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)

Gastrodia elata (G. elata) is a traditional Chinese herbal medicine for treating headaches, dizziness, tetanus, and epilepsy. In this study, differential methanol (MeOH) extracts of G. elata were found to prevent serum-deprived rat pheochromocytoma (PC12) cell apoptosis by the MTT assay and Hoechst staining. A serine/threonine kinase inhibitor attenuated this protection. G. elata resulted in phosphorylation and dephosphorylation of ERK1/2 and JNK1/2-p38 MAPKs (members of the serine/threonine kinase family), respectively, as revealed by Western blot analysis. An upstream ERK inhibitor attenuated G. elata-induced ERK phosphorylation but not protective effect. Although JNK and p38 inhibitors attenuated their related enzyme activities during serum deprivation, only JNK inhibitor prevented serum-deprived apoptosis. Thus, G. elata prevents serum-deprived apoptosis through activation of the serine/threonine kinase-dependent pathway and suppression of JNK activity.
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PMID:Gastrodia elata prevents rat pheochromocytoma cells from serum-deprived apoptosis: the role of the MAPK family. 1526 68

Although migraine is more common in women than men and often linked to the menstrual cycle, few studies have investigated the biological basis of hormonal influences on the trigeminovascular system. In the present study we investigated the effect of physiological levels (10(-9) m) oestrogen on female rat trigeminal ganglia in vitro. Immunocytochemical analysis demonstrated the presence of oestrogen receptor-alpha in a predominantly cytoplasmic location and in neurites. Microarray analysis demonstrated that oestrogen treatment regulates several genes with potential relevance to menstrual migraine. The genes that were upregulated included synapsin-2, endothelin receptor type B, activity and neurotransmitter-induced early gene 7 (ania-7), phosphoserine aminotransferase, MHC-1b, and ERK-1. Down-regulated genes included IL-R1, bradykinin B2 receptor, N-tropomodulin, CCL20, GABA transporter protein, fetal intestinal lactase-phlorizin hydrolase, carcinoembryonic antigen-related protein, zinc finger protein 36, epsin 1 and cysteine string protein. Protein activity assays demonstrated that exposure of the cultured neurons to oestrogen leads to activation of ERK, which has been linked to inflammatory pain. Immunocytochemistry demonstrated that activated ERK was present in neurons containing peripherin, a marker of nociceptive neurons. Several of the genes in the present study may provide potential targets for understanding the association of oestrogen with migraine and other hormone-related orofacial pain.
Cephalalgia 2006 Jan
PMID:Effects of oestrogen on trigeminal ganglia in culture: implications for hormonal effects on migraine. 1639 64

LIGHT acted as a new player in the atherogenesis. The dried, unripe fruit of Evodia Fructus (EF) has long been used as a traditional Chinese herbal medicine, and is currently widely used for the treatment of headache, abdominal pain, vomiting, colds and reduced blood circulation. Evodiamine and rutaecarpine are active components of EF. In this study, we investigated the inhibitory effect of evodiamine and rutaecarpine on LIGHT-induced migration in human monocytes. Evodiamine and rutaecarpine decreased the LIGHT-induced production of ROS, IL-8, monocyte chemoattractant protein-1 (MCP-1), TNF-alpha, and IL-6, as well as the expression of chemokine receptor (CCR) 1, CCR2 and ICAM-1 and the phosphorylation of the ERK 1/2 and p38 MAPK. Furthermore, NADPH oxidase assembly inhibitor, AEBSF, blocked LIGHT-induced migration and activation of CCR1, CCR2, ICAM-1, and MAPK such as ERK and p38 in a manner similar to evodiamine and rutaecarpine. These findings indicate that the inhibitory effects of evodiamine and rutaecarpine on LIGHT-induced migration and the activation of CCR1, CCR2, ICAM-1, ERK, and p38 MAPK occurs via decreased ROS production and NADPH oxidase activation. Taken together, these results indicate that evodiamine and rutaecarpine have the potential for use as an anti-atherosclerosis agent.
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PMID:Evodiamine and rutaecarpine inhibit migration by LIGHT via suppression of NADPH oxidase activation. 1924 41

Experimental and occupational exposure to methyl tert-butyl ether (MTBE) has been reported to induce neurotoxicological and neurobehavioral effects, such as headache, nausea, dizziness, and disorientation, etc. However, the molecular mechanisms involved in MTBE-induced neurotoxicity are still not well understood. In the present study, we investigated the effects of MTBE on spatial memory and the expression and function of GABA(A) receptor in the hippocampus. Our results demonstrated that intraventricular injection of MTBE impaired the performance of the rats in a Morris water maze task, and significantly increased the expression of GABA(A) receptor alpha1 subunit in the hippocampus. The phosphorylation of ERK1/2 decreased after the MTBE injection. Furthermore, the decreased ability of learning and the reduction of phosphorylated ERK1/2 level of the MTBE-treated rats was partly reversed by bicuculline injected 30 min before the training. These results suggested that MTBE exposure could result in impaired spatial memory. GABA(A) receptor may play an important role in the MTBE-induced impairment of learning and memory by regulating the phosphorylation of ERK in the hippocampus.
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PMID:gamma-Aminobutyric acid(A) (GABA(A)) receptor regulates ERK1/2 phosphorylation in rat hippocampus in high doses of methyl tert-butyl ether (MTBE)-induced impairment of spatial memory. 1934 68

Trigeminal nerve-mediated pain disorders such as migraine, temporomandibular joint disorder, and classical trigeminal neuralgia are more prevalent in women than in men. Female laboratory animals also show greater responses to various nociceptive stimuli than male animals. However, current knowledge of migraine pathogenesis is based primarily on experimental studies conducted in male animals and lack of migraine research with female animals limits clinical relevance. Migraine is triggered by any alteration in the intrinsic or extrinsic milieu and women at reproductive age are continuously prone to waxing and waning effects of female sex hormones. The experimental approach to this problem is complex because the rodent estrous cycle differs from the human cycle, and because exogenous hormone replacement in ovariectomized females has its limitations. The existence of multiple estrogen receptors in the trigeminal system also presents a challenge. Estrogens do not seem to directly affect calcitonin gene-related peptide or 5-HT(1D) receptors in the trigeminal system. Nonetheless, 2 estrogen receptors activate MAPK/ERK signaling pathway that mediates nociceptive processing in trigeminal nucleus caudalis. In addition, estrogen enhances susceptibility to cortical spreading depression, the neurobiological event underlying migraine aura, which may be independent of the estrous cycle. Further studies in female animals are required to clarify mechanisms underlying sex differences with respect to fluctuating sex hormones, cortical spreading depression, and excitability of the trigeminovascular system.
Headache 2011 Jun
PMID:Sex-related differences in animal models of migraine headache. 2163 75

Detection of external irritants by head nociceptor neurons has deep evolutionary roots. Irritant-induced aversive behavior is a popular pain model in laboratory animals. It is used widely in the formalin model, where formaldehyde is injected into the rodent paw, eliciting quantifiable nocifensive behavior that has a direct, tissue-injury-evoked phase, and a subsequent tonic phase caused by neural maladaptation. The formalin model has elucidated many antipain compounds and pain-modulating signaling pathways. We have adopted this model to trigeminally innervated territories in mice. In addition, we examined the involvement of TRPV4 channels in formalin-evoked trigeminal pain behavior because TRPV4 is abundantly expressed in trigeminal ganglion (TG) sensory neurons, and because we have recently defined TRPV4's role in response to airborne irritants and in a model for temporomandibular joint pain. We found TRPV4 to be important for trigeminal nocifensive behavior evoked by formalin whisker pad injections. This conclusion is supported by studies with Trpv4(-/-) mice and TRPV4-specific antagonists. Our results imply TRPV4 in MEK-ERK activation in TG sensory neurons. Furthermore, cellular studies in primary TG neurons and in heterologous TRPV4-expressing cells suggest that TRPV4 can be activated directly by formalin to gate Ca(2+). Using TRPA1-blocker and Trpa1(-/-) mice, we found that both TRP channels co-contribute to the formalin trigeminal pain response. These results imply TRPV4 as an important signaling molecule in irritation-evoked trigeminal pain. TRPV4-antagonistic therapies can therefore be envisioned as novel analgesics, possibly for specific targeting of trigeminal pain disorders, such as migraine, headaches, temporomandibular joint, facial, and dental pain, and irritation of trigeminally innervated surface epithelia.
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PMID:TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor. 2528 28

Salicin from willow bark has been used throughout centuries in China and Europe for the treatment of pain, headache, and inflammatory conditions. Recently, it could be demonstrated that salicin binds and activates the bitter taste receptor TAS2R16. Studies on rodent tissues showed the general expression of bitter taste receptors (TAS2Rs) in rodent brain. Here, we demonstrate the expression of hTAS2R16 in human neuronal tissues and the neuroblastoma cell line SH-SY5Y. The functionality was analyzed in the neuroblastoma cell line SH-SY5Y after stimulation with salicin, a known TAS2R16 agonist. In this setting salicin induced in SH-SY5Y cells phosphorylation of ERK and CREB, the key transcription factor of neuronal differentiation. PD98059, an inhibitor of the ERK pathway, as well as probenecid, a TAS2R16 antagonist, inhibited receptor phosphorylation as well as neurite outgrowth. These data show that salicin might modulate neurite outgrowth by bitter taste receptor activation.
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PMID:Salicin from Willow Bark can Modulate Neurite Outgrowth in Human Neuroblastoma SH-SY5Y Cells. 2609 5

Cortex Mori Radicis is a traditional Chinese herbal medicine which has a long history of use for the treatment of headaches, cough, edema and diabetes. However, its function and mode of action within nervous system remain largely unclear. In the present study, we have attempted to determine the effects of Cortex Mori Radicis Extract (CMRE) on neuronal differentiation. Here, we reported that CMRE induces the neurite outgrowth in pheochromocytoma PC12 cells and primary cortical neuron. Following the generation of neurite outgrowth, extracellular Ca(2+) influx was inhibited and intracellular Ca(2+) decreased. In addition, CMRE induced the extracellular signal-regulated kinase 1/2 (ERK1/2) activation and also stimulated the Rap1-GTP expression, which is closely linked to neuritogenesis. Moreover, the neurite outgrowth induced by CMRE was antagonized to a marked degree by suppressing activation of p-ERK1/2 with the specific ERK1/2 inhibitor (PD98059), suggesting the involvement of Rap1-GTP and ERK1/2 in CMRE-induced neurite outgrowth. Taken together, these results demonstrate that CMRE induces neurite outgrowth of PC12 cells through Rap1-ERK signaling pathway via inhibiting Ca(2+) influx, and provide a novel insight into the manner in which CMRE participates in neuritogenesis.
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PMID:Cortex Mori Radicis Extract induces neurite outgrowth in PC12 cells activating ERK signaling pathway via inhibiting Ca(2+) influx. 2613 Oct 75

Background Calcitonin gene-related peptide (CGRP) is a neuropeptide that acts in the trigeminovascular system and is believed to play an important role in migraine. CGRP activates two receptors that are both present in the trigeminovascular system; the CGRP receptor and the amylin 1 (AMY1) receptor. CGRP receptor antagonists, including olcegepant (BIBN4096BS) and telcagepant (MK-0974), can treat migraine. This study aimed to determine the effectiveness of these antagonists at blocking CGRP receptor signalling in trigeminal ganglia (TG) neurons and transfected CGRP and AMY1 receptors in Cos7 cells, to better understand their mechanism of action. Methods CGRP stimulation of four intracellular signalling molecules relevant to pain (cAMP, CREB, p38 and ERK) were examined in rat TG neurons and compared to transfected CGRP and AMY1 receptors in Cos7 cells. Results In TG neurons, olcegepant displayed signal-specific differences in antagonism of CGRP responses. This effect was also evident in transfected Cos7 cells, where olcegepant blocked CREB phosphorylation more potently than expected at the AMY1 receptor, suggesting that the affinity of this antagonist can be dependent on the signalling pathway activated. Conclusions CGRP receptor antagonist activity appears to be assay-dependent. Thus, these molecules may not be as selective for the CGRP receptor as commonly reported.
Cephalalgia 2018 03
PMID:CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured. 2816 87

Lorcaserin (LOR) is a selective 5-HT2C receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT2C agonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT2C agonists having better tolerability, the present studies were designed to further investigate this apparent difference. In a conditioned gaping model, a rodent test of nausea, LOR produced significantly higher gapes compared to CP consistent with it having higher emetogenic properties. Subsequent studies were designed to identify features of each drug that may account for such differences. In rats trained to discriminate CP-809101 from saline, both CP and LOR produced full generalization suggesting a similar interoceptive cue. In vitro tests of functional selectivity designed to examine signaling pathways activated by both drugs in CHO (Chinese hamster ovary) cells expressing h5-HT2C receptors failed to identify evidence for biased signaling differences between LOR and CP. Thus, both drugs showed similar profiles across PLC, PLA2, and ERK signaling pathways. In studies designed to examine pharmacokinetic differences between LOR and CP, while drug plasma levels correlated with increasing dose, CSF levels did not. CSF levels of LOR increased proportionally with dose; however CSF levels of CP plateaued from 6 to 12 mg/kg. Thus, the apparently improved tolerability of CP likely reflects a limit to CNS levels attained at relatively high doses.
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PMID:Studies To Examine Potential Tolerability Differences between the 5-HT2C Receptor Selective Agonists Lorcaserin and CP-809101. 2833 24


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