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Inflammatory mediators and modulation of blood-brain barrier permeability

nanonug

Senior Member
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Virginia, USA
Cell Mol Neurobiol. 2000 Apr;20(2):131-47.
Inflammatory mediators and modulation of blood-brain barrier permeability.

Abbott NJ.
Source

Division of Physiology, GKT School of Biomedical Sciences, King's College London, UK. joan.abbott@kcl.ac.uk
Abstract

1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia. 7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase. 8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP. 9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations. 10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways. 11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.

PMID: 10696506
 

alex3619

Senior Member
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13,810
Location
Logan, Queensland, Australia
For many years I pursued an arachidonic acid modification strategy, with mixed results. It works, but it does not work consistently. According to this paper, this would have decreased BBB permeability.
 

Sushi

Moderation Resource Albuquerque
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19,935
Location
Albuquerque
For many years I pursued an arachidonic acid modification strategy, with mixed results. It works, but it does not work consistently. According to this paper, this would have decreased BBB permeability.

How did you modify arachidonic acid? In blood tests, mine was almost unmeasurable and I looked for ways to supplement but didn't find much? I don't even know if blood would be the best place to measure it?

Sushi
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi Sushi, I have discussed arachidonic acid issues at length on PR before. From the biochemistry I predict we have two problems. First, there is a slow down in synthesis. Second, there is an increase in utilization. Areas of ME related inflammation, probably including brain and gut, would hyperutilize it. So you can't fix the problem without fixing inflammation - thats where the early arachidonic acid based protocol was wrong.

Part of that protocol was eating lots of fruit and vege, which supply vegetable polyphenols and other things.

Arachidonic acid is a product of omega-6 fats. The problem is its proinflammatory. So if you just take evening primrose oil you risk increasing inflammation. I prefer short chain omega-6s even though they are not converted fast in us probably due to glutathione insufficiency. Glutathione status is closely associated with the function of the desaturase enzymes needed to make arachidonic acid. I have also emphasized extra virgin olive oil, but almost nobody else suggests that ... though I note its becoming a popular suggestion now, finally.

Restoring arachidonic acid to normal is a huge problem. We need it, but if we have it we can get sicker. If it can disrupt the BBB this is an extra clue as to how it might harm us. Its also worth noting that alcohol has as its primary destructive mechanism the release of free arachidonic acid. This can cause death. Those who are alcohol intolerant fit my description of what is going on.

Omega-3 fats, especially EPA, inhibit arachidonic acid in various ways (though DHA is very ineffective).

Almost everyone talking about essential fatty acids talk about how to increase the synthesis, or how to balance omega-3s and omega-6s. Almost nobody aside from me talk about how to alter its utilization, at least in relation to ME. That is the real key in my view. Curcumin has potential but I never found it effective. However I do eat tumeric regularly.

Currently I am experimenting with resverotrol in combination with the antioxidant quartet and methylation B vitamins.

Bye, Alex
 

Sushi

Moderation Resource Albuquerque
Messages
19,935
Location
Albuquerque
alex3619

Thanks! I've been using resverotrol, curcumin and lots of olive oil. I have no idea what the effect is--nothing startling. And I really have no idea what I am doing on this question. :confused:

Sushi
 

Enid

Senior Member
Messages
3,309
Location
UK
Nanonug - out of my depth here but any chance of virals (entero or neuro) crossing the blood brain barrier too. They do seem to - eg polio ?. Is that their exposure perhaps ? inflammation.
 

nanonug

Senior Member
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1,709
Location
Virginia, USA
Nanonug - out of my depth here but any chance of virals (entero or neuro) crossing the blood brain barrier too. They do seem to - eg polio ?. Is that their exposure perhaps ? inflammation.

No idea! My guess would be that with excessive permeability, pretty much everything will find a way in, eventually...
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Viruses can indeed cross the blood brain barrier. I got that from measles, and wound up with measles encephalitis at age 7. Its hard for viruses to infect the brain, and the brain has extra defences, but its not impossible. Also, due to additional layers of immune system in the brain, if a virus gets into the brain the complexity of the immune response will be increased. I have long wondered if viruses crossing into the brain massively increased ME likelihood, regardless of virus. The same might go for intracellular pathogens. The immune system probably will have a higher chance of a very strong response if the brain is infected. Such a strong response is a possible trigger for ME. Bye, Alex
 

natasa778

Senior Member
Messages
1,774
Viruses can indeed cross the blood brain barrier. I got that from measles, and wound up with measles encephalitis at age 7. Its hard for viruses to infect the brain, and the brain has extra defences, but its not impossible. Also, due to additional layers of immune system in the brain, if a virus gets into the brain the complexity of the immune response will be increased. I have long wondered if viruses crossing into the brain massively increased ME likelihood, regardless of virus. The same might go for intracellular pathogens. The immune system probably will have a higher chance of a very strong response if the brain is infected. Such a strong response is a possible trigger for ME. Bye, Alex

Or could their presence in the brain be only a (non-pathological) consequence of BBB permeability? One study found lots of polyomaviruses in about 70% of autism postmortem brains, but they were also present (in lower levels I believe but don't have the paper to hand so could be wrong) in about 20-30% of brains of normal controls. So is this merely indicative of 'leaky' BBB or of decreased immunity in autism.

Or if these particular viruses being present in the brain ARE contributing to neurological symptoms, then are they pathological only when combined with something else (eg aberrant immune responses) or could the pathology be linked to timing or of viruses crossing the BBB, and exact location/s in the brain etc... So many questions here.
 

Enid

Senior Member
Messages
3,309
Location
UK
Many questions - apart from donating my own brain - what are the "intense high spots" found in MRI brain scans.