Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of chronic, low-dose amitriptyline on serotonin (5-HT) synthesis rate were measured in rat brain using autoradiography and the trapping of alpha-[14C]-methyl-L-tryptophan (alpha-[14C]-MTrp). Rats received amitriptyline (2 mg/kg per day) or saline via intraperitoneal osmotic minipumps for 21 days. Amitriptyline had no effect on any physiological parameters measured, or on free or total plasma tryptophan levels. However, amitriptyline exerted selective decreases of 15% and 17% (P < 0.001) in serotonin synthesis rates in the dorsal and median raphe nuclei, respectively. There was no reduction in any of the projection areas studied, including the cerebral cortex, hippocampus, thalamus, hypothalamus or striatum. The data suggest that chronic low doses of amitriptyline can lead to sustained 5-HT re-uptake inhibition selectively in the raphe nuclei, an effect compatible with tonic activation of 5-HT(1A) autoreceptors and inhibition of 5-HT synthesis. The failure of chronic amitriptyline treatment to affect 5-HT synthesis rate in the projection areas may ensure an adequate regulation of pain pathways implicated in migraine headache, an effect possibly related to amitriptyline anti-migraine efficacy.
Cephalalgia 2003 Jun
PMID:Selective decrease in serotonin synthesis rate in rat brainstem raphe nuclei following chronic administration of low doses of amitriptyline: an effect compatible with an anti-migraine effect. 1278 Jul 67

Triptans are 5-HT1 receptor agonists used as anti-migraine drugs. They act primarily on meningeal blood vessels and on trigeminovascular afferents, but they may also exert central effects. We studied the regional effects of acute and chronic treatment with sumatriptan or zolmitriptan on the rate of serotonin (5-HT) synthesis in the rat brain, using the alpha-14C-methyl-L-tryptophan quantitative autoradiographic method. Sumatriptan at low (300 microg/kg, s.c.) and high (1 mg/kg) doses, as well as zolmitriptan (100 microg/kg), acutely decreased (15-40%, P < 0.05-0.001) 5-HT synthetic rate in many brain regions, including the dorsal raphe nucleus. Chronically, sumatriptan (21 days, approximately 300 microg/kg per day via osmotic minipumps) induced significant increases in the 5-HT synthesis rate in many projection areas but had no effect in the dorsal raphe nucleus. The acute effects on 5-HT synthesis rate would be compatible with activation of 5-HT1 autoreceptors that inhibit serotonin release. In contrast, the increased 5-HT synthesis rate observed after chronic sumatriptan might possibly result from a down-regulation/desensitization of 5-HT1 receptors and/or unmasking of excitatory triptan-sensitive 5-HT receptors. Overall, the present findings indicate that not only zolmitriptan but also sumatriptan affect brain serotonergic neurotransmission.
Cephalalgia 2004 Jan
PMID:Effects of acute or chronic administration of anti-migraine drugs sumatriptan and zolmitriptan on serotonin synthesis in the rat brain. 1468 6

Sensitivity to light was investigated 5 and 8 h after consumption of an amino acid drink which contained L-tryptophan (balanced amino acid condition: 19 controls and 22 migraine sufferers) or which produced a short-term reduction in brain serotonin synthesis by omitting L-tryptophan (tryptophan depletion condition: 16 controls and 16 migraine sufferers). Migraine sufferers reported more intense nausea, headache, glare- and light-induced pain than controls. In addition, glare- and light-induced pain were greater in the tryptophan depletion condition than in the balanced amino acid condition, in both migraine sufferers and controls. Eight hours after the amino acid drink, after participants had completed tests of pain sensitivity and motion sickness provocation, tryptophan depletion augmented headache in migraine sufferers and aggravated nausea in migraine sufferers and controls. These findings suggest that a reduction in brain synthesis of serotonin intensifies photophobia and other migrainous symptoms and thus might contribute to the pathogenesis of migraine.
Cephalalgia 2006 Oct
PMID:Tryptophan depletion increases nausea, headache and photophobia in migraine sufferers. 1696 91

Catecholamine-secreting metastatic carcinoid should be considered in differential diagnosis of malignant pheochromocytoma. Paroxysmal functioning or hormonally silent gastroenteropancreatic neuroendocrine tumors (GEP NETs) require repeat biochemical measurements and sensitive anatomic and functional imaging studies overlapping those for malignant pheochromocytoma. This report presents clinical, laboratory, and radiologic findings in a patient presenting with heart rate variability; vasoactive headaches reactive to ethanol, tyramine and tryptophan; labile blood pressure; diaphoresis; diarrhea; abdominal pain; unexplained pancreatitis; joint pain; and paroxysmal flushing with pallor. GI studies (including endoscopic ultrasound) and multiple imaging modalities (including 2D CT, MRI with gadolinium, [18]FDG PET/CT, [123I]MIBG, and SRS [111In]Octreotide [OctreoScan]) were not diagnostic. 24-h BP, Holter and 30-day cardiac event monitors plus urinary biochemical studies consistently suggested catecholamine-synthesizing NET. NIH plasma metanephrines studies and [6]-[18F]Fluorodopamine PET ruled out malignant pheochromocytoma (pheo). Repeated studies showed persistently abnormal GEP NET biomarkers and urinary catecholamines. Capsule endoscopy revealed suspicious submucosal lesions throughout the small intestine. Dual-phase 64-slice multidetector computed tomography (MDCT) with 3D volumetric reconstruction of the abdomen and pelvis revealed multiple diffuse liver metastases and three extrahepatic lesions consistent with metastatic carcinoid. In combination, intensive biochemical testing repeated over time, dual-phase 64-slice MDCT with 3D image reconstruction and volume-rendering (VR) technique, and advanced radionuclide imaging are required to detect NETs' sporadic or paroxysmal functioning, rule out extra-adrenal pheochromocytoma, and localize and characterize metastatic carcinoid. If pheochromocytoma is ruled out, yet symptoms and biochemical markers for catecholamine excess are present, then carcinoid and other amine-precursor-uptake decarboxylation (APUD) tumors must remain in the differential diagnosis.
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PMID:Catecholamine-secreting metastatic carcinoid as differential diagnosis in pheochromocytoma: clinical, laboratory, and imaging clues in the search for the lurking neuroendocrine tumor (NET). 1710 73

Headache and/or migraine, a common problem in pediatrics and internal medicine, affect about 5% to 10% children and adolescents, and nearly 30% of middle-aged women. Headache is also one of the most common clinical manifestations of acquired Toxoplasma gondii infection of the central nervous system (CNS) in immunosuppressed subjects. We present 11 apparently nonhuman immunodeficiency virus-infected children aged 7 to 17 years (8 girls, 3 boys) and 1 adult woman with recurrent severe headaches in whom latent chronic CNS T. gondii infection not manifested by enlarged peripheral lymph nodes typical for toxoplasmosis, was found. In 7 patients, the mean serum IgG Toxoplasma antibodies concentration was 189 +/- 85 (SD) IU/mL (range 89 to 300 IU/mL), and in 5 other subjects, the indirect fluorescent antibody test titer ranged from 1:40 to 1:5120 IU/mL (n= <1:10 IU/mL). Some of the patients suffered also from atopic dermatitis (AD) and were exposed to cat and/or other pet allergens, associated with an increased IL-4 and decreased IFN-gamma production. These cytokine irregularities caused limited control of cerebral toxoplasmosis probably because IL-4 down-regulated both the production of IFN-gamma and its activity, and stimulated production of a low NO-producing population of monocytes, which allowed cysts rupture, increased parasite multiplication and finally reactivation of T. gondii infection. The immune studies performed in 4 subjects showed a decreased percentage of T lymphocytes, increased total number of lymphocytes B and serum IgM concentration, and impaired phagocytosis. In addition, few of them had also urinary tract diseases known to produce IL-6 that can mediate immunosuppressive functions, involving induction of the anti-inflammatory cytokine IL-10. These disturbances probably resulted from the host protective immune reactions associated with the chronic latent CNS T. gondii infection/inflammation. This is consistent with significantly lower enzyme indoleamine 2,3-dioxygenase (IDO) activity reported in atopic than in nonatopic individuals, and an important role that IDO and tryptophan degradation pathways plays in both, the host resistance to T. gondii infection and its reactivation. Analysis of literature information on the subjects with different types of headaches caused by foods, medications, and other substances, may suggest that their clinical symptoms and changes in laboratory data result at least in part from interference of these factors with dietary tryptophan biotransformation pathways. Several of these agents caused headache attacks through enhancing NO production via the conversion of arginine to citrulline and NO by the inducible nitric oxide synthase enzyme, which results in the high-output pathway of NO synthesis. This increased production of NO is, however, quickly down-regulated by NO itself because this biomolecule can directly inactivate NOS, may inhibit Ia expression on IFN-gamma-activated macrophages, which would limit antigen-presenting capability, and block T-cell proliferation, thus decreasing the antitoxoplasmatic activity. Moreover, NO inhibits IDO activity, thereby suppressing kynurenine formation, and at least one member of the kynurenine pathway, 3-hydroxyanthranilic acid, has been shown to inhibit NOS enzyme activity, the expression of NOS mRNA, and activation of the inflammatory transcription factor, nuclear factor-kB. In addition, the anti-inflammatory cytokines IL-4 and IL-10, TGF-beta, and a cytokine known as macrophage deactivating factor, have been shown to directly modulate NO production, sometimes expressing synergistic activity. On the other hand, IL-4 and TGF-beta can suppress IDO activity in some cells, for example human monocytes and fibroblasts, which is consistent with metabolic pathways controlled by IDO being a significant contributor to the proinflammatory system. Also, it seems that idiopathic intracranial hypertension, pseudotumor cerebri, and aseptic meningitis, induced by various factors, may result from their interference with IDO and inducible nitric oxide synthase activities, endogenous NO level, and cytokine irregularities which finally affect former T. gondii status 2mo in the brain. All these biochemical disturbances caused by the CNS T. gondii infection/inflammation may also be responsible for the relationship found between neurologic symptoms, such as headache, vertigo, and syncope observed in apparently immunocompetent children and adolescents, and physical and psychiatric symptoms in adulthood. We therefore believe that tests for T. gondii should be performed obligatorily in apparently immunocompetent patients with different types of headaches, even if they have no enlarged peripheral lymph nodes. This may help to avoid overlooking this treatable cause of the CNS disease, markedly reduce costs of hospitalization, diagnosis and treatment, and eventually prevent developing serious neurologic and psychiatric disorders.
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PMID:Recurrent headache as the main symptom of acquired cerebral toxoplasmosis in nonhuman immunodeficiency virus-infected subjects with no lymphadenopathy: the parasite may be responsible for the neurogenic inflammation postulated as a cause of different types of headaches. 1730 77

Mollaret meningitis (MM) occurs mainly in females and is characterized by recurrent episodes of headache, transient neurological abnormalities, and the cerebrospinal fluid containing mononuclear cells. HSV-2 was usually identified as the causative agent. Recently, we found that recurrent headaches in non-HIV-infected subjects were due to acquired cerebral toxoplasmosis (CT). The aim of the study was therefore to focus on molecular pathomechanisms that may lead to reactivation of latent CT and manifest as MM. Literature data cited in this work were selected to illustrate that various factors may affect latent CNS Toxoplasma gondii infection/inflammation intensity and/or host defense mechanisms, i.e., the production of NO, cytokines, tryptophan degradation by indoleamine 2,3-dioxygenase, mechanisms mediated by an IFN-gamma responsive gene family, limiting the availability of intracellular iron to T. gondii, and production of reactive oxygen/nitrogen species, finally inducing choroid plexitis and/or vasculitis. Examples of triggers revealing MM and accompanying disturbances of IFN-gamma-mediated immune responses that control HSV-2 and T. gondii include: female predominance (female mice are more susceptible to T. gondii infection than males); HSV-2 infection (increased IFN-gamma, IL-12); metaraminol (increased plasma catecholamine levels, changes in cytokine expression favoring T(H)2 cells responses); probably cholesterol contained in debris from ruptured epidermoid cysts (decreased NO; increased TNF-alpha, IL-6, IL-8). These irregularities induced by the triggers may be responsible for reactivation of latent CT and development of MM. Thus, subjects with MM should have test(s) for T. gondii infection performed obligatorily.
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PMID:Mollaret meningitis may be caused by reactivation of latent cerebral toxoplasmosis. 1992 80

5-Hydroxytryptophan (5-HTP) is a drug that is clinically effective against depression, insomnia, obesity, chronic headaches, etc. It is only commercially produced by the extraction from the seeds of Griffonia simplicifolia because of a lack of synthetic methods. Here, we report the efficient microbial production of 5-HTP via combinatorial protein and metabolic engineering approaches. First, we reconstituted and screened prokaryotic phenylalanine 4-hydroxylase activity in Escherichia coli. Then, sequence- and structure-based protein engineering dramatically shifted its substrate preference, allowing for efficient conversion of tryptophan to 5-HTP. Importantly, E. coli endogenous tetrahydromonapterin (MH4) could be utilized as the coenzyme, when a foreign MH4 recycling mechanism was introduced. Whole-cell bioconversion allowed the high-level production of 5-HTP (1.1-1.2 g/L) from tryptophan in shake flasks. On this basis, metabolic engineering efforts were further made to achieve the de novo 5-HTP biosynthesis from glucose. This work not only holds great scale-up potential but also demonstrates a strategy for expanding the native metabolism of microorganisms.
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PMID:Engineering bacterial phenylalanine 4-hydroxylase for microbial synthesis of human neurotransmitter precursor 5-hydroxytryptophan. 2493 77

The primary aim of this study (TA-CH, Tryptophan Amine in Chronic Headache) was to investigate a possible role of tryptophan (TRP) metabolism in chronic migraine (CM) and chronic tension-type headache (CTTH). It is not known if TRP metabolism plays any role in CM and/or CTTH. Plasma levels of serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), metabolite of 5-HT, and tryptamine (TRY) were tested in 73 patients with CM, 15 patients with CTTH and 37 control subjects. Of these, plasmatic TRY was significantly lower in CM (p < 0.001) and in CTTH (p < 0.002) patients with respect to control subjects, while 5-HIAA levels in plasma were within the same range in all groups. 5-HT was undetectable in the plasma of almost all subjects. Our results support the hypothesis that TRP metabolism is altered in CM and CTTH patients, leading to a reduction in plasma TRY. As TRY modulates the function of pain matrix serotonergic system, this may affect modulation of incoming nociceptive inputs from the trigeminal endings and posterior horns of the spinal cord. We suggest that these biochemical abnormalities play a role in the chronicity of CM and CTTH.
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PMID:Tryptamine levels are low in plasma of chronic migraine and chronic tension-type headache. 2501 60

The pathogenesis of migraine as well as cluster headache (CH) is yet a debated question. In this review, we discuss the possible role of the of tyrosine and tryptophan metabolism in the pathogenesis of these primary headaches. These include the abnormalities in the synthesis of neurotransmitters: high level of DA, low level of NE and very elevated levels of octopamine and synephrine (neuromodulators) in plasma of episodic migraine without aura and CH patients. We hypothesize that the imbalance between the levels of neurotransmitters and elusive amines synthesis is due to a metabolic shift directing tyrosine toward an increased decarboxylase and reduced hydroxylase enzyme activities. The metabolic shift of the tyrosine is favored by a state of neuronal hyperexcitability and a reduced mitochondrial activity present in migraine. In addition we present biochemical studies performed in chronic migraine and chronic tension-type headache patients to verify if the same anomalies of the tyrosine and tryptophan metabolism are present in these primary headaches and, if so, their possible role in the chronicity process of CM and CTTH. The results show that important abnormalities of tyrosine metabolism are present only in CM patients (very high plasma levels of DA, NE and tryptamine). Tryptamine plasma levels were found significantly lower in both CM and CTTH patients. In view of this, we propose that migraine and, possibly, CH attacks derive from neurotransmitter and neuromodulator metabolic abnormalities in a hyperexcitable and hypoenergetic brain that spread from the frontal lobe, downstream, resulting in abnormally activated nuclei of the pain matrix. The low tryptamine plasma levels found in CM and CTTH patients suggest that these two primary chronic headaches are characterized by a common insufficient serotoninergic control of the pain threshold.
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PMID:Biochemistry of primary headaches: role of tyrosine and tryptophan metabolism. 2670 50

Patients with mastocytosis can display various disabling general and neuropsychological symptoms among one third of them, including general signs such as fatigue and musculoskeletal pain, which can have a major impact on quality of life. Neurological symptoms are less frequent and mainly consist of acute or chronic headache (35%), rarely syncopes (5%), acute onset back pain (4%), and in a few cases, clinical and radiological symptoms resembling or allowing the diagnosis of multiple sclerosis (1.3%). Headaches are associated with symptoms related to mast cell activation syndrome (flushes, prurit, and so forth) and more frequently present as migraine (37.5%), with often aura (66%). Depression-anxiety like symptoms can occur in 40% to 60% of the patients and cognitive impairment is not rare (38.6%). The pathophysiology of these symptoms could be linked to tissular mast cell infiltration or to mast cell mediators release or both. The tryptophan metabolism could be involved in mast cell-induced neuroinflammation through indoleamine-2,3-dioxygenase activation. Treatments targeting mast cell may be useful to target neuropsychological features associated with mastocytosis, including tyrosine kinase inhibitors.
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PMID:Mastocytosis in adulthood and neuropsychiatric disorders. 2706 57


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