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Invasion: the source of neuroinflammation in ME/CFS (follow-up to "Brain on Fire"

Murph

:)
Messages
1,792
I am growing more interested in the brain inflammation theory since reading cort's first post, and became even more interested when I learned the Blood-Brain-Barrier is a layer of endothelial cells. The blood vessels and the gut are also lined with endothelial cells. Endothelial cells rely a lot on calcium signalling to do their job. It is all starting to fit together!

However, there is one interesting counter-vailing point. I searched to see if low Adenosine might contribute to a permeable Blood-Brain-Barrier, but it seems to do the reverse. Adenosine opens the barrier. Perhaps symptoms would be worse in patients if we had normal adenosine levels, and this might be a natural brake on the vicious cycle that permits some of us to keep ticking at mild/moderate levels? Perhaps patients who by chance have higher levels of adenosine might get more neurological symptoms?

Adenosine receptor signaling: a key to opening the blood–brain door
Margaret S. Bynoe,
corrauth.gif
Christophe Viret,Angela Yan,andDo-Geun Kim


Abstract
The aim of this review is to outline evidence that adenosine receptor (AR) activation can modulate blood–brain barrier (BBB) permeability and the implications for disease states and drug delivery. Barriers of the central nervous system (CNS) constitute a protective and regulatory interface between the CNS and the rest of the organism. Such barriers allow for the maintenance of the homeostasis of the CNS milieu.

Among them, the BBB is a highly efficient permeability barrier that separates the brain micro-environment from the circulating blood. It is made up of tight junction-connected endothelial cells with specialized transporters to selectively control the passage of nutrients required for neural homeostasis and function, while preventing the entry of neurotoxic factors. The identification of cellular and molecular mechanisms involved in the development and function of CNS barriers is required for a better understanding of CNS homeostasis in both physiological and pathological settings.

It has long been recognized that the endogenous purine nucleoside adenosine is a potent modulator of a large number of neurological functions. More recently, experimental studies conducted with human/mouse brain primary endothelial cells as well as with mouse models, indicate that adenosine markedly regulates BBB permeability. Extracellular adenosine, which is efficiently generated through the catabolism of ATP via the CD39/CD73 ecto-nucleotidase axis, promotes BBB permeability by signaling through A1and A2AARs expressed on BBB cells. In line with this hypothesis, induction of AR signaling by selective agonists efficiently augments BBB permeability in a transient manner and promotes the entry of macromolecules into the CNS.

Conversely, antagonism of AR signaling blocks the entry of inflammatory cells and soluble factors into the brain. Thus, AR modulation of the BBB appears as a system susceptible to tighten as well as to permeabilize the BBB. Collectively, these findings point to AR manipulation as a pertinent avenue of research for novel strategies aiming at efficiently delivering therapeutic drugs/cells into the CNS, or at restricting the entry of inflammatory immune cells into the brain in some diseases such as multiple sclerosis.
 

pattismith

Senior Member
Messages
3,926
I

However, there is one interesting counter-vailing point. I searched to see if low Adenosine might contribute to a permeable Blood-Brain-Barrier, but it seems to do the reverse. Adenosine opens the barrier. Perhaps symptoms would be worse in patients if we had normal adenosine levels, and this might be a natural brake on the vicious cycle that permits some of us to keep ticking at mild/moderate levels? Perhaps patients who by chance have higher levels of adenosine might get more neurological symptoms?

Adenosine receptor signaling: a key to opening the blood–brain door
Margaret S. Bynoe,
corrauth.gif
Christophe Viret,Angela Yan,andDo-Geun Kim


Abstract
….

Conversely, antagonism of AR signaling blocks the entry of inflammatory cells and soluble factors into the brain. Thus, AR modulation of the BBB appears as a system susceptible to tighten as well as to permeabilize the BBB. Collectively, these findings point to AR manipulation as a pertinent avenue of research for novel strategies aiming at efficiently delivering therapeutic drugs/cells into the CNS, or at restricting the entry of inflammatory immune cells into the brain in some diseases such as multiple sclerosis.

Adenosine is metabolized into Inosine, which also binds efficiently on A1 and A2A receptors., so I guess Inosine has the same effect on BBB.

And interestingly Inosine has been proposed to treat MS as a blood uric acid enhancer