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)

Calcitonin gene-related peptide (CGRP) is involved in the underlying pathophysiology of all vascular headaches, including migraines. Elevated levels of CGRP during migraine are restored to normal coincident with headache relief after treatment with the antimigraine drug sumatriptan. We have used primary cultures of trigeminal neurons under conditions simulating migraine pathology and therapy to study the mechanisms controlling the CGRP promoter. Using reporter genes in transient transfection assays, we demonstrate that an 18 bp enhancer containing a helix-loop-helix element is both necessary and sufficient for full promoter activity. NGF treatment and cotransfection with an upstream activator of the extracellular signal-regulated MAP kinases (MAPKs) activated the enhancer. Treatment with sumatriptan repressed NGF- and MAPK-stimulated CGRP promoter activity. Repression was also observed using a synthetic MAPK-responsive reporter gene. Sumatriptan regulation of CGRP gene expression did not couple to a G(i)/G(o) pathway, but rather caused a prolonged increase in intracellular calcium. The importance of the prolonged calcium signal in repression of MAPK activity was demonstrated by using the ionophore ionomycin to mimic sumatriptan action. We propose that activation of MAPK pathways may increase CGRP gene expression during migraine, and that sumatriptan can diametrically oppose that activation via a prolonged elevation of intracellular calcium.
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PMID:Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinases and repression by an antimigraine drug in trigeminal ganglia neurons. 1257 9

Expression of the neuropeptide calcitonin gene-related peptide (CGRP) in trigeminal ganglion is implicated in neurovascular headaches and temporomandibular joint disorders. Elevation of cytokines contributes to the pathology of these diseases. However, a connection between cytokines and CGRP gene expression in trigeminal ganglion nerves has not been established. We have focused on the effects of the cytokine tumor necrosis factor-alpha (TNF-alpha). TNFR1 receptors were found on the majority of CGRP-containing rat trigeminal ganglion neurons. Treatment of cultures with TNF-alpha stimulated CGRP secretion. In addition, the intracellular signaling intermediate from the TNFR1 receptor, ceramide, caused a similar increase in CGRP release. TNF-alpha caused a coordinate increase in CGRP promoter activity. TNF-alpha treatment activated the transcription factor NF-kappaB, as well as the Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways. The importance of TNF-alpha induction of MAP kinase pathways was demonstrated by inhibiting MAP kinases with pharmacological reagents and gene transfer with an adenoviral vector encoding MAP kinase phosphatase-1 (MKP-1). We propose that selective and regulated inhibition of MAP kinases in trigeminal neurons may be therapeutically beneficial for inflammatory disorders involving elevated CGRP levels.
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PMID:Tumor necrosis factor-alpha stimulation of calcitonin gene-related peptide expression and secretion from rat trigeminal ganglion neurons. 1627 6

MEK inhibitors are an emerging therapy with increasing use in mitogen-activated protein kinase-driven central nervous system (CNS) tumors. There is limited data regarding efficacy and toxicity in pediatric patients. We report our clinical experience with trametinib-based therapy for the treatment of 14 consecutive pediatric patients with recurrent low-grade glioma (N=11) or high-grade CNS tumors (N=3) with MAP kinase pathway mutations. Patients received trametinib as monotherapy (N=9) or in combination (N=5) with another antineoplastic agent. Nine patients (64%) were progression free during treatment. Five patients showed a partial response, while 4 had stable disease. Two patients (14%) progressed on therapy. All partial responses were in patients with low-grade tumors. The remaining 3 patients were not evaluable due to toxicity limiting duration of therapy. Two of 3 patients with low-grade glioma with leptomeningeal dissemination showed radiographic treatment response. Five patients reported improved clinical symptoms while on trametinib. Adverse events on trametinib-based therapy included dermatologic, mouth sores, fever, gastrointestinal, infection, neutropenia, headache, and fatigue, and were more common in patients using combination therapy. Trametinib-based therapy demonstrated signals of efficacy in our single institutional cohort of pediatric patients with mitogen-activated protein kinase-driven CNS tumors. Our observations need to be confirmed in a clinical trial setting.
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PMID:Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience. 3239 1