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Purinergic Signalling and CNS Disorders by Professor Geoffrey Burnstock

Discussion in 'General ME/CFS Discussion' started by Jo Best, Aug 26, 2017.

  1. Jo Best

    Jo Best Senior Member

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    This is a presentation from the 6th Invest in ME Research international conference in 2011 (IIMEC6) so it's not new, but I had not seen it before as I don't have the IIMEC6 DVD set. I will have to watch it over a few times over to take it all in, but am sharing here now while I have the link handy in case it's of interest to anyone else. Source of extract below: http://www.investinme.org/IIMER-Newslet-17-08-01.shtml

    Source: http://www.investinme.org/IIMER-Newslet-17-08-01.shtml




     
    Last edited: Aug 27, 2017
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  2. Jo Best

    Jo Best Senior Member

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    Not specific to ME or CFS research, but a lot that resonates in this interview with Geoff Burnstock.
     
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  3. Philipp

    Philipp

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    cliffs of what seems worth mentioning to to me:
    - on the 'p2 receptor antagonists' slides, suramin is mentioned several times.
    - methylxanthines (caffeine, theobromine etc) are p1 antagonists. adenosine and adenosine monophosphate (which might accumulate when ATP synthesis is slowed down) are the stronger agonists of these receptors.
    - p2 has the reverse affinity order, i.e. ATP and ADP are the most potent agonists. so maybe some underactivation is in play (probably keeping in the back of one's head that this does not have to be a systemic effect or a very strong effect all the time)
    - the 'main sources of ATP' slide mentions at lot of different cell types that have been mentioned in the ME literature at one point or another
    - release of ATP from endothelial cells and a subsequent signaling cascade leading to release of NO (-> vasodilation) is a very integral part of a functioning vascular system
    - the stuff from ~ minute 15 on about ischemic and neuropathic pain seems relevant as well, but is over my head right now and I can't really shorten it in meaningful way ;)
     
  4. Jo Best

    Jo Best Senior Member

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  5. anciendaze

    anciendaze Senior Member

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    I want to mention that this process is not entirely inside any nervous system. Endothelial cells can respond to nerve signals, but they can also respond to local hypoxia by releasing ATP to help cells survive via anaerobic metabolism. Another major source of ATP in regions of localized hypoxia comes from red blood cells (erythrocytes), after they have released oxygen they carry. Since these cells spend most of their time in other regions of the body, they have considerable capacity to generate new ATP which can be released later. This could be the answer to contradictions about amounts of ATP, and whether mitochondria are creating it. We could be looking at the wrong cells, or assuming all cells are functioning the same way.

    This response to exercise, called functional sympatholysis or exercise hyperemia, is a normal means of supplying increased oxygenated blood to muscles that require it. You are most likely to find the term in sports medicine. It is rare for defects in this process to be described as actual illness. Usually, this is mentioned as a condition associated with more conventional diseases not as a cause. Here's an exception. The idea that defects in this process may trap patients in a situation where exercise leads to reduced capacity for several days has yet to make much headway.

    A large subset of us seem to be stuck in the phase of vasodilation along venous return to the heart, leading to low cardiac fill pressures. Customary measurements of cardiovascular health will miss this, but there is an invasive cardio-pulmonary exercise test that will find it.
     
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  6. mariovitali

    mariovitali Senior Member

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    Giving my two cents here :

    From the paper named "The role of nucleotides and purinergic signaling in apoptotic cell clearance – implications for chronic inflammatory diseases " we read :


    But also interesting is the mention of GAS6 in the same paper


    I now plug in "purinergic_receptor" on the Feature Selection Algorithm to uncover any indirect associations on Purinergic functioning and get this :

    suramin.png


    The tool identifies Suramin, nucleotides, calcium homeostasis, inflammatory_cytokines but also things that perhaps are less well known (GAS6 is also selected but not shown below):

    -Intestinal motility
    -Vitamin B6
    -Vitamin D3
    -Vitamin K
    -VKORC1

    The association of Purinergic receptors with these Topics may require further investigation.
     
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  7. anciendaze

    anciendaze Senior Member

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    I just want to add some appreciation of scale here. A great deal of biochemical signalling takes place at nerve synapses, where the molecules only travel micrometers between release and reception. When purines like ATP, ADP, etc. are released into the bloodstream they can travel several centimeters or more before they reach receptors on endothelial tissue inside blood vessels. The scale is many thousands of times greater. This is on the scale of individual muscles, but still much smaller than the scale of your whole body. Measurements of O2sat will not show much change because most tissues in your body are not hypoxic. This doesn't rule out localized hypoxia due to hypoperfusion.

    Another chemical signal for vasodilation involves NO, nitric oxide. I remember my surprise, long ago, when this was first reported as a neurotransmitter. From experience in chemistry I know that this is a very reactive molecule, and I had been taught (incorrectly) that the chemicals used in biochemistry were much less reactive. This property makes NO difficult to work with in normal clinical laboratory practice. There have been some very delicate experiments in which tiny tubes were threaded through a patient's skin, and these showed differences in NO release between ME/CFS patients and healthy people. For the most part we don't even know how purinergic signalling and NO release operate in people like athletes, where it works very well.

    A recent search turned up more recent research than I had seen at an institute in Copenhagen, Denmark. Several other molecules mentioned here, like NA (noradrenaline) or ROS (reactive oxygen species) are on my list of interest. Anything to do with sympathetic nervous system activity and muscles will also pique my interest.
     
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