Serotonin Is The Likely Cause Of Septic And Anaphylactic Shock

haidut

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I am hoping that as a result of this study, mainstream medicine will finally start to take the pathogenic role of peripheral serotonin more seriously. More importantly, this study points to a rather simple and safe way of treating two of deadliest acute reactions (sepsis and allergic shock) especially for hospitalized patients) - administering either a serotonin antagonist like cyproheptadine or aspirin (which platelet serotonin release). A combination therapy would likely be even more effective, and should be able to protect from the immune over-activation in any infectious or allergic pathology.
@Travis @Koveras @aguilaroja

http://www.pnas.org/content/early/2018/01/30/1720553115
"...There is a growing appreciation for the contribution of platelets to immunity; however, our knowledge mostly relies on platelet functions associated with vascular injury and the prevention of bleeding. Circulating immune complexes (ICs) contribute to both chronic and acute inflammation in a multitude of clinical conditions. Herein, we scrutinized platelet responses to systemic ICs in the absence of tissue and endothelial wall injury. Platelet activation by circulating ICs through a mechanism requiring expression of platelet Fcγ receptor IIA resulted in the induction of systemic shock. IC-driven shock was dependent on release of serotonin from platelet-dense granules secondary to platelet outside-in signaling by αIIbβ3 and its ligand fibrinogen. While activated platelets sequestered in the lungs and leaky vasculature of the blood–brain barrier, platelets also sequestered in the absence of shock in mice lacking peripheral serotonin. Unexpectedly, platelets returned to the blood circulation with emptied granules and were thereby ineffective at promoting subsequent systemic shock, although they still underwent sequestration. We propose that in response to circulating ICs, platelets are a crucial mediator of the inflammatory response highly relevant to sepsis, viremia, and anaphylaxis. In addition, platelets recirculate after degranulation and sequestration, demonstrating that in adaptive immunity implicating antibody responses, activated platelets are longer lived than anticipated and may explain platelet count fluctuations in IC-driven diseases."

https://medicalxpress.com/news/2018-02-unexpected-role-platelets-immune-response.html
"...The results were similar in all three cases. The mice showed the classic symptoms of septic or anaphylactic shock, namely, a drop in body temperature, tremors, impaired cardiac function, vasodilation, and loss of consciousness. "We repeated the tests on mice with almost all platelets removed and on mice with no antigen-antibody complex receptors on their platelets. These mice had no physiological response, which clearly demonstrates the key role of platelets in the process. Platelets, and not white blood cells, are first on the scene during an immune response," said the professor. The researchers established that the mice went into shock because the platelets had released serotonin. "It's the same molecule as the neurotransmitter in the brain, but the molecule in the platelets is produced by cells in the intestine. Platelets store serotonin—they contain 90% of the body's entire serotonin supply—and release it in certain situations," Boilard explained. One of the study's clinical implications is that platelet transfusion for patients in septic or anaphylactic shock could aggravate their condition by increasing the amount of serotonin in the blood. "Transfusion remains important, especially since those patients often show low platelet levels, but in order to prevent the problem the antigen-antibody complex receptors on the platelets should be blocked before transfusion," Boilard said. He is now researching the role of the antigen-antibody complex receptor in auto-immune diseases like arthritis and lupus. "We believe that by blocking the receptor, we should be able to improve a patient's condition without affecting everything else that platelets do," he noted."
 

Travis

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I am hoping that as a result of this study, mainstream medicine will finally start to take the pathogenic role of peripheral serotonin more seriously. More importantly, this study points to a rather simple and safe way of treating two of deadliest acute reactions (sepsis and allergic shock) especially for hospitalized patients) - administering either a serotonin antagonist like cyproheptadine or aspirin (which platelet serotonin release). A combination therapy would likely be even more effective, and should be able to protect from the immune over-activation in any infectious or allergic pathology.
@Travis @Koveras @aguilaroja

Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration
"...There is a growing appreciation for the contribution of platelets to immunity; however, our knowledge mostly relies on platelet functions associated with vascular injury and the prevention of bleeding. Circulating immune complexes (ICs) contribute to both chronic and acute inflammation in a multitude of clinical conditions. Herein, we scrutinized platelet responses to systemic ICs in the absence of tissue and endothelial wall injury. Platelet activation by circulating ICs through a mechanism requiring expression of platelet Fcγ receptor IIA resulted in the induction of systemic shock. IC-driven shock was dependent on release of serotonin from platelet-dense granules secondary to platelet outside-in signaling by αIIbβ3 and its ligand fibrinogen. While activated platelets sequestered in the lungs and leaky vasculature of the blood–brain barrier, platelets also sequestered in the absence of shock in mice lacking peripheral serotonin. Unexpectedly, platelets returned to the blood circulation with emptied granules and were thereby ineffective at promoting subsequent systemic shock, although they still underwent sequestration. We propose that in response to circulating ICs, platelets are a crucial mediator of the inflammatory response highly relevant to sepsis, viremia, and anaphylaxis. In addition, platelets recirculate after degranulation and sequestration, demonstrating that in adaptive immunity implicating antibody responses, activated platelets are longer lived than anticipated and may explain platelet count fluctuations in IC-driven diseases."

https://medicalxpress.com/news/2018-02-unexpected-role-platelets-immune-response.html
"...The results were similar in all three cases. The mice showed the classic symptoms of septic or anaphylactic shock, namely, a drop in body temperature, tremors, impaired cardiac function, vasodilation, and loss of consciousness. "We repeated the tests on mice with almost all platelets removed and on mice with no antigen-antibody complex receptors on their platelets. These mice had no physiological response, which clearly demonstrates the key role of platelets in the process. Platelets, and not white blood cells, are first on the scene during an immune response," said the professor. The researchers established that the mice went into shock because the platelets had released serotonin. "It's the same molecule as the neurotransmitter in the brain, but the molecule in the platelets is produced by cells in the intestine. Platelets store serotonin—they contain 90% of the body's entire serotonin supply—and release it in certain situations," Boilard explained. One of the study's clinical implications is that platelet transfusion for patients in septic or anaphylactic shock could aggravate their condition by increasing the amount of serotonin in the blood. "Transfusion remains important, especially since those patients often show low platelet levels, but in order to prevent the problem the antigen-antibody complex receptors on the platelets should be blocked before transfusion," Boilard said. He is now researching the role of the antigen-antibody complex receptor in auto-immune diseases like arthritis and lupus. "We believe that by blocking the receptor, we should be able to improve a patient's condition without affecting everything else that platelets do," he noted."
That's interesting. I knew that peripheral serotonin was bound to platelets bud didn't know why; I had thought it was more‐or‐less just its binding protein, similar to the tryptophan–albumin relationship. I didn't think I'd ever see the term 'platelet degranulation,' a term I'd only seen to describe mast cells. But however strange this may seem at first thought, the evidence speaks for itself: serotonin is obligatory for septic shock.

Even before its more well‐known neurotransmitter role had been discovered, its pressor effect had been demonstrated; it had been so named for this effect. I think this makes sense once it's realized that blood vessels have myosin light chain, tiny muscles which act to constrict. Some muscle proteins are high in tryptophan, and serotonin could perhaps be there to help facilitate nerve transmission through π‐stacking.

The Förster resonance energy transfer equation is distance(R)‐dependent. If one accepts that nerve speed is mediated by such interactions, then reducing the distance—i.e. increasing serotonin—between aromatic side‐chains would increase nerve velocity and perhaps muscle contraction.

forster.png

Alternatively, it could be working more specifically through its G protein‐coupled receptors somehow (are these even found in the blood vessels?)

Craddock, T. "The feasibility of coherent energy transfer in microtubules." Journal of the Royal Society Interface (2014)
Szent-Györgyi, A. "On resonance transfer of excitation energy between aromatic aminoacids in proteins." Proceedings of the National Academy of Sciences (1958)
Förster, T. "Transfer mechanisms of electronic excitation energy." Radiation Research Supplement (1960)
 
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haidut

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reducing the distance—i.e. increasing serotonin—between aromatic side‐chains would increase nerve velocity and perhaps muscle contraction

Is this why high serotonin often causes muscle twitching and sometimes seizures?
 

aguilaroja

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I am hoping that as a result of this study, mainstream medicine will finally start to take the pathogenic role of peripheral serotonin more seriously. More importantly, this study points to a rather simple and safe way of treating two of deadliest acute reactions (sepsis and allergic shock) especially for hospitalized patients) - administering either a serotonin antagonist like cyproheptadine or aspirin (which platelet serotonin release). ...

http://www.pnas.org/content/early/2018/01/30/1720553115

https://medicalxpress.com/news/2018-02-unexpected-role-platelets-immune-response.html
"...The results were similar in all three cases. The mice showed the classic symptoms of septic or anaphylactic shock, namely, a drop in body temperature, tremors, impaired cardiac function, vasodilation, and loss of consciousness.... The researchers established that the mice went into shock because the platelets had released serotonin. "It's the same molecule as the neurotransmitter in the brain, but the molecule in the platelets is produced by cells in the intestine. Platelets store serotonin—they contain 90% of the body's entire serotonin supply—and release it in certain situations," Boilard explained. One of the study's clinical implications is that platelet transfusion for patients in septic or anaphylactic shock could aggravate their condition by increasing the amount of serotonin in the blood....

Very interesting finding. As @haidut notes, the observation could readily lead to testable therapy.

Septic and anaphylactic shock are regarding as subtypes of distributive shock.
Distributive Shock: Background, Pathophysiology, Etiology
“Distributive shock results from excessive vasodilation and the impaired distribution of blood flow.”

The cartoon view of platelets as “blood clot cells” is falling away to reveal intelligent function. Platelets also carry many mitochondria in circulation. The idea of “mitochondria-derived damage-associated molecular patterns (DAMPs)” has also attracted considerable attention.

Mitochondrial damage-associated molecular patterns as potential proinflammatory mediators in post-platelet transfusion adverse effects. - PubMed - NCBI
Platelet concentrates (PCs) are the most common blood components eliciting nonhemolytic transfusion reactions (NHTRs), such as allergic transfusion reactions and febrile reactions….Previous studies reported that mitochondria-derived damage-associated molecular patterns (DAMPs) could be important mediators of innate cell inflammation. Platelets (PLTs) represent a major reservoir of mitochondria in the blood circulation.

Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. - PubMed - NCBI
“…the mitochondrion is an endogenous substrate of secreted phospholipase A2 IIA (sPLA2-IIA), a phospholipase otherwise specific for bacteria, likely reflecting the ancestral proteobacteria origin of mitochondria. The hydrolysis of the mitochondrial membrane by sPLA2-IIA yields inflammatory mediators (ie, lysophospholipids, fatty acids, and mtDNA) that promote leukocyte activation.”
 

aguilaroja

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Is this why high serotonin often causes muscle twitching and sometimes seizures?

One possible route for a decline-inducing to produce specific decline, such as seizure.:

Severe hyponatremia associated with escitalopram. - PubMed - NCBI
“Hyponatremia is a rare but potentially fatal complication of selective serotonin reuptake inhibitor (SSRI) therapy….”
“…a 54-year-old hypertensive female who was admitted to the hospital with seizure episode and subsequently diagnosed to have severe hyponatremia due to SSRI-induced syndrome of inappropriate antidiuretic hormone (SIADH) with the cause attributed to the short history of intake of escitalopram for depression. All SSRIs, including escitalopram, can cause SIADH and should be used with caution in the depressive patients with regular monitoring of electrolytes, especially in the elderly.”
 

Koveras

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Dec 17, 2015
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Is this why high serotonin often causes muscle twitching and sometimes seizures?

I thought that had to do with serotonin's ability to interfere with ATP production (along the same lines as what you see with rigor mortis) - or are these complimentary mechanisms?

Gen Pharmacol. 1994 Oct;25(6):1257-62.
Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma hemoglobin; the protective action of calmodulin antagonists.
Koren-Schwartzer N1, Chen-Zion M, Ben-Porat H, Beitner R.
1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level, accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of anaerobic glycolysis was also reflected by a marked increase in lactate content in brain. 2. Brain glucose 1,6-bisphosphate level was decreased, whereas fructose 2,6-bisphosphate was unaffected by serotonin. 3. All these serotonin-induced changes in brain, which are characteristic for cerebral ischemia, were prevented by treatment with the calmodulin (CaM) antagonists, trifluoperazine or thioridazine. 4. Injection of serotonin also induced a marked elevation of plasma hemoglobin, reflecting lysed erythrocytes, which was also prevented by treatment with the CaM antagonists. 5. The present results suggest that CaM antagonists may be effective drugs in treatment of many pathological conditions and diseases in which plasma serotonin levels are known to increase.
 
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