Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following a fortuitous observation that migraine headaches ceased in a patient receiving glucosamine therapy for osteoarthritis, a further ten patients with migraine or migraine-like vascular headaches, refractory to established preventive or abortive therapies, have been treated with daily oral glucosamine. After a lag of 4-6 weeks, a substantial reduction in headache frequency and/or intensity has been noted; in some cases, the benefit appears to be dose-dependent. Since glucosamine can be a rate-limiting precursor for mucopolysaccharide synthesis, it is germane to note previous reports that heparin and pentosan polysulfate may have migraine-preventive activity. There is reason to suspect that mast cells are central mediators of the neurogenic inflammation associated with migraine and cluster headaches. The heparin produced by mast cells may function to provide feedback down-regulation of mast cell activation, and exerts a range of other anti-inflammatory effects. We postulate that supplemental glucosamine can boost mast cell heparin synthesis - perhaps correcting a functional heparin deficiency - thereby preventing or ameliorating the neurogenic inflammation that mediates pain in vascular headache. Whether or not this idea has validity, a controlled study of glucosamine for migraine prophylaxis appears to be warranted.
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PMID:Glucosamine for migraine prophylaxis? 1098 8

The study of the mechanisms of action of the triptan group of drugs has largely contributed to the progress made in the understanding of the physiopathological processes that are possibly responsible for migraine. In this context, two discoveries have been especially important: 1) these anti-migraine drugs are specifically recognized by three main types of serotonin receptors (5-HT1B, 5-HT1D, and 5-HT1F); and 2) these receptors are present in the meninges, where they are expressed by both smooth muscle cells and/or endothelial cells of the vascular wall and/or the perivascular trigeminal to be deleted axon terminals. These two findings have led to the most currently accepted physiopathogenic hypothesis, whereby the migraine attack would start with an excitation of the perivascular trigeminal to be deleted fibers, which would then trigger the release of vasoactive peptides (substance P, calcitonin gene-related peptide/CGRP) within the dura mater. Locally, i.e., in the dura mater in particular, these substances can provoke vasodilatation (CGRP) and plasmatic extravasation (substance P) with platelet lysis and mast cell degranulation, thereby leading to the release of algogenic substances that excite the neighboring trigeminal fibers, and this neurogenic inflammatory response can progressivelly extend to the meninges as a whole. This reaction subsequently reaches the bulbar and thalamic nuclei and then the sensory cortex, where it is integrated and expressed as migraine pain. The aim of this article was to report the main findings on endogenous substances (serotonin, peptides, nitric oxide [NO], etc.) which appear to play a key role in this physiopathogenic sequence.
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PMID:[Role of serotonin and other neuroactive molecules in the physiopathogenesis of migraine. Current hypotheses]. 1107 40

Despite considerable research into the pathogenesis of idiopathic headaches, such as migraine, the pathophysiological mechanisms underlying them remain poorly understood. Although it is well established that the trigeminal nerve becomes activated during migraine, the consequences of this activation remain controversial. One theory, based on preclinical observations, is that activation of trigeminal sensory fibers leads to a painful neurogenic inflammation within the meningeal (dural) vasculature mediated by neuropeptide release from trigeminal sensory fibres and characterized by plasma protein extravasation, vasodilation, and mast cell degranulation. Effective antimigraine agents such as ergots, triptans, opioids, and valproate inhibit preclinical neurogenic dural extravasation, suggesting that this activity may be a predictor of potential clinical efficacy of novel agents. However, several clinical trials with other agents that inhibit this process preclinically have failed to show efficacy in the acute treatment of migraine in man. Alternatively, it has been proposed that painful neurogenic vasodilation of meningeal blood vessels could be a key component of the inflammatory process during migraine headache. This view is supported by the observation that jugular plasma levels of the potent vasodilator, calcitonin gene-related peptide (CGRP) are elevated during the headache and normalized by successful sumatriptan treatment. Preclinically, activation of trigeminal sensory fibers evokes a CGRP-mediated neurogenic dural vasodilation, which is blocked by dihydroergotamine, triptans, and opioids but unaffected by NK1 receptor antagonists that failed in clinical trials. These observations suggest that CGRP release with associated neurogenic dural vasodilation may be important in the generation of migraine pain, a theory that would ultimately be tested by the clinical testing of a CGRP receptor antagonist.
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PMID:Neurogenic inflammation in the context of migraine. 1130 92

Migraine headaches are often precipitated by stress and seem to involve neurogenic inflammation (NI) of the dura mater associated with the sensation of throbbing pain. Trigeminal nerve stimulation had been reported to activate rat dura mast cells and increase vascular permeability, effects inhibited by neonatal pretreatment with capsaicin implicating sensory neuropeptides, such as substance P (SP). The aim of the present study was to investigate NI, assessed by extravasation of 99-Technetium-gluceptate (99Tc-G), as well as the role of mast cells, SP and its receptor (NK-1R) in dura mater of mice in response to acute stress. Restraint stress for thirty min significantly increased 99Tc-G extravasation in the dura mater of C57BL mice. This effect was absent in W/W(v) mast cell-deficient mice and NK-1 receptor knockout mice (NK-1R-/-), but was unaltered in SP knockout mice (SP-/-). Acute restraint stress also resulted in increased dura mast cell activation in C57BL mice, but not in NK-1R-/- mice. These data demonstrate for the first time that acute stress triggers NI and mast cell activation in mouse dura mater through the activation of NK-1 receptors. The fact that SP-/- mice had intact vascular permeability response to stress indicates that some other NK-1 receptor agonist may substitute for SP. These results may help explain initial events in pathogenesis of stress-induced migraines.
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PMID:Stress-induced dura vascular permeability does not develop in mast cell-deficient and neurokinin-1 receptor knockout mice. 1286 61

Migraine may affect as many as 9% of all schoolchildren and often presents with abdominal symptoms of pain, nausea, and vomiting. Even though the pathophysiology of migraine remains unknown, self-regulation techniques appear to be more effective in prevention of childhood migraine than conventional pharmacotherapy which is often associated with adverse effects. Mast cells have been implicated in the pathogenesis of migraine in adults, but have not been previously studied in children with migraine. Mast cells are found close to the vessels and nerves in the meninges where they can release multiple vasoactive, neurosensitizing, and pro-inflammatory mediators. Therefore, we investigated whether children with migraine may have increased urinary levels of mast cell mediators and whether practicing relaxation imagery exercises has an effect on the frequency of headache, as well as on mast cell activation. Urine was collected for 24 hours from children with and without migraine after a 5-day amine-restricted diet. Children with migraine also collected urine during migraine episodes. The mean levels of urinary histamine, its main metabolite, methylhistamine, and the mast cell enzyme, tryptase, were higher in children than generally found in adults, but they did not differ statistically in any of the categories studied. However, in 8 of 10 children who practiced relaxation imagery techniques and successfully reduced the number of migraines, the urine tryptase levels were also significantly lower. There was no relationship between successful practice and sex or age of the child. These results suggest that stress may activate mast cells which could be involved in the pathophysiology of migraine.
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PMID:Mast cell activation in children with migraine before and after training in self-regulation. 1561 2

Mast cells are critical players in allergic reactions, but they have also been shown to be important in immunity and recently also in inflammatory diseases, especially asthma. Migraines are episodic, typically unilateral, throbbing headaches that occur more frequently in patients with allergy and asthma implying involvement of meningeal and/or brain mast cells. These mast cells are located perivascularly, in close association with neurons especially in the dura, where they can be activated following trigeminal nerve, as well as cervical or sphenopalatine ganglion stimulation. Neuropeptides such as calcitonin gene-related peptide (CGRP), hemokinin A, neurotensin (NT), pituitary adenylate cyclase activating peptide (PACAP), and substance P (SP) activate mast cells leading to secretion of vasoactive, pro-inflammatory, and neurosensitizing mediators, thereby contributing to migraine pathogenesis. Brain mast cells can also secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), selectively in response to corticotropin-releasing hormone (CRH), a mediator of stress which is known to precipitate or exacerbate migraines. A better understanding of brain mast cell activation in migraines would be useful and could lead to several points of prophylactic intervention.
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PMID:The role of mast cells in migraine pathophysiology. 1596 Sep 87

Fibromyalgia (FMS) is a debilitating disorder characterized by chronic diffuse muscle pain, fatigue, sleep disturbance, depression and skin sensitivity. There are no genetic or biochemical markers and patients often present with other comorbid diseases, such as migraines, interstitial cystitis and irritable bowel syndrome. Diagnosis includes the presence of 11/18 trigger points, but many patients with early symptoms might not fit this definition. Pathogenesis is still unknown, but there has been evidence of increased corticotropin-releasing hormone (CRH) and substance P (SP) in the CSF of FMS patients, as well as increased SP, IL-6 and IL-8 in their serum. Increased numbers of activated mast cells were also noted in skin biopsies. The hypothesis is put forward that FMS is a neuro-immunoendocrine disorder where increased release of CRH and SP from neurons in specific muscle sites triggers local mast cells to release proinflammatory and neurosensitizing molecules. There is no curative treatment although low doses of tricyclic antidepressants and the serotonin-3 receptor antagonist tropisetron, are helpful. Recent nutraceutical formulations containing the natural anti-inflammatory and mast cell inhibitory flavonoid quercetin hold promise since they can be used together with other treatment modalities.
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PMID:Fibromyalgia--new concepts of pathogenesis and treatment. 1656 42

Migraine attacks are triggered by a variety of conditions including endogenous and exogenous factors. Evidence suggests that activation and sensitization of primary afferent meningeal nociceptive neurons, the peripheral arm of the trigeminovascular system, constitutes one of the earliest events promoting the intracranial pain of migraine. However, the link between the varied triggering factors and activation of meningeal nociceptive neurons is not completely understood. Local inflammation with release of mediators from local immune/inflammatory cells is thought to play a critical role in such neuronal response. Meningeal mast cells may play such a role by virtue of their proximity both to meningeal blood vessels and nociceptive axons and their ability to release a host of proinflammatory/algesic mediators. This paper reviews data relevant to the hypothesis that mast cells, upon activation by migraine triggers, contribute to the genesis of migraine headache. Epidemiologic findings, clinical data, and observations on anatomical and physiological characteristics of mast cells converge to suggest an important role of these immune cells in the pathogenesis of migraine. Migraine triggers might directly or indirectly promote mediator secretion from meningeal mast cells, and thereby cause inflammation and activation of the trigeminovascular system. While consistent, the evidence supporting mast cell involvement in the genesis of migraine is largely circumstantial to date. Further studies are needed to test directly the nature of mast cell involvement in the pathogenesis of migraine headache.
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PMID:Mast cell involvement in the pathophysiology of migraine headache: A hypothesis. 1692 59

Mast cells are involved in allergic reactions, where they secrete numerous vasoactive, inflammatory and nociceptive mediators in response to immunoglobulin E (IgE) and antigen. However, they have also been implicated in inflammatory conditions, such as painful bladder syndrome/interstitial cystitis (PBS/IC), irritable bowel syndrome (IBS) and migraines, all of which occur more often in women and are exacerbated during ovulation, but are suppressed during pregnancy. Mast cells express high affinity estrogen receptors and estradiol augments their secretion, while tamoxifen inhibits it. Here we report that progesterone (100 nM), but not the structurally related cholesterol, inhibits histamine secretion from purified rat peritoneal mast cells stimulated immunologically or by substance P (SP), an effect also documented by electron microscopy. These results suggest that mast cell secretion may be regulated by progesterone and may explain the reduced symptoms of certain inflammatory conditions during pregnancy.
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PMID:Progesterone inhibits mast cell secretion. 1716

Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood. In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura mater. Using in vivo electrophysiological single unit recording of meningeal nociceptors in the rat we observed that degranulation of dural mast cells using intraperitoneal administration of the basic secretagogue agent compound 48/80 (2 mg/kg) induced a prolonged state of excitation in meningeal nociceptors. Such activation was accompanied by increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), an anatomical marker for nociceptor activation. Mast cell-induced nociceptor interaction was also associated with downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression. Our findings provide evidence linking dural mast cell degranulation to prolonged activation of the trigeminal pain pathway believed to underlie intracranial headaches such as that of migraine.
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PMID:Mast cell degranulation activates a pain pathway underlying migraine headache. 1745 86


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