Dihydroergotamine protects against ischemic stroke by modulating microglial/macrophage polarization and inhibiting inflammation in mice.

OBJECTIVES: The search for drugs that can protect the brain tissue and reduce nerve damage in acute ischemic stroke has emerged as a research hotspot. We investigated the potential protective effects and mechanisms of action of dihydroergotamine against ischemic stroke. METHODS: C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO), and dihydroergotamine at a dose of 10 mg/kg/day was intraperitoneally injected for 14 days. Adhesive removal and beam walking tests were conducted 1, 3, 5, 7, 10, and 14 days after MCAO surgery. Thereafter, the mechanism by which dihydroergotamine regulates microglia/macrophage polarization and inflammation and imparts ischemic stroke protection was studied using enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting. RESULTS: From the perspective of a drug repurposing strategy, dihydroergotamine was found to inhibit oxygen-glucose deprivation damage to neurons, significantly improve cell survival rate, and likely exert a protective effect on ischemic brain injury. Dihydroergotamine significantly improved neural function scores and survival rates and reduced brain injury severity in mice. Furthermore, dihydroergotamine manifests its protective effect on ischemic brain injury by reducing the expression of TNF-α and IL-1ß in mouse ischemic brain tissue, inhibiting the polarization of microglia/macrophage toward the M1 phenotype and promoting polarization toward the M2 phenotype. CONCLUSION: This study is the first to demonstrate the protective effect of dihydroergotamine, a first-line treatment for migraine, against ischemic nerve injury in vitro and in vivo.

Dihydroergotamine mesylate enhances the anti-tumor effect of sorafenib in liver cancer cells.

Liver cancer is the most common and frequentlyoccurring cancer. In addition to radiotherapy, chemotherapy and surgery are recommended as part of liver cancer treatment. The efficacy of sorafenib and sorafenib-based combination treatment against tumors has been verified. Although, clinical trials have revealed that some individuals are not sensitive to sorafenib therapy, and current therapeutic approaches are ineffective. Consequently, it is urgent to explore effective drug combinations and innovative techniques for increasing the effectiveness of sorafenib in the curing of liver tumor. Herein, we show that dihydroergotamine mesylate (DHE), an anti-migraine agent, could effectively suppress liver cancer cells proliferation by inhibiting STAT3 activation. However, DHE can enhance the protein stability of Mcl-1 by activating ERK, making DHE less effective in apoptosis induction. Specifically, DHE enhances the effects of sorafenib on liver cancer cells, such as decreased viability and increased apoptosis. Furthermore, the mixture of sorafenib and DHE could enhance DHE-triggered STAT3 suppression and inhibit DHE-mediated ERK-Mcl-1 pathway activation. In vivo, the combination of sorafenib with DHE produced a substantial synergy in suppressing tumour growth and causing apoptosis, ERK inhibition and Mcl-1 degradation. These findings suggest that DHE can effectively inhibit cell proliferation and enhance sorafenib anti-cancer activity in liver cancer cells. The current study provides some new insights that DHE asa novel anti-liver cancer therapeutic agent has been shown to improve treatment outcomes of sorafenib, which might be helpful in order to advance sorafenib in liver cancer therapeutics.

STOP 301: A Phase 3, open-label study of safety, tolerability, and exploratory efficacy of INP104, Precision Olfactory Delivery (POD® ) of dihydroergotamine mesylate, over 24/52 weeks in acute treatment of migraine attacks in adult patients.

OBJECTIVE: To report the safety, tolerability, exploratory efficacy, and patient acceptability of INP104 for the acute treatment of migraine from the Phase 3 STOP 301 trial. BACKGROUND: Dihydroergotamine (DHE) has long been used to treat migraine, but intravenous administration is invasive, frequently associated with adverse events (AEs), and not suitable for at-home administration. INP104 is an investigational drug device that delivers DHE mesylate to the upper nasal space using a Precision Olfactory Delivery technology and was developed to overcome the shortcomings of available DHE products. METHODS: STOP 301 was an open-label, 24-week safety study, with a 28-week extension period. After a 28-day screening period where patients used their "best usual care" to treat migraine attacks, patients were given INP104 (1.45 mg) to self-administer nasally with self-recognized attacks. The primary objective of this study was to assess safety and tolerability, with a specific focus on nasal mucosa and olfactory function. Exploratory objectives included efficacy assessments of migraine measures and a patient acceptability questionnaire. RESULTS: A total of 360 patients entered the 24-week treatment period, with 354 patients dosing at least once. INP104-related treatment-emergent AEs were reported by 36.7% (130/354) of patients, and 6.8% (24/354) discontinued treatment due to AEs over 24 weeks. No new safety signals were observed following delivery to the upper nasal space. Pain freedom, the most bothersome symptom freedom, and pain relief at 2 h post-INP104 were self-reported by 38.0% (126/332), 52.1% (173/332), and 66.3% (167/252) of patients, respectively. A low recurrence rate at 24 and 48 h was observed (7.1% [9/126] and 14.3% [18/126], respectively). Most patients found INP104 easy to use and preferred it over their current therapy. CONCLUSIONS: INP104 has the potential to deliver rapid symptom relief, without injection, that is well tolerated and suitable for outpatient use. Results suggest INP104 may be a promising treatment for patients with migraine.

Implementation of an Intravenous Dihydroergotamine Protocol for Refractory Migraine in Children.

OBJECTIVE: Retrospective chart review to assess the effectiveness of an institutional intravenous (IV) dihydroergotamine (DHE) therapy protocol for refractory migraine in the pediatric population. BACKGROUND: Limited high-quality evidence exists to guide the approach to treatment of refractory migraine with IV DHE, particularly in the pediatric population. This study reviews our institutional experience in implementing an IV DHE protocol in children to identify areas for improvement. We specifically sought to determine whether the outcome differed at follow-up between children who completed the full course of DHE (8 or 9 doses) as specified in our institutional protocol and those who did not. In addition, given the limited Food and Drug Administration-approved treatments for chronic migraine (CM) in the pediatric population, re-evaluating the response rate in this group of patients was of particular interest. METHODS: A retrospective cohort based on a chart review of 159 consecutive pediatric patients who received IV DHE while inpatient at University of Virginia Children's Hospital over a 9-year period (January 2011-January 2019) was identified. Patients were classified according to the International Classification of Headache Disorders, 3rd edition criteria as having CM, status migrainosus, or, in a small number of patients, Other headache with migrainous features. To investigate any benefit of completing the full course of DHE, patients were categorized as having completed the DHE protocol ("Protocol Complete" 8 or 9 doses) or not completing the protocol ("Protocol Incomplete" <8 doses). Patient-reported pain scores upon admission and discharge were recorded, and follow-up outcomes were categorized as headache freedom, >50% relief, <50% relief, or no relief. Pain outcomes were analyzed with respect to DHE protocol complete status and headache classification. RESULTS: A total of 159 patients were included in the analysis. The headache diagnosis was CM in 49% (78/159), status migrainosus in 44% (70/159), and Other headache with migrainous features in 7% (11/159). At discharge, 60% (96/159) of patients achieved headache freedom, and no statistically significant difference was found in relative change in headache among the CM, status migrainosus, and Other headache groups. Patients who completed the full 8 or 9 dose IV DHE protocol were more likely to have persistent headache at discharge, with a median pain score of 1.0 (IQR 0.0-4.0) compared to a score of 0.0 (IQR 0.0-1.0) in the DHE incomplete group (P < .001). No difference was found in pain relief outcomes at follow-up in the DHE protocol complete and DHE protocol incomplete groups. CONCLUSIONS: Although limited by the absence of a control group, our data support repetitive IV DHE as an abortive therapy for pediatric patients with status migrainosus or CM, with no evidence of differential efficacy in these groups. A higher rate of headache at discharge in the DHE protocol complete group reflects in large part the common decision to discontinue treatment once headache freedom was achieved, resulting in nonresponders being more likely to complete the full course of DHE. In our cohort, there was no difference in pain relief at follow-up between patients who completed the full 8 or 9 doses of DHE and those that did not. Discontinuing DHE once the patient has achieved headache freedom would therefore achieve the therapeutic goal while shortening the hospital stay. To potentially impact longer term pain relief, incorporation of a comprehensive treatment approach into the IV DHE admission is of interest for future study and quality improvement initiatives.

Targeting Oncogenic Super Enhancers in MYC-Dependent AML Using a Small Molecule Activator of NR4A Nuclear Receptors.

Epigenetic reprogramming in Acute Myeloid Leukemia (AML) leads to the aberrant activation of super enhancer (SE) landscapes that drive the expression of key oncogenes, including the oncogenic MYC pathway. These SEs have been identified as promising therapeutic targets, and have given rise to a new class of drugs, including BET protein inhibitors, which center on targeting SE activity. NR4A nuclear receptors are tumor suppressors of AML that function in part through transcriptional repression of the MYC-driven oncogenic program via mechanisms that remain unclear. Here we show that NR4A1, and the NR4A inducing drug dihydroergotamine (DHE), regulate overlapping gene expression programs in AML and repress transcription of a subset of SE-associated leukemic oncogenes, including MYC. NR4As interact with an AML-selective SE cluster that governs MYC transcription and decommissions its activation status by dismissing essential SE-bound coactivators including BRD4, Mediator and p300, leading to loss of p300-dependent H3K27 acetylation and Pol 2-dependent eRNA transcription. DHE shows similar efficacy to the BET inhibitor JQ1 at repressing SE-dependent MYC expression and AML growth in mouse xenografts. Thus, DHE induction of NR4As provides an alternative strategy to BET inhibitors to target MYC dependencies via suppression of the AML-selective SE governing MYC expression.

Drug targeting of NR4A nuclear receptors for treatment of acute myeloid leukemia.

NR4As are AML tumor suppressors that are frequently silenced in human acute myeloid leukemia (AML). Despite their potential as novel targets for therapeutic intervention, mechanisms of NR4A silencing and strategies for their reactivation remain poorly defined. Here we show that NR4A silencing in AML occurs through blockade of transcriptional elongation rather than epigenetic promoter silencing. By intersection of NR4A-regulated gene signatures captured upon acute, exogenous expression of NR4As in human AML cells with in silico chemical genomics screening, we identify several FDA-approved drugs including dihydroergotamine (DHE) that reactivate NR4A expression and regulate NR4A-dependent gene signatures. We show that DHE induces NR4A expression via recruitment of the super elongation complex to enable elongation of NR4A promoter paused RNA polymerase II. Finally, DHE exhibits AML selective NR4A-dependent anti-leukemic activity in cytogenetically distinct human AML cells in vitro and delays AML progression in mice revealing its potential as a novel therapeutic agent in AML.

Diagnosis and treatment of migraine in the patient with depression.

BACKGROUND AND PURPOSE: Migraine headache is an enormous health care burden resulting in billions of dollars in workforce revenue lost and millions of lost workdays per year. Migraine headaches and depression are common comorbidities and require expertise in treatment and prevention. METHODS: The aim of this article is to update the nurse practitioner (NP) on best clinical practices for managing the patient with migraine and previously diagnosed depression. This will include an overview of the pathophysiology of migraine, as well as criteria for diagnosis, treatment, prevention, and patient teaching. CONCLUSIONS: Migraine and depression are commonly linked and require expertise in treatment to achieve the best patient outcomes. IMPLICATIONS FOR PRACTICE: Patients with migraine are more likely to have depression than the general population. Both conditions require optimal treatment and patient education to reduce overall disease burden. A better understanding of the relationship between depression and migraine will enable the NP to better manage patients with migraine and comorbid depression.

Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of α2-adrenoceptors and 5-HT1 receptors.

BACKGROUND: Dihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow. METHODS: Pithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 µg/kg·min) and DHE (3.1 µg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure. RESULTS: DHE inhibited the vasodepressor responses to electrical stimulation (0.56-5.6 Hz), without affecting those to i.v. α-CGRP (0.1-1 µg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists rauwolscine (α2-adrenoceptor; 310 µg/kg) plus GR127935 (5-HT1B/1D; 31 µg/kg); and (ii) remained unaffected after rauwolscine (310 µg/kg), GR127935 (31 µg/kg) or haloperidol (D2-like; 310 µg/kg) given alone, or after the combination of rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses. CONCLUSION: DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional rauwolscine-sensitive α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/2C-adrenoceptors and 5-HT1B receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE's vasoconstrictor properties resulting in an increased vascular resistance.

The role of α1- and α2-adrenoceptor subtypes in the vasopressor responses induced by dihydroergotamine in ritanserin-pretreated pithed rats.

BACKGROUND: Dihydroergotamine (DHE) is an acute antimigraine agent that displays affinity for dopamine D2-like receptors, serotonin 5-HT1/2 receptors and α1/α2-adrenoceptors. Since activation of vascular α1/α2-adrenoceptors results in systemic vasopressor responses, the purpose of this study was to investigate the specific role of α1- and α2-adrenoceptors mediating DHE-induced vasopressor responses using several antagonists for these receptors. METHODS: For this purpose, 135 male Wistar rats were pithed and divided into 35 control and 100 pretreated i.v. with ritanserin (100 µg/kg; to exclude the 5-HT2 receptor-mediated systemic vasoconstriction). Then, the vasopressor responses to i.v. DHE (1-3100 µg/kg, given cumulatively) were determined after i.v. administration of some α1/α2-adrenoceptor antagonists. RESULTS: In control animals (without ritanserin pretreatment), the vasopressor responses to DHE were: (i) unaffected after prazosin (α1; 30 µg/kg); (ii) slightly, but significantly, blocked after rauwolscine (α2; 300 µg/kg); and (iii) markedly blocked after prazosin (30 µg/kg) plus rauwolscine (300 µg/kg). In contrast, after pretreatment with ritanserin, the vasopressor responses to DHE were: (i) attenuated after prazosin (α1; 10 and 30 µg/kg) or rauwolscine (α2; 100 and 300 µg/kg); (ii) markedly blocked after prazosin (30 µg/kg) plus rauwolscine (300 µg/kg); (iii) attenuated after 5-methylurapidil (α1A; 30-100 µg/kg), L-765,314 (α1B; 100 µg/kg), BMY 7378 (α1D; 30-100 µg/kg), BRL44408 (α2A; 100-300 µg/kg), imiloxan (α2B; 1000-3000 µg/kg) or JP-1302 (α2C; 1000 µg/kg); and (iv) unaffected after the corresponding vehicles (1 ml/kg). CONCLUSION: These results suggest that the DHE-induced vasopressor responses in ritanserin-pretreated pithed rats are mediated by α1- (probably α1A, α1B and α1D) and α2- (probably α2A, α2B and α2C) adrenoceptors. These findings could shed light on the pharmacological profile of the vascular side effects (i.e. systemic vasoconstriction) produced by DHE and may lead to the development of more selective antimigraine drugs devoid vascular side effects.

Acute and chronic triptan exposure neither alters rodent cerebral blood flow nor worsens ischemic brain injury.

Although it is still debated whether vasoconstriction underlies migraine resolution by triptans, they are not recommended in patients at cardiovascular risk. However, relationship between stroke incidence and triptan use is unclear, and it is unknown whether acute or chronic use of these drugs worsens ischemic brain injury. To address this issue, we investigated the effect of clinically-relevant doses of the potent cerebral artery vasoconstrictor eletriptan on cerebral blood flow (CBF) and brain infarct volumes, as well as on expression of genes involved in cerebrovascular regulation. We report that acute treatment of rats or mice with eletriptan did not reduce basal CBF, which promptly dropped upon treatment with prazosin or dihydroergotamine. Acute of chronic (1month) eletriptan also did not affect CBF changes and infarct volumes in mice undergoing brain ischemia/reperfusion. Finally, chronic eletriptan reduced brain mRNAs for PACAP and VIP, leaving unaffected those for 5HT1B/DR and CGRP. No significant transcript changes were found in dura mater. Data suggest that the impact of triptans on cerebral hemodynamic should be re-evaluated, as well as their propensity to increase stroke risk in migraineurs.

Dihydroergotamine Tartrate Induces Lung Cancer Cell Death through Apoptosis and Mitophagy.

BACKGROUND: Mitochondria have emerged as a major target for anticancer therapy because of their critical role in cancer cell survival. Our preliminary works have suggested that dihydroergotamine tartrate (DHE), an antimigraine agent, may have effects on mitochondria. METHODS: We examined the effect of DHE on the survival of several lung cancer cells and confirmed that DHE suppressed diverse lung cancer cell growth effectively. To confirm whether such effects of DHE would be associated with mitochondria, A549 cells were employed for the evaluation of several important parameters, such as membrane potential, reactive oxygen species (ROS) generation, apoptosis, ATP production and autophagy. RESULTS: DHE decreased membrane permeability, increased ROS generation as well as apoptosis, and disturbed ATP production. Eventually, mitophagy was activated for damaged mitochondria. CONCLUSION: Taken together, our findings demonstrate that DHE induces lung cancer cell death by the induction of apoptosis and mitophagy, thus suggesting that DHE can be developed as an anti-lung cancer therapeutic agent.

Dihydroergotamine and sumatriptan in isolated human coronary artery, middle meningeal artery and saphenous vein.

BACKGROUND: Dihydroergotamine (DHE) and sumatriptan are contraindicated in patients with cardiovascular disease because of their vasoconstricting properties, which have originally been explored in proximal coronary arteries. Our aim was to investigate DHE and sumatriptan in the proximal and distal coronary artery, middle meningeal artery and saphenous vein. METHODS: Blood vessel segments were mounted in organ baths and concentration response curves for DHE and sumatriptan were constructed. RESULTS: In the proximal coronary artery, meningeal artery and saphenous vein, maximal contractions to DHE (proximal: 8 ± 4%; meningeal: 32 ± 7%; saphenous: 52 ± 11%) and sumatriptan (proximal: 17 ± 7%; meningeal: 61 ± 18%, saphenous: 37 ± 8%) were not significantly different. In the distal coronary artery, contractions to DHE (5 ± 2%) were significantly smaller than those to sumatriptan (17 ± 9%). At clinically relevant concentrations, mean contractions to DHE and sumatriptan were below 3% in proximal coronary arteries and below 6% in distal coronary arteries. Contractions in the meningeal artery and saphenous vein were higher (7%-38%). CONCLUSIONS: Contractions to DHE in distal coronary arteries are smaller than those to sumatriptan, while at clinical concentrations they both induce only slight contractions. In meningeal arteries contractions to DHE and sumatriptan are significantly larger, showing their cranioselectivity. Contractions to DHE in the saphenous vein are higher than those in the arteries, confirming its venous contractile properties.

Dihydroergotamine: a review of formulation approaches for the acute treatment of migraine.

Dihydroergotamine (DHE) was first used to treat migraine in 1945 and is currently included among migraine-specific treatments for moderate-severe migraine. DHE may be administered through several routes of delivery, with efficacy and tolerability varying among formulations. We review DHE formulation approaches for the acute treatment of migraine, reviewing pharmacokinetics/dynamics and comparing clinical response among various formulations. Pharmacokinetic properties vary among DHE formulations, with peak concentration occurring in 6 min with intravenous, 34 min with intramuscular, 56 min with intranasal, 12 min with oral inhalation and 75 min with oral administration. DHE is a potent agonist at serotonin 5-HT1B and 5-HT1D receptors. Adverse effects due to binding to select adrenergic and dopaminergic receptors are significantly less with orally inhaled than intravenous DHE when comparing therapeutically effective doses. Among parenteral formulations (including subcutaneous, intramuscular, intravenous and nasal spray), efficacy is superior with injectable dosing. Nasal spray DHE is generally more effective than placebo, but less effective than sumatriptan. Orally inhaled DHE is likewise more effective than placebo, but there are no head-to-head comparisons with triptans available for review. Adverse effects, particularly nausea, may limit use of parenteral DHE. Nausea is generally less frequent with non-injectable dosing.

Intrathecal dihydroergotamine inhibits capsaicin-induced vasodilatation in the canine external carotid circulation via GR127935- and rauwolscine-sensitive receptors.

It has been suggested that during a migraine attack trigeminal nerves release calcitonin gene-related peptide (CGRP), producing central nociception and vasodilatation of cranial arteries, including the extracranial branches of the external carotid artery. Since trigeminal inhibition may prevent this vasodilatation, the present study has investigated the effects of intrathecal dihydroergotamine on the external carotid vasodilatation to capsaicin, α-CGRP and acetylcholine. Anaesthetized vagosympathectomized dogs were prepared to measure blood pressure, heart rate and external carotid conductance. A catheter was inserted into the right common carotid artery for the continuous infusion of phenylephrine (to restore the carotid vascular tone), whereas the corresponding thyroid artery was cannulated for one-min intracarotid infusions of capsaicin, α-CGRP and acetylcholine (which dose-dependently increased the external carotid conductance). Another cannula was inserted intrathecally (C(1)-C(3)) for the administration of dihydroergotamine, the α(2)-adrenoceptor antagonist rauwolscine or the serotonin 5-HT(1B/1D) receptor antagonist GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide hydrochloride monohydrate). Intrathecal dihydroergotamine (10, 31 and 100µg) inhibited the vasodilatation to capsaicin, but not that to α-CGRP or acetylcholine. This inhibition was: (i) unaffected by 10µg GR127935 or 100µg rauwolscine, but abolished by 31µg GR127935 or 310µg rauwolscine at 10µg dihydroergotamine; and (ii) abolished by the combination 10µg GR127935+100µg rauwolscine at 100µg dihydroergotamine. Thus, intrathecal (C(1)-C(3)) dihydroergotamine seems to inhibit the external carotid vasodilatation to capsaicin by spinal activation of serotonin 5-HT(1B/1D) (probably 5-HT(1B)) receptors and α(2) (probably α(2A/2C))-adrenoceptors.

The effects of serotonin/norepinephrine reuptake inhibitors and serotonin receptor agonist on morphine analgesia and tolerance in rats.

Several studies have demonstrated that serotonergic and noradrenergic systems have important roles in morphine analgesia and tolerance. However, the exact mechanism underlying the development of morphine tolerance is not fully understood. The aim of this study was to investigate the possible role of serotonin/norepinephrine reuptake inhibitors (amitriptyline, venlafaxine) and serotonin receptor (5-HT(1A) and 5-HT(1B/1D)) agonist (dihydroergotamine) in morphine analgesia and tolerance in rats. To constitute morphine tolerance, animals received morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of amitriptyline (20 mg/kg; i.p.), venlafaxine (20 mg/kg; s.c.), dihydroergotamine (100 µg/kg; i.v.) and morphine (5 mg/kg) were considered at 15- to 30-min intervals (0, 15, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. In this study, the data obtained suggested that amitriptyline and venlafaxine significantly increased the analgesic effect of morphine and attenuated the expression of morphine tolerance. However, dihydroergotamine significantly increased the analgesic effect of morphine but did not reduce the expression of morphine tolerance. In conclusion, we determined that co-administration of morphine with amitriptyline and venlafaxine increased the analgesic effects of morphine and attenuated the morphine analgesic tolerance.

N-methyl-D-aspartate receptor-mediated modulations of the anti-allodynic effects of 5-HT1B/1D receptor stimulation in a rat model of trigeminal neuropathic pain.

Previous studies showed that triptans and other 5-HT(1B/1D)-receptor agonists attenuate hyper-responsiveness to mechanical stimulation of the face in a rat model of trigeminal neuropathic pain, probably by activating 5-HT(1B/1D)-receptors on primary afferent nociceptive fibers. We now tested whether blockade of post-synaptic receptors for the excitatory amino acid glutamate released by these fibers would increase this action. We thus evaluated whether (±)1-hydroxy-3-aminopyrrolidine-2-one (HA-966), an antagonist at the glycine/D-serine site of N-methyl-D-aspartate (NMDA)-receptors, would potentiate the anti-allodynic action of dihydroergotamine and zolmitriptan in rats with chronic constriction injury to the infraorbital nerve (CCI-ION). Complementary studies were performed with other NMDA-receptor ligands and in rats with chronic constriction injury to the sciatic nerve (CCI-SN) for comparison. Injury was produced by loose ligatures of the nerves. Responsiveness to mechanical stimulation (vibrissae or hindpaw territories) with von Frey filaments was used to evaluate allodynia 2 weeks after nerve ligature. Rats received NMDA-receptor ligands or saline 20 min before dihydroergotamine (25-100 µg/kg, i.v.) or zolmitriptan (25-100 µg/kg, s.c.). HA-966 (2.5mg/kg, s.c.), inactive on its own, enhanced the anti-allodynic effects of dihydroergotamine (eightfold increase) and zolmitriptan (threefold increase) in CCI-ION rats, but these drugs exerted no effects in allodynic CCI-SN rats. NMDA-receptor blockade by memantine (5mg/kg, i.p.) also enhanced, whereas activation at glycine/NMDA site by D-cycloserine (3mg/kg, i.p.) reduced the anti-allodynic properties of zolmitriptan in CCI-ION rats. Combined administration of NMDA-receptor antagonist and 5-HT(1B/1D)-receptor agonist may be a promising approach for alleviating trigeminal neuropathic pain.

Where is dihydroergotamine mesylate in the changing landscape of migraine therapy?

IMPORTANCE OF THE FIELD: Migraine affects approximately 18% of women and 6% of men, and has an immense impact on quality of life and productivity. Advancement in therapeutic options has been slow. For many patients with difficult-to-treat migraine, the appropriate use of dihydroergotamine mesylate (DHE) can result in treatment success and unprecedented patient satisfaction. AREAS COVERED IN THIS REVIEW: Migraine treatment guidelines regarding the role of DHE are highlighted. An overview of the market for antimigraine drugs is provided in the context of DHE, since its introduction in 1943, and the novel agents that are likely to be available in the near future. An extensive literature search was undertaken using Medline and the Cochrane Systematic Review and Clinical Trial databases. WHAT THE READER WILL GAIN: An understanding of which migraine patients are likely to benefit maximally from treatment with DHE in its various forms. TAKE HOME MESSAGE: In the most difficult patient groups - including those with status migrainosus, migraine recurrence, medication-overuse headache, and chronic daily headache - DHE has therapeutic efficacy superior to other agents. The side-effect profile of DHE is more benign than is often perceived and should not be a deterrent for use in well-chosen cases.

Effect of calcitonin gene-related peptide receptor antagonism on the systemic blood pressure responses to mechanistically diverse vasomodulators in conscious rats.

The effects of calcitonin gene-related peptide (CGRP) receptor antagonism with CGRP 8-37 on blood pressure changes evoked by the intravenous administration of the vasoactive modulators angiotensin II, phenylephrine, adenosine, nitroglycerine, and sodium nitroprusside were assessed in conscious rats. The effects of sumatriptan and dihydroergotamine on the blood pressure responses evoked by these vasomodulators also were assessed. The intravenous test dose of CGRP 8-37 was validated through block of depressor responses to intravenous CGRP in conscious rats, whereas the intravenous test doses of sumatriptan and dihydroergotamine were validated by reductions in carotid blood flow in anesthetized rats. CGRP 8-37 had no significant effects on blood pressure dose-response profiles and individual dose blood pressure responses to any of the vasomodulators tested. In contrast, sumatriptan altered the blood pressure dose-response profiles to angiotensin II and sodium nitroprusside (P < 0.03) and dihydroergotamine altered the blood pressure dose-response profile to sodium nitroprusside (P < 0.02) and tended to alter that of phenylephrine (P = 0.06). Both sumatriptan and dihydroergotamine displayed frequent alterations of individual dose blood pressure responses to all vasomodulators. These findings are consistent with concerns for sumatriptan and dihydroergotamine to alter systemic hemodynamics, whereas CGRP receptor antagonism did not display the same hemodynamic liability.

DHE repression of ATP-mediated sensitization of trigeminal ganglion neurons.

OBJECTIVE: To investigate the mechanism by which adenosine triphosphate (ATP) causes sensitization of trigeminal neurons and how dihydroergotamine (DHE) represses this modulatory effect. BACKGROUND: Dihydroergotamine is an effective treatment of migraine. The cellular mechanisms of action of DHE in treating migraine attacks remain unclear. METHODS: In this study, neonatal rat trigeminal ganglia cultures were used to investigate effects of ATP, alpha, beta-methyl ATP (α,ß-meATP), and DHE on intracellular calcium levels and calcitonin gene-related peptide (CGRP) secretion. RESULTS: Pretreatment with ATP or α,ß-meATP caused sensitization of neurons, via P2X(3) receptors, such that a subthreshold amount of potassium chloride (KCl) significantly increased intracellular calcium levels and CGRP secretion. Pretreatment with DHE repressed increases in calcium and CGRP secretion in response to ATP-KCl or α,ß-meATP-KCl treatment. Importantly, these inhibitory effects of DHE were blocked with an α(2) -adrenoceptor antagonist and unaffected by a 5HT(1B/D) receptor antagonist. DHE also decreased neuronal membrane expression of the P2X(3) receptor. CONCLUSIONS: Our findings provide evidence for a novel mechanism of action for DHE that involves blocking ATP-mediated sensitization of trigeminal neurons, repressing stimulated CGRP release, and decreasing P2X(3) membrane expression via activation of α(2) -adrenoceptors.

New therapeutic developments in chronic migraine.

PURPOSE OF REVIEW: Chronic migraine is a common cause of chronic daily headache, which is often refractory to standard treatment. New research has increased our understanding of this disorder and its treatment. This review focuses on recent clinical trials and advances in our understanding of migraine pathophysiology. RECENT FINDINGS: Migraine research has traditionally focused on the more common episodic form of the disorder, but recent clinical trials have started to focus on chronic migraine or chronic daily headache. Topiramate, onabotulinum toxin type A, gabapentin, petasites and tizanidine are among the agents that appear to be effective in the treatment of chronic migraine. New acute medications including an inhaled form of dihydroergotamine will soon be available and neuromodulatory procedures such as occipital nerve stimulation may be effective for the most disabled patients. In the past few years, other studies have shed light on potential risk factors for chronic migraine such as medication-overuse headache, temporomandibular disorders, obstructive sleep apnea and obesity. SUMMARY: This review explains advances in the treatment of chronic migraine, a common disorder seen in neurological practice. These new advances in preventive treatment and a better understanding of its risk factors will allow clinicians to better identify individuals at greatest risk and prevent the development of chronic migraine.