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Serotonin As The Cause Of Acute Pancreatitis

Discussion in 'Scientific Studies' started by haidut, Jul 13, 2016.

  1. haidut

    haidut Member

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    As some of you know, pancreatitis is a condition very common among alcoholics and people on SSRI drugs. When it is acute it can be quite deadly and its incidence has been skyrocketing lately, which concided with rising rates of alcohol abuse among middle-class citizens in the Western world. The drug companies continue to deny that serotonin is involved in the pathology of any GI disease, but quietly they are running trials with inhibitors of TPH as treatment for IBS, IBD, and even some GI cancers.
    This study shows that the activation of the 5-HT2 receptor is crucial for the development of the acute pancreatitis pathology and antagonists at that receptor (cyproheptadine, ritanserin, etc) can successfully treat the condition.

    Possible involvement of endogenous 5-HT in aggravation of cerulein-induced acute pancreatitis in mice. - PubMed - NCBI

    "...The aim of the present study was to elucidate the pathogenic role of endogenous 5-HT in pancreatitis. Injections of cerulein at hourly intervals caused edematous pancreatitis in mice characterized by hyperenzymemia and histological alterations. While the cerulein-induced hyperenzymemia was attenuated in mice pretreated with p-CPA, a 5-HT depletor, it was exaggerated by the preferential 5-HT2A agonist (DOI), but not by the preferential 5-HT2B agonist (BW723C86) or the preferential 5-HT2C agonist (mCPP). Selective 5-HT2A antagonists (risperidone, spiperone, ketanserin, AMI-193, and MDL 11,939) dose-dependently attenuated the hyperenzymemia; and their potency order, excepting that of ketanserin which has considerable affinity at the 5-HT2C receptor as well, paralleled their reported pKi values at the 5-HT2A receptor. Selective 5-HT2B (SB204741) and 5-HT2C (SB242084) antagonists hardly affected the hyperenzymemia. Although the non-selective 5-HT2A/2B/2C antagonists (metergoline, ritanserin, and methysergide) dose-dependently attenuated the hyperenzymemia, they were relatively less potent compared to their high pKi values at the 5-HT2A receptor. In another set of experiments, risperidone, but not SB204741 and SB242084, dose-dependently reversed the cerulein-induced histological alteration of the pancreas (inflammatory cell infiltration). These results suggest that endogenously released 5-HT activates 5-HT2A receptors to aggravate cerulein-induced pancreatitis. We propose that selective 5-HT2A antagonists may provide a new therapy for acute pancreatitis."
     
  2. Nadine Sokie

    Nadine Sokie New Member

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    Thank you for the info. am going to see a thyroid doc on Aug 10th. Haidut. what test would I have them do to check the pancreace? What other test could i have done? I have had problems for along time now I have hashimoto. Mother died of ovarian cancer at 44 yrs.
     
  3. OP
    haidut

    haidut Member

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    The tests for lipase, amilase and protease will show if there is pancreatic inflammation. There are other tests the doctor can also order but usually these are good as a start.
     
  4. ecstatichamster

    ecstatichamster Member

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    what's a decent Peat-friendly way to treat this?
     
  5. OP
    haidut

    haidut Member

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    You mean, aside from blocking serotonin? I think lowering fat intake and increasing the proportion of SFA should also help. Pancreatitis is similar to hepatitis in the sense that PUFA and alcohol aggravates it and SFA alleviates it. Aspirin may help too.
     
  6. ecstatichamster

    ecstatichamster Member

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  7. Amazoniac

    Amazoniac Member

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    - Zymogen - Wikipedia

    "The pancreas secretes zymogens partly to prevent the enzymes from digesting proteins in the cells in which they are synthesised. Enzymes like pepsin are created in the form of pepsinogen, an inactive zymogen. Pepsinogen is activated when chief cells release it into the gastric acid, whose hydrochloric acid partially activates it. Another partially activated pepsinogen completes the activation by removing the peptide, turning the pepsinogen into pepsin. Accidental activation of zymogens can happen when the secretion duct in the pancreas is blocked by a gallstone, resulting in acute pancreatitis."​

    - The role of calcium in acute pancreatitis

    "Mitochondrial calcium overload and subsequent decreased production of ATP result in dysfunction of the first line of defense, the calcium extrusion pumps. With perpetuation of calcium overload, complete ATP depletion ensues, which prevents the acinar cell from entering the second line of defense mechanism, the apoptotic pathway. This process leads the cell to necrosis and subsequent cell destruction, with spillage of activated proteases into the interstitial space, affecting surrounding acinar cells and initiating a vicious circle that ends in macroscopic inflammation (acute pancreatitis) and systemic illness (systemic inflammatory response syndrome)."

    "Research into the role of intracellular calcium suggests that an excessive increase in cytosolic calcium may be the common pathway to all forms of cell death in mammalian cells.[1] As for the pancreatic acinar cell, toxic concentrations of cytosolic calcium precipitate apoptosis or necrosis, depending on the severity of the insult.[2-4] Whereas apoptosis leads the cell to a controlled shutdown to allow programmed, controlled removal of the dead cells from the tissue,[5] necrosis results in cell disintegration and spillage of debris into the adjacent tissue. In the pancreas, this course of events is of paramount clinical relevance because activated zymogens destroy the surrounding acinar cells, thus perpetuating the process. The incited inflammation by leukocyte infiltration and vascular permeability leads to local acute pancreatitis and the resultant systemic response.[6]"

    "Besides hyperparathyroidism, acute pancreatitis has been linked to hypercalcemic states resulting from multiple other causes, including iatrogenic calcium administration, side effects of thiazide diuretics, cholecalciferol intoxication, and familial hypocalciuric hypercalcemia.[9] Most of these reports were anecdotal, but there were 2 systematic studies of patients undergoing cardiopulmonary bypass[20] and renal transplantation.[21]"

    "With calcium being an important element in acinar cell stimulus-secretion coupling and hyperstimulation being an effective technique to induce pancreatitis, we speculated whether disruption in the secretory process could be the mechanism by which hypercalcemia induces pancreatitis."

    "Acinar cell stimulation by acetylcholine or cholecystokinin induces spikes in cytosolic calcium concentration by repetitively releasing calcium from intracellular stores, which activates the normal secretory process of digestive enzymes from intracellular zymogen stores.[39] Increases in extracellular calcium concentrations or hyperstimulation by supramaximal doses of secretagogues, however, lead to sustained increases in cytosolic calcium, resulting in vacuole formation and trypsinogen activation. Adding a membrane-permeable calcium chelator or incubating in a calcium-free medium prevents the development of pathologic changes, indicating that these changes are calcium dependent.[31,40-42]"

    "Research into intracellular calcium homeostasis was extended to new models of gallstone-, alcoholic-, and hypotension-induced pancreatitis. Acinar cells exposed to pathophysiologically relevant concentrations of bile acids showed a consistent sustained increase in cytosolic calcium, followed eventually by acinar cell death.[2,43] Similarly, fatty-acid ethyl esters, which are nonoxidative alcohol metabolites known to promote pancreatic injury and pancreatitis,[44] increased global cytosolic calcium concentrations persistently.[45] Finally, a low extracellular pH level, a model for hypotension-induced pancreatitis, induced pathologic increases in intracellular calcium, trypsinogen activation, and acinar cell injury.[46]"

    "Repetitive physiologic spikes of intracellular calcium as a result of acinar cell stimulation lead to similarly repetitive increases in mitochondrial calcium, each of which activates ATP production. Sustained intracellular increases in calcium have a detrimental impact on mitochondrial function, of which the major step is disruption of ATP production.[53-55] Recent work showed that ATP-dependent clearance of calcium into intracellular stores or across the plasma membrane serves as a rescue mechanism for calcium overload.[45] If cytosolic and mitochondrial increases in calcium persist, intramitochondrial reactive oxygen species lead the cell to apoptosis[56] through energy-dependent caspase activation, which is regarded as the second line of defense. [57,58] ATP depletion, however, abolishes maintenance of calcium homeostasis, perpetuates calcium overload, and prevents the cell from entering the apoptosis pathway, thereby resulting in acinar cell necrosis. Necrotic cell disintegration then exposes neighboring cells to toxic waste which, in turn, leads to a sustained increase of calcium in the cytoplasm of these cells.[57,58]"

    "Caffeine has a slight inhibitory effect on type 2 and type 3 IP3 receptors of calcium stores. If these receptors are blocked by antibodies or are absent in knockout animals, premature trypsinogen activation is largely inhibited.[42,64]"

    "Using the natural calcium antagonist magnesium or a calcium chelator in vivo, trypsinogen activation as well as pancreatitis could be ameliorated. [68,69] There is evidence to suggest that calcium channel blockers may decrease the severity of experimental pancreatitis.[70]"

    "Lipase has been shown to reverse sustained cytosolic calcium levels to physiologic calcium oscillations in a model of severe hypertrigliceridemiainduced pancreatitis by inducing amylase secretion and increasing intracellular cGMP levels.[72,73]"

    "The prosurvival proteins Bcl-xL and Bcl-2, which are known to stabilize mitochondria, protect acinar cells from necrosis and counteract the loss of mitochondrial membrane potential in hyperstimulation pancreatitis.[75] ATP depletion is attenuated by insulin, resulting in protection of acinar cells from calcium overload.[76] Caspases, receptor-interacting protein, and the X-linked inhibitor of apoptosis protein (XlAP) protect from necrotizing pancreatitis.[77] Store-operated calcium entry channels such as the calcium releaseactivated calcium channel are important in refilling calcium stores, in ATP production, in exocytosis, and even in cell proliferation. Physiologic calcium release–activated calcium channel opening can be induced by energizing mitochondria with metabolic substrates that favor apoptosis rather than necrosis.[6]"

    - Hypocalcemia in acute pancreatitis revisited

    "Exact mechanism of hypocalcemia in acute pancreatitis is unknown. Mechanism of hypocalcemia during early stage (within 1st week) is different from hypocalcemia developing in late phase of the disease. Several mechanisms proposed for hypocalcemia seen in early phase are autodigestion of mesenteric fat by pancreatic enzymes and release of free fatty acids, which form calcium salts, transient hypoparathyroidism, and hypomagnesaemia.[13,14,15]"​
     
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