acids. When trying to prove that the brain, like other major organs, are made of polyunsaturated fatty acids, Dr. Kim and his team were surprised by the results.

"We found the opposite of what science has widely believed -- phospholipids containing polyunsaturated fatty acids in the brain are lower than other major organs," said Dr. Kim. "Knowing that there are lower amounts of polyunsaturated fatty acids in the brain, we may need to rethink how this acid impacts brain health and conditions like oxygen deprivation."



https://www.sciencedaily.com/releases/2017/10/171030123345.htm

@haidut @Travis @Amazoniac @Diokine @ecstatichamster you guys might find this interesting.

Fantastic find, @lisaferraro thank you! SO interesting!

I have looked into Peat's work and he's right of course. DHA and EPA in the brain are especially bad, as they bind to protective alpha-synuclein proteins and can aggregate into fibrotic forms and cause dementia, Alzheimer's and Parkinson's.

 

[ecstatichamster]

@Spokey, your demonstration is interesting and makes sense.
But according to Ray, the brain's fat turnover is very high, unlike our subcutaneous fat (one of the places where toxins mainly accumulate). Given those facts and in the hypothesis of an individual's diet limiting the availability of long chain PUFAs, following your logic, the fat composition should change overtime (pretty quickly in fact if 25% of the fats are renewed each day).
Have someone here heard about this actually happening?

it might not happen because the PUFAs stored in adipose tissue and liver etc. may empty into the bloodstream and continuously bathe the brain, preventing the brain from getting rid of PUFAs.

NOTE: The above study is wrong at the conclusion, because it touts DHA as protective in the brain.

The dietary ratio of AA to DHA may affect neurodegeneration associated with acute neural trauma and neurodegenerative diseases. The dietary intake of docosahexaenoic acid offers the possibility of counter-balancing the harmful effects of high levels of AA-derived pro-inflammatory lipid mediators.

OUCH!!!!!

Polyunsaturated Fatty Acids Induce α-Synuclein-Related Pathogenic Changes in Neuronal Cells - ScienceDirect

The misfolding and aggregation of normally soluble proteins has emerged as a key feature of several neurodegenerative diseases. In Parkinson's disease, progressive loss of dopaminergic neurons is accompanied by polymerization of the cytoplasmic protein α-synuclein (αS) into filamentous inclusions found in neuronal somata (Lewy bodies) and dendrites (Lewy neurites). Similar αS aggregates occur in cortical neurons in dementia with Lewy bodies. Numerous reports now indicate that αS can interact with lipids. We previously found that treating dopaminergic cells expressing αS with polyunsaturated fatty acids (PUFAs) induced the formation of soluble, sodium dodecyl sulfate-stable oligomers whereas treatment with saturated fatty acids did not. Here, we examine the relevance of αS-PUFA interactions to the development of Parkinson's disease-like cytopathology. Exposure of αS-overexpressing dopaminergic or neuronal cell lines to physiological levels of a PUFA induced the formation of proteinaceous inclusions in the cytoplasm. Kinetic experiments in-dicated that PUFA-induced soluble oligomers of αS precede these Lewy-like inclusions. Importantly, we found that αS oligomers were associated with cyto-toxicity, whereas the development of Lewy-like inclusions appeared to be protective. We conclude that alterations in PUFA levels can lead to aggregation of αS and subsequent deposition into potentially cyto-toxic oligomers that precede inclusions in dopa-minergic cells.

α-Synuclein (αS) is a presynaptic protein implicated in Parkinson's disease (PD) at the levels of cytopathology and genetics.1–3 In PD and the various clinically distinct but neuropathologically related neurodegenerative disorders in which αS also accumulates (the synucleinopathies), there appears to be a progressive conversion of the highly soluble αS protein into insoluble, β-sheet-rich filamentous assemblies, resulting in its intraneuronal deposition into Lewy bodies (LBs) and Lewy neurites, the cytopathological hallmarks of this group of disorders.

Biophysical studies have shown that αS is “natively unfolded”4; however, on it's binding to acidic phospholipid vesicles in vitro, αS undergoes major conformational changes, resulting in an α-helical structure.5 The interactions of αS with phospholipids are mediated by its N-terminal region, which contains sequence homologies to the amphipathic, lipid-binding α-helices of class A2 apolipoproteins.5–7 The conserved structural similarity to the exchangeable apolipoproteins appears to explain the normal partitioning of αS between the aqueous and membranous compartments of the cytoplasm.5,8–11

αS-Lipid interactions can affect the kinetics of its aggregation in vitro.12–17 In particular, αS interactions with polyunsaturated fatty acids (PUFAs) can rapidly and dynamically affect its oligomerization and further aggregation.17,18–21 Given its primary structure, subcellular distribution to membranes, and conformational change on lipid binding, it is likely that αS interacts with lipids as part of its still undefined physiological function. For example, αS has been implicated by some studies in membrane lipid regulation and membrane trafficking.21–26

In accord with the initial discovery that αS expression regulates cytosolic and membrane PUFAs levels,20 several studies have recently shown that αS expression affects fatty acid (FA) uptake and metabolism.27–29Specifically, decreases in certain PUFAs and increases in certain saturated fatty acid (SFA) levels were detected in phospholipids of αS−/−mouse brains. Moreover, the steady-state mass of neutral lipids is increased in brains of αS−/− mice.29 In addition to the evidences for a role for αS in FA regulation, αS gene expression was reported to be up-regulated in response to PUFA-enriched diets in rats.30,31 In the context of the fact that αS gene duplication or triplication and resultant αS overexpression causes familial PD,32 it is possible that qualitative or quantitative changes in PUFAs could serve as risk factors for PD through an effect on αS expression and/or aggregation.

Here, we report that PUFA-induced soluble oligomers precede the formation of proteinaceous cytoplasmic inclusions in neuronal cell lines. The resultant Lewy-like inclusions react with antibodies to αS, phosphorylated αS, ubiquitin, and HSP-70. Further, we provide evidence that PUFA-induced soluble oligomers confer cytotoxicity, whereas PUFA-induced inclusions may be protective. We discuss the implications of these new findings for the mechanism of neuronal dysfunction in PD and other synucleinopathies.

 

[ecstatichamster]

α-Synuclein Structural Features Inhibit Harmful Polyunsaturated Fatty Acids Oxidation, Suggesting Roles in Neuroprotection

α-Synuclein (aS) is a protein abundant in presynaptic nerve terminals in Parkinson disease (PD) and is a major component of intracellular Lewy bodies, the pathological hallmark of neurodegenerative disorders such as PD. Accordingly, the relationships between aS structure, its interaction with lipids, and its involvement in neurodegeneration have attracted great interest. Previously, we reported on the interaction of aS with brain polyunsaturated fatty acids, in particular docosahexaenoic acid (DHA). aS acquires an α-helical secondary structure in the presence of DHA and, in turn, affects DHA structural and aggregative properties. Moreover, aS forms a covalent adduct with DHA. Here, we provide evidence that His50 is the main site of this covalent modification. To better understand His50 role, we analyzed the effect of DHA on aS-derived species: a naturally occurring variant, H50Q; an oxidized aS in which all methionines are sulfoxides (aS4ox); a fully lysine-alkylated aS (acetyl-aS); and aS fibrils, testing their ability to be chemically modified by DHA. We show, by mass spectrometry and spectroscopic techniques, that H50Q and aS4ox are modified by DHA, while acetyl-aS is not. We correlated this modification with aS structural features, and we suggest a possible functional role of aS in sequestering the early peroxidation products of fatty acids, thereby reducing the level of highly reactive lipid species. Finally, we show that fibrillar aS loses almost 80% of its scavenging activity, thus lacking a potentially protective function. Our findings linking aS scavenging activity with brain lipid composition suggest a possible etiological mechanism in some neurodegenerative disorders

 

[haidut]

OH MY look at this guys:

“It has long been a belief in the scientific field that the building blocks of brain cells, phospholipids, are enriched by polyunsaturated fatty acids. When trying to prove that the brain, like other major organs, are made of polyunsaturated fatty acids, Dr. Kim and his team were surprised by the results.

"We found the opposite of what science has widely believed -- phospholipids containing polyunsaturated fatty acids in the brain are lower than other major organs," said Dr. Kim. "Knowing that there are lower amounts of polyunsaturated fatty acids in the brain, we may need to rethink how this acid impacts brain health and conditions like oxygen deprivation."



https://www.sciencedaily.com/releases/2017/10/171030123345.htm

@haidut @Travis @Amazoniac @Diokine @ecstatichamster you guys might find this interesting.

Wow! This is amazing find! And sad at the same because "paradigm shifts" like or "paradoxical findings" like this are unlikely to make their way into the mainstream until decades later. And this was common knowledge in the early 20th century...
Thanks so much for posting this. I think it deserves its own thread so please do one if you want.

 

[haidut]

DHA and EPA in the brain are especially bad, as they bind to protective alpha-synuclein proteins and can aggregate into fibrotic forms and cause dementia, Alzheimer's and Parkinson's.

And apparently, the link between PUFA and Alzheimer is quite well known. But not to the common clinician who is likely to treat you or your relatives.
Increased Pufa Oxidation May Be Biomarker For Alzheimers
https://raypeatforum.com/community/...olism-may-reverse-alzheimer-disease-ad.14707/
Another Study Links PUFA To Alzheimer Disease (AD)

 

[Travis]

OH MY look at this guys:

“It has long been a belief in the scientific field that the building blocks of brain cells, phospholipids, are enriched by polyunsaturated fatty acids. When trying to prove that the brain, like other major organs, are made of polyunsaturated fatty acids, Dr. Kim and his team were surprised by the results.

"We found the opposite of what science has widely believed -- phospholipids containing polyunsaturated fatty acids in the brain are lower than other major organs," said Dr. Kim. "Knowing that there are lower amounts of polyunsaturated fatty acids in the brain, we may need to rethink how this acid impacts brain health and conditions like oxygen deprivation."
[...]

Nice article. This is a wealth of information at 23 pages (minus 7 pages of citations). Doctor Farooqui talks on the same lines as Ray Peat, and differs only in his recommendation of DHA.

• Farooqui, AA., LA. Horrocks, and Tahira Farooqui. "Modulation of inflammation in brain: a matter of fat." Journal of neurochemistry 101.3 (2007): 577-599.

With the initials of AA Farooqui, you'd almost expect him to take it easy on arachidonic acid [2 corny jokes remaining this year] but he doesn't. He implicates it—and its linoleic acid precursor—as the cause of brain damage, inflammation, and dementia.

I pulled-out what I thought were the most interesting comments; deparethacized, subscripted, indented them and even marginalized them further with 3-point font (for space).

All neural cells, including microglia, astrocytes, neurons, and oligodendrocytes, participate in inflammatory responses. ―AA Farooqui​

Harold Hillman, in this video, informs the viewer that the "astrocyte" is a misnomer; that is to say, it's nor really "star shaped" in vivo. Hillman states that this is merely an artefact, a result of aldehyde fixation: The star shape is formed only as the neuroglial cells (or was a the neurons?) are fixed by certain stains and fixatives they "are sensitive to", dehydrated by graded ethanol and their protein membranes crosslinked. Harold Hillman is of the opinion that there are far less cell types in the brain than widely though (only two).

Glial cells, the microglia, astrocytes, and oligodendrocytes neurons, constitute more than 70% 100% of the total cell population in the brain tissue. ―AA Farooqui
​

As would likely be edited by Harold Hillman.

The overall cytokine response may be dependent on the synergistic or antagonistic activities of various cytokines. ―AA Farooqui​

At least cytokines respond (unlike @Diokines (where did he go?)). [1 corny jokes remaining this year.]

In the nucleus NFκB mediates the transcription of many genes implicated in inflammatory and immune responses. These genes include COX-2, intracellular adhesion molecule-1, vascular adhesion molecule-1, E-selectin, TNFα, IL-1β, IL-6, phospholipase 2, inducible nitric oxide synthase, and matrix metalloproteinases. Its activation also leads to the local generation of more cytokines, which in turn promulgate inflammatory signals. NFκB is also stimulated by polyunsaturated fatty acids, products of reactions catalyzed by cPLA₂, iPLA₂, and sPLA₂ [all phospholipases]. This induction of NFκB is blocked by N-acetylcysteine as well as vitamin E (Mazie`re et al. 1999), suggesting the involvement of ROS during NFjB-mediated processes. ―AA Farooqui​

The transcription factor NFκB seems to be very powerful in sensing lipid peroxidation. Since both N-acetylcysteine and vitamin E prevent the activation of this, you might be tempted to think that it has an arginine residue at an important DNA-binding site. Paul Thornally proved that methylglyoxal controls transcription by turning arginine into a cylclic imidizole. In this way, proteins can sense peroxidation directly—no need for some of the drawn-out, speculative, ill-defined, and almost unbelievable reaction cascades. Thornally also says that arginine is the most common amino acid found in enzymes catalytic domain. Like Pauling and Ling, Thornally is thinking on the molecular level.

• Yao, Dachun: Thronally, Paul: "High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A." Journal of Biological Chemistry 282.42 (2007): 31038-31045.

Endogenous ligands for PPAR-γ include long-chain polyunsaturated fatty acids (products of PLA₂ catalyzed reactions), eicosanoid derivatives (products of COX catalyzed reactions), and oxidized phospholipids (products of non-enzymic oxidation). ―AA Farooqui​

The nuclear receptor PPARγ is how the cell senses eicosanoids. Perhaps not surprisingly, this signals hibernation is some species (and a diabetic state in non-hibernatory mammals.) In this way, linoleic acid suppresses metabolism.

• Storey, Kenneth B. "Mammalian hibernation. Transcriptional and translational controls." Adv Exp Med Biol 543 (2003):

I'm getting the impression from this article that nearly any cellular damage creates eicosanoids through the breakdown and release of linoleic and and arachidonic acids from the lipid membrane. Through eicasanoids you can view linoleic acid as almost hormonal in action.

Activated microglia have been observed around degenerative neurons in Alzheimer disease (AD) [aluminum], Parkinson disease (PD) [aluminum], Down syndrome (DS) [homocysteine], Huntington disease (HD)[?], multiple sclerosis (MS) [?], and AIDS-dementia [AZT]. ―AA Farooqui
​

I can see how other things contribute, or could even cause these conditions in some cases. But I think it's important never to forget how quickly aluminum can initiate these conditions.

Daniel Perl found neurofibrillary tangles in Alzheimer's, Parkinsons, and ALS. He seemed convinced, at least in the 80s, that these three conditions were all caused by aluminum—differing only in the quantity, quality, and location of tangles. These are the Gordian Knot of inclusion bodies; they are resistant to proteolysis and make lipofuscin look like a kitten. The have only been experimentally induced by aluminum—in rats, rabbits, and monkeys—and are likely the result of the natural affinity of Al³⁺ for –PO₄²⁻. The protein τ is highly-phosphorylated and Al³⁺ has been shown to form aggregates with it in vitro, more than any other ion tested. With the same size charge as ferrous iron, and nearly identical atomic radius, aluminum goes wherever iron goes in the body. It can be displaced, carried, and delivered by ferritin. Calcium antagonizes it while pregnenolone and progesterone form protective myelin.

According to Bazan and Flower, neural membranes are a Pandora’s box of lipid mediators, many of which have powerful neurochemical effects, some beneficial and others harmful. ―AA Farooqui

They differ from PGs. In IsoPs the side chains are cis to the cyclopentane ring, whereas in PGs they have the trans orientation. ―AA Farooqui​

This is interesting. Perhaps only trans-eicasanoids activate PPAR receptors? It would be nice to know a few simple rules for determining which of the eicosanoids can do what, besides based solely on their fatty acid origin. You could then almost anticipate the effects of certain drugs, like individual cannabinoids, by their structure.

I just had a thought. Perhaps some of these protein hormones, like prolactin (which bind but don't penetrate the cell), work partly by cleaving eicosanoid precursors from the cell membrane. This would make sense, as phosphates and inositol phosphates are released in response to this (the other products of some phospholipases). The inositol phosphates are probably what cause calcium influx, as they're known as strong calcium attractants and chelators—even in vitro acellular conditions.

• Luttrell, B. M. "The biological relevance of the binding of calcium ions by inositol phosphates." Journal of Biological Chemistry268.3 (1993): 1521-1524.

EPA-derived eicosanoids are much less active than AA-derived eicosanoids. ―AA Farooqui

In contrast, DHA is not a substrate for cyclooxygenase. ―AA Farooqui​

Actions of a 15- lipoxygenase-like enzyme on DHA produce 17S-resolvins, 10-,17S-docosatrienes, and protectins. These second messengers have the collective name of docosanoids. They are potent endogenous antiinflammatory and pro-resolving chemical lipid mediators. ―AA Farooqui​

These sound like the inflammation off-signal. Perhaps chronic linoleic acid ingestion could keep inflammation in the on mode?

Actions of a 15- lipoxygenase-like enzyme on DHA produce 17S-resolvins, 10-,17S-docosatrienes, and protectins. These second messengers have the collective name of docosanoids. They are potent endogenous antiinflammatory and pro-resolving chemical lipid mediators. ―AA Farooqui​

This is interesting. Apparently DHA is considered protective for the types of eicosdocosanoids it produces. However, he does say later in another section.

Non-enzymic oxidation of DHA also produces neuroketals (NK). Like IsoK, NK are very reactive. They form not only lactam and Schiff base adducts, but also generate lysine adducts suggesting that these metabolites may be involved in protein–protein cross-linking in brain tissue under oxidative stress. ―AA Farooqui​

He admits that they form reactive aldehydes—the mediator of lipofuscin and most likely a participant in neurofibrillary tangles. @ecstatichamster also mentions Lewy bodies inclusion products, but I must admit that this is a new concept for me. Must look into Lewy bodies.

Aldehydes, and especially dialdehydes, are highly-reactive. They crosslink proteins at the nitrogen-groups. Dialdehydes are the worst since they have two aldehydic groups, one at each end. The longer the worse, since longer dialdehydes can span longer distances. Gluaraldehyde is used as a histological tissue fixative for this reason, and the TBARs assay measures lipid-derived malondialdehyde directly as a metric of lipid peroxidation (although the detection of superoxide UV-emission is the most sensitive assay for lipid peroxidation.)

Brain tissue is enriched in AA and DHA. Despite their abundance in the nervous system, AA and DHA cannot be synthesized de novo by mammals; they, or their precursors, must be ingested from dietary sources and transported to the brain. ―AA Farooqui​

Ergo: Peatarians have less AA and DHA in their brains (than the general population.)

The present day western diet has a ratio of AA to DHA of about 15:1. The Paleolithic diet on which human beings have evolved, and lived for most of their existence, has a ratio of AA to DHA of 1 : 1. ―AA Farooqui​

The next section reads almost like a fish oil advertisement, the way he speaks about DHA. While it's undeniable that the docosanoids produced from such are generally neuroprotective, they noncatalytic reaction products are crosslinkers. Also, DHA can be produced endogenously. I have to agree with Peat that simply avoiding all PUFA is better than the post hoc frantic attempt of balancing linoleic acid by guzzling fish oil (GTFO Masterjohn!).

Similarly, the degradation of sphingomyelin through the stimulation of SMase increases the levels of ceramide and its metabolic products including the generation of psychosine. The levels of psychosine are markedly increased in twitcher mice, a murine model of Krabbe disease ―AA Farooqui​

Psychosine: Interesting. A psychedelic product myelin degradation.

In biomembranes, transition metal ions (copper and iron) initiate lipid peroxidation by generating peroxyl and alkoxyl radicals from the decomposition of lipid hydroperoxides (Murphy 2001). ―AA Farooqui​

He cites a 2001 article but he could have cited articles from the 50s and 60s. Nothing is more firmly established than this.

DHA administration reduces L-DOPA induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- treated monkeys suggesting that that DHA can reduce the severity or delay the development of L-DOPA induced dyskinesias in a nonhuman primate model of Parkinson disease. ―AA Farooqui​

I read an article that the enzymatic product of catechol-O-methyltransferase with dopamine (2-methoxytyramine) was actually responsible for this.

This suggests that DHA treatment after spinal cord compression greatly increases the survival of neurons and results in significantly better locomotor performance for up to 6 weeks after injury. ―AA Farooqui​

Yeah, but probably not as well as progesterone and cannabinoids—together! Cannabinoids are plant-based regulators of the eicosanoid and docosanoid pathways. The structures of cannabinoids and eicosanoids/docosanoids are indeed similar.

A balanced ratio of n-6 to n-3 fatty acid also plays an important role in prevention of cancer. Implantation of mouse melanoma B16 in fat-1 transgenic mice, which have a balanced ratio of n-6 to n-3 fatty acids in their tissues and can convert n-6 fatty acids to n-3 fatty acids, produces a dramatic reduction of melanoma formation and growth compared to WT littermates. The levels of n-3 fatty acids and their metabolite PGE₃ were higher in the tumor and surrounding tissues of fat-1 mice than in WT mice, suggesting that n-3 fatty acids inhibit the growth of melanoma caused by the implanted B16 cell line. Collectively these studies indicate that n-3 fatty acids have anticancer properties and can be used as therapeutic agents to treat this cancer in mice. ―AA Farooqui​

He should have mentioned and cited Godley 1996, which shows a prostate cancer vs tissue linoleic acid risk ratio of 9.o7 (Table 4).

• Godley, Paul A., et al. "Biomarkers of essential fatty acid consumption and risk of prostatic carcinoma." Cancer Epidemiology and Prevention Biomarkers 5.11 (1996): 889-895.

"Although neuroinflammation serves as a neuroprotective mechanism associated with repair and recovery, it can also cause brain damage." ―AA Farooqui​

 

[lollipop]

Nice article. This is a wealth of information at 23 pages (minus 7 pages of citations). Doctor Farooqui talks on the same lines as Ray Peat, and differs only in his recommendation of DHA.

• Farooqui, AA., LA. Horrocks, and Tahira Farooqui. "Modulation of inflammation in brain: a matter of fat." Journal of neurochemistry 101.3 (2007): 577-599.

With the initials of AA Farooqui, you'd almost expect him to take it easy on arachidonic acid [2 corny jokes remaining this year] but he doesn't. He implicates it—and its linoleic acid precursor—as the cause of brain damage, inflammation, and dementia.

I pulled-out what I thought were the most interesting comments; deparethacized, subscripted, indented them and even marginalized them further with 3-point font (for space).

All neural cells, including microglia, astrocytes, neurons, and oligodendrocytes, participate in inflammatory responses. ―AA Farooqui​

Harold Hillman, in this video, informs the viewer that the "astrocyte" is a misnomer; that is to say, it's nor really "star shaped" in vivo. Hillman states that this is merely an artefact, a result of aldehyde fixation: The star shape is formed only as the neuroglial cells (or was a the neurons?) are fixed by certain stains and fixatives they "are sensitive to", dehydrated by graded ethanol and their protein membranes crosslinked. Harold Hillman is of the opinion that there are far less cell types in the brain than widely though (only two).

Glial cells, the microglia, astrocytes, and oligodendrocytes neurons, constitute more than 70% 100% of the total cell population in the brain tissue. ―AA Farooqui
​

As would likely be edited by Harold Hillman.

The overall cytokine response may be dependent on the synergistic or antagonistic activities of various cytokines. ―AA Farooqui​

At least cytokines respond (unlike @Diokines (where did he go?)). [1 corny jokes remaining this year.]

In the nucleus NFκB mediates the transcription of many genes implicated in inflammatory and immune responses. These genes include COX-2, intracellular adhesion molecule-1, vascular adhesion molecule-1, E-selectin, TNFα, IL-1β, IL-6, phospholipase 2, inducible nitric oxide synthase, and matrix metalloproteinases. Its activation also leads to the local generation of more cytokines, which in turn promulgate inflammatory signals. NFκB is also stimulated by polyunsaturated fatty acids, products of reactions catalyzed by cPLA₂, iPLA₂, and sPLA₂ [all phospholipases]. This induction of NFκB is blocked by N-acetylcysteine as well as vitamin E (Mazie`re et al. 1999), suggesting the involvement of ROS during NFjB-mediated processes. ―AA Farooqui​

The transcription factor NFκB seems to be very powerful in sensing lipid peroxidation. Since both N-acetylcysteine and vitamin E prevent the activation of this, you might be tempted to think that it has an arginine residue at an important DNA-binding site. Paul Thornally proved that methylglyoxal controls transcription by turning arginine into a cylclic imidizole. In this way, proteins can sense peroxidation directly—no need for some of the drawn-out, speculative, ill-defined, and almost unbelievable reaction cascades. Thornally also says that arginine is the most common amino acid found in enzymes catalytic domain. Like Pauling and Ling, Thornally is thinking on the molecular level.

• Yao, Dachun: Thronally, Paul: "High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A." Journal of Biological Chemistry 282.42 (2007): 31038-31045.

Endogenous ligands for PPAR-γ include long-chain polyunsaturated fatty acids (products of PLA₂ catalyzed reactions), eicosanoid derivatives (products of COX catalyzed reactions), and oxidized phospholipids (products of non-enzymic oxidation). ―AA Farooqui​

The nuclear receptor PPARγ is how the cell senses eicosanoids. Perhaps not surprisingly, this signals hibernation is some species (and a diabetic state in non-hibernatory mammals.) In this way, linoleic acid suppresses metabolism.

• Storey, Kenneth B. "Mammalian hibernation. Transcriptional and translational controls." Adv Exp Med Biol 543 (2003):

I'm getting the impression from this article that nearly any cellular damage creates eicosanoids through the breakdown and release of linoleic and and arachidonic acids from the lipid membrane. Through eicasanoids you can view linoleic acid as almost hormonal in action.

Activated microglia have been observed around degenerative neurons in Alzheimer disease (AD) [aluminum], Parkinson disease (PD) [aluminum], Down syndrome (DS) [homocysteine], Huntington disease (HD)[?], multiple sclerosis (MS) [?], and AIDS-dementia [AZT]. ―AA Farooqui
​

I can see how other things contribute, or could even cause these conditions in some cases. But I think it's important never to forget how quickly aluminum can initiate these conditions.

Daniel Perl found neurofibrillary tangles in Alzheimer's, Parkinsons, and ALS. He seemed convinced, at least in the 80s, that these three conditions were all caused by aluminum—differing only in the quantity, quality, and location of tangles. These are the Gordian Knot of inclusion bodies; they are resistant to proteolysis and make lipofuscin look like a kitten. The have only been experimentally induced by aluminum—in rats, rabbits, and monkeys—and are likely the result of the natural affinity of Al³⁺ for –PO₄²⁻. The protein τ is highly-phosphorylated and Al³⁺ has been shown to form aggregates with it in vitro, more than any other ion tested. With the same size charge as ferrous iron, and nearly identical atomic radius, aluminum goes wherever iron goes in the body. It can be displaced, carried, and delivered by ferritin. Calcium antagonizes it while pregnenolone and progesterone form protective myelin.

According to Bazan and Flower, neural membranes are a Pandora’s box of lipid mediators, many of which have powerful neurochemical effects, some beneficial and others harmful. ―AA Farooqui

They differ from PGs. In IsoPs the side chains are cis to the cyclopentane ring, whereas in PGs they have the trans orientation. ―AA Farooqui​

This is interesting. Perhaps only trans-eicasanoids activate PPAR receptors? It would be nice to know a few simple rules for determining which of the eicosanoids can do what, besides based solely on their fatty acid origin. You could then almost anticipate the effects of certain drugs, like individual cannabinoids, by their structure.

I just had a thought. Perhaps some of these protein hormones, like prolactin (which bind but don't penetrate the cell), work partly by cleaving eicosanoid precursors from the cell membrane. This would make sense, as phosphates and inositol phosphates are released in response to this (the other products of some phospholipases). The inositol phosphates are probably what cause calcium influx, as they're known as strong calcium attractants and chelators—even in vitro acellular conditions.

• Luttrell, B. M. "The biological relevance of the binding of calcium ions by inositol phosphates." Journal of Biological Chemistry268.3 (1993): 1521-1524.

EPA-derived eicosanoids are much less active than AA-derived eicosanoids. ―AA Farooqui

In contrast, DHA is not a substrate for cyclooxygenase. ―AA Farooqui​

Actions of a 15- lipoxygenase-like enzyme on DHA produce 17S-resolvins, 10-,17S-docosatrienes, and protectins. These second messengers have the collective name of docosanoids. They are potent endogenous antiinflammatory and pro-resolving chemical lipid mediators. ―AA Farooqui​

These sound like the inflammation off-signal. Perhaps chronic linoleic acid ingestion could keep inflammation in the on mode?

Actions of a 15- lipoxygenase-like enzyme on DHA produce 17S-resolvins, 10-,17S-docosatrienes, and protectins. These second messengers have the collective name of docosanoids. They are potent endogenous antiinflammatory and pro-resolving chemical lipid mediators. ―AA Farooqui​

This is interesting. Apparently DHA is considered protective for the types of eicosdocosanoids it produces. However, he does say later in another section.

Non-enzymic oxidation of DHA also produces neuroketals (NK). Like IsoK, NK are very reactive. They form not only lactam and Schiff base adducts, but also generate lysine adducts suggesting that these metabolites may be involved in protein–protein cross-linking in brain tissue under oxidative stress. ―AA Farooqui​

He admits that they form reactive aldehydes—the mediator of lipofuscin and most likely a participant in neurofibrillary tangles. @ecstatichamster also mentions Lewy bodies inclusion products, but I must admit that this is a new concept for me. Must look into Lewy bodies.

Aldehydes, and especially dialdehydes, are highly-reactive. They crosslink proteins at the nitrogen-groups. Dialdehydes are the worst since they have two aldehydic groups, one at each end. The longer the worse, since longer dialdehydes can span longer distances. Gluaraldehyde is used as a histological tissue fixative for this reason, and the TBARs assay measures lipid-derived malondialdehyde directly as a metric of lipid peroxidation (although the detection of superoxide UV-emission is the most sensitive assay for lipid peroxidation.)

Brain tissue is enriched in AA and DHA. Despite their abundance in the nervous system, AA and DHA cannot be synthesized de novo by mammals; they, or their precursors, must be ingested from dietary sources and transported to the brain. ―AA Farooqui​

Ergo: Peatarians have less AA and DHA in their brains (than the general population.)

The present day western diet has a ratio of AA to DHA of about 15:1. The Paleolithic diet on which human beings have evolved, and lived for most of their existence, has a ratio of AA to DHA of 1 : 1. ―AA Farooqui​

The next section reads almost like a fish oil advertisement, the way he speaks about DHA. While it's undeniable that the docosanoids produced from such are generally neuroprotective, they noncatalytic reaction products are crosslinkers. Also, DHA can be produced endogenously. I have to agree with Peat that simply avoiding all PUFA is better than the post hoc frantic attempt of balancing linoleic acid by guzzling fish oil (GTFO Masterjohn!).

Similarly, the degradation of sphingomyelin through the stimulation of SMase increases the levels of ceramide and its metabolic products including the generation of psychosine. The levels of psychosine are markedly increased in twitcher mice, a murine model of Krabbe disease ―AA Farooqui​

Psychosine: Interesting. A psychedelic product myelin degradation.

In biomembranes, transition metal ions (copper and iron) initiate lipid peroxidation by generating peroxyl and alkoxyl radicals from the decomposition of lipid hydroperoxides (Murphy 2001). ―AA Farooqui​

He cites a 2001 article but he could have cited articles from the 50s and 60s. Nothing is more firmly established than this.

DHA administration reduces L-DOPA induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- treated monkeys suggesting that that DHA can reduce the severity or delay the development of L-DOPA induced dyskinesias in a nonhuman primate model of Parkinson disease. ―AA Farooqui​

I read an article that the enzymatic product of catechol-O-methyltransferase with dopamine (2-methoxytyramine) was actually responsible for this.

This suggests that DHA treatment after spinal cord compression greatly increases the survival of neurons and results in significantly better locomotor performance for up to 6 weeks after injury. ―AA Farooqui​

Yeah, but probably not as well as progesterone and cannabinoids—together! Cannabinoids are plant-based regulators of the eicosanoid and docosanoid pathways. The structures of cannabinoids and eicosanoids/docosanoids are indeed similar.

A balanced ratio of n-6 to n-3 fatty acid also plays an important role in prevention of cancer. Implantation of mouse melanoma B16 in fat-1 transgenic mice, which have a balanced ratio of n-6 to n-3 fatty acids in their tissues and can convert n-6 fatty acids to n-3 fatty acids, produces a dramatic reduction of melanoma formation and growth compared to WT littermates. The levels of n-3 fatty acids and their metabolite PGE₃ were higher in the tumor and surrounding tissues of fat-1 mice than in WT mice, suggesting that n-3 fatty acids inhibit the growth of melanoma caused by the implanted B16 cell line. Collectively these studies indicate that n-3 fatty acids have anticancer properties and can be used as therapeutic agents to treat this cancer in mice. ―AA Farooqui​

He should have mentioned and cited Godley 1996, which shows a prostate cancer vs tissue linoleic acid risk ratio of 9.o7 (Table 4).

• Godley, Paul A., et al. "Biomarkers of essential fatty acid consumption and risk of prostatic carcinoma." Cancer Epidemiology and Prevention Biomarkers 5.11 (1996): 889-895.

"Although neuroinflammation serves as a neuroprotective mechanism associated with repair and recovery, it can also cause brain damage." ―AA Farooqui​

Fascinating @Travis. Bookmarked. I am so enjoying your posts. This part cracked me up:

“At least cytokines respond (unlike @Diokines (where did he go?)). [1 corny jokes remaining this year.]”

Who said “only 1 corny joke remaining this year? I cry mutiny - lol.

 

[Spokey]

@Spokey, your demonstration is interesting and makes sense.
But according to Ray, the brain's fat turnover is very high, unlike our subcutaneous fat (one of the places where toxins mainly accumulate). Given those facts and in the hypothesis of an individual's diet limiting the availability of long chain PUFAs, following your logic, the fat composition should change overtime (pretty quickly in fact if 25% of the fats are renewed each day).
Have someone here heard about this actually happening?

The premise makes sense. I'd expect the brain's fat composition to change rapidly since it's a very metabolically expensive organ (mine does need a lot of prompting sometimes though). Subcutaneous fat and fat stored in less metabolically active tissue, I'd expect that to take longer. But if the slower tissues are releasing FFAs into circulation, that's probably going to hinder the brain's turnover too. I need to read the rest of this suddenly much longer thread though!

 

[haidut]

Collectively these studies indicate that n-3 fatty acids have anticancer properties and can be used as therapeutic agents to treat this cancer in mice

I don't quite agree with this. Omega-3 consumption has been solidly linked to higher, not lower rates of melanoma.
Fish oil consumption increases melanoma risk

 

[Travis]

I couldn't find a full-text link for that study, but they did say this in the abstract:

"Use of cod liver oil supplementation and intake of polyunsaturated fat were associated with significant increased risk and drinking coffee with significant decreased risk of CMM in women. Adjusting for height, body mass index, body surface area, education, smoking or occupational or recreational physical activity did not change the results." ―Veierød
​

Well, ω−3 fatty acids still contribute to lipofuscin.. . ..so they should be avoided regardless. I certainly don't like the idea of trying to simply dilute linoleic acid with ω−3 fatty acids like some of these scientists are implying. The Peat approach of avoiding both seems to be the better idea.

And fish oil is also very high in retinol:

➫ "Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in β-carotene and retinol, and people having higher serum β-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg β-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18,314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group."

➫ Omenn, Gilbert S., et al. "Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial." JNCI: Journal of the National Cancer Institute 88.21 (1996): 1550-1559.
​

Certainly not anything wrong with vitamin A, but very large doses seem to be capable of stimulating cell division. Fish oil has very large retinol concentrations, and that Veierød study was done in a Norwegian population—a country which had vitamin A fortified milk during that time. Most Norewegians were getting vitamin A over-and-above what was necessary, even without consuming fish oil.

 

[Mito]

I couldn't find a full-text link for that study,

http://onlinelibrary.wiley.com/stor...9q&s=52476f94fa05307add978b3acc69be5cc56a062d