-
[show abstract]
[hide abstract]
ABSTRACT: Objective: Migraine with aura is a severe debilitating neurological disorder with few relatively specific therapeutic options. Methods: We used amiloride, a blocker of epithelial sodium channels, to evaluate its pharmacological potential and explored the biology of a potential mechanism of action in well-established experimental models. Results: Amiloride was shown to block cortical spreading depression, the experimental correlate of aura, and inhibited trigeminal activation in in vivo migraine models, via an acid-sensing ion channel 1 mechanism. Remarkably, amiloride then demonstrated good clinical efficacy in a small open-labeled pilot study of patients, reducing aura and headache symptoms in 4 of 7 patients with otherwise intractable aura. Interpretation: The observations here identify an entirely novel treatment strategy for migraine. ANN NEUROL 2012;72:559–563 M igraine is a common neurological disorder with an annual prevalence of at least 12%, 1 costing nearly $20 billion in the United States alone. 2 Approximately 20 to 30% of patients report aura, 3 focal neurological disturbances thought to be an expression of the experi-mental phenomenon of cortical spreading depression (CSD). 4 The most urgent unmet clinical need in mi-graine therapeutics is the provision of new approaches to preventive treatment, with only about 1 = 3 of patients who might require it currently being treated. 5 Even with knowledge of several mutations in familial forms of mi-graine, 6 there is a dearth of novel compounds in phase II development. Amiloride is known to block the widely expressed epithelial sodium channels (ENaCs)/degenerin gene fam-ily, 7 which includes the acid-sensing ion channels (ASICs). The ASICs represent proton-gated channels that are able to flux Na þ and Ca 2þ and are encoded by 4 genes responsible for 6 different subunits. ASIC1, which is encoded by the ACCN2 7 gene, has been linked to a va-riety of functions ranging from mechanotransduction to seizure termination 8 and neuroprotection. 9 Pharmacolog-ical blockade or transgenic deletion of the ASICs has been shown to protect against tissue damage in models of multiple sclerosis and ischemic brain injury. 9 Given the known involvement of ASICs in seizurelike behav-ior, 8 the induction of tissue hypoxia and disruption by CSD 10 and the further comorbidity data between migraine and epilepsy, 11 as well as that a number of anti-epileptic agents are proven preventive treatments in mi-graine, 12 we proposed that blockade of the amiloride-sen-sitive ENaCs could be a novel beneficial treatment option for migraine, particularly for patients with aura. 13
Annals of Neurology 10/2012; · 11.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Migraine with aura is a severe debilitating neurological disorder with few relatively specific therapeutic options.
We used amiloride, a blocker of epithelial sodium channels, to evaluate its pharmacological potential and explored the biology of a potential mechanism of action in well-established experimental models.
Amiloride was shown to block cortical spreading depression, the experimental correlate of aura, and inhibited trigeminal activation in in vivo migraine models, via an acid-sensing ion channel 1 mechanism. Remarkably, amiloride then demonstrated good clinical efficacy in a small open-labeled pilot study of patients, reducing aura and headache symptoms in 4 of 7 patients with otherwise intractable aura.
The observations here identify an entirely novel treatment strategy for migraine. ANN NEUROL 2012;72:559-563.
Annals of Neurology 10/2012; 72(4):559-63. · 11.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The transient receptor potential vanilloid channel 1 (TRPV1) is a nociceptive transducer located on nociceptive neurons. TRPV1 channels located on peripheral neurons mainly transduce the sense of heat and are also activated by low pH or capsaicin. The role of centrally located TRPV1 channels is not fully understood. Likewise their importance in pain syndromes of central origin, such as migraine, is not known. Experimental data suggest a relationship to migraine. However, experimental studies with TRPV1 receptor antagonists indicate that the receptor may not be a useful target for new acute migraine treatments. Any potential role for the receptor in the chronification of migraine has not been investigated. The present study aimed at analyzing the use of the TRPV1 channel as a target to desensitize trigeminal neurons and thereby inhibit neuronal activity in the trigeminocervical complex. The TRPV1 receptor agonist olvanil was used for desensitization because, as compared with capsaicin, it is non-noxious and lacks capsaicin's pungency and CGRP release potential. We further investigated a possible effect of olvanil on cannabinoid (CB(1)) receptors, as an interaction between both receptor systems has been described previously. The results show that olvanil dose-dependently inhibited spontaneous and stimulus-induced activity within the trigeminocervical complex, whereas it had no effect on CSD susceptibility. We further demonstrated that the inhibiting effect of olvanil is mediated by vanilloid and cannabinoid receptor systems, thereby using the synergistic effects this dual mechanism offers. Curiously, TRPV1 receptor agonism may have anti-nociceptive properties through central mechanisms that would be of considerable interest to elucidate.
Pain 08/2012; 153(11):2226-32. · 5.78 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Familial hemiplegic migraine type 1 (FHM-1) is caused by mutations in the CACNA1A gene, with the R192Q mutation being the most common. Elevated calcitonin gene-related peptide (CGRP) levels in acute migraine and clinical trials using CGRP receptor antagonists suggest CGRP-related mechanisms are important in migraine.
Wild-type and R192Q knock-in mice were anaesthetized and perfused. Using immunohistochemical staining, the expression of CGRP in the trigeminocervical complex (TCC) and in the trigeminal and dorsal root ganglia was characterized.
There was a 38% reduction in the percentage of CGRP-immunoreactive cells in the trigeminal ganglia (p < 0.001) of R192Q knock-in mice compared to wild-type animals. The size distribution profile of CGRP-immunoreactive cells within the trigeminal ganglia demonstrated no significant difference in cell diameter between the two groups (p ≥ 0.56). CGRP expression was also reduced in thoracic ganglia of R192Q knock-in mice (21% vs. 27% in wild-type group; p < 0.05), but not in other ganglia. In addition, decreased CGRP immunoreactivity was observed in the superficial laminae of the TCC in R192Q knock-in mice, when compared to the control group (p < 0.005).
The data demonstrates that the FHM-1 CACNA1A mutation alters CGRP expression in the trigeminal ganglion and TCC. This suggests further study of these animals is warranted to characterize better the role of these mutations in the neurobiology of migraine.
Cephalalgia 09/2011; 31(13):1368-80. · 3.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The development of new agents for the preventive treatment of migraine is the greatest unmet need in the therapeutics of primary headaches. Topiramate, an anticonvulsant drug, is an effective anti-migraine preventive whose mechanism of action is not fully elucidated. Since glutamate plays a major role in migraine pathophysiology, the potential action of topiramate through glutamatergic mechanisms is of considerable interest.
Recordings of neurons in the trigeminocervical complex (TCC) and the ventroposteromedial thalamic nucleus (VPM) of anesthetized rats were made using electrophysiological techniques. The effects of intravenous or microiontophorezed topiramate on trigeminovascular activation of second- and third-order neurons in the trigeminothalamic pathway were characterized. The potential interactions of topiramate with the ionotropic glutamate receptors were studied using microiontophoresis.
Both intravenous and microiontophorized topiramate significantly inhibited trigeminovascular activity in the TCC and VPM. In both nuclei microiontophoretic application of topiramate significantly attenuated kainate receptor-evoked firing but had no effect on N-methyl-d-aspartic acid or α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor activation.
The data demonstrate for the first time that topiramate modulates trigeminovascular transmission within the trigeminothalamic pathway with the kainate receptor being a potential target. Understanding the mechanism of action of topiramate may help in the design of new medications for migraine prevention, with the data pointing to glutamate-kainate receptors as a fruitful target to pursue.
Cephalalgia 09/2011; 31(13):1343-58. · 3.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) that act as cyclo-oxygenase (COX) inhibitors are commonly used in the treatment of a range of headache disorders, although their mechanism of action is unclear. Indomethacin is of particular interest given its very special effect in some primary headaches. Here the in vivo technique of intravital microscopy in rats has been utilised as a model of trigeminovascular nociception to study the potential mechanism of action of indomethacin. Dural vascular changes were produced using electrical (neurogenic) dural vasodilation (NDV), calcitonin gene-related peptide (CGRP) induced dural vasodilation and nitric oxide (NO) induced dural vasodilation using NO donors. In each of these settings the effect of intravenously administered indomethacin (5 mg kg(-1)), naproxen (30 mg kg(-1)) and ibuprofen (30 mg kg(-1)) was tested. All of the tested drugs significantly inhibited NDV (between 30 and 52%). Whilst none of them was able to inhibit CGRP-induced dural vasodilation, only indomethacin reduced NO induced dural vasodilation (35 ± 7%, 10 min post administration). We conclude NSAIDs inhibit release of CGRP after NDV without an effect on CGRP directly. Further we describe a differentiating effect of indomethacin inhibiting nitric oxide induced dural vasodilation that is potentially relevant to understanding its unique action in disorders such as paroxysmal hemicrania and hemicrania continua.
The Journal of Headache and Pain 10/2010; 11(6):477-83. · 2.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Calcitonin gene-related peptide receptor antagonists are effective acute migraine treatments without the vascular contraindications associated with triptans. While it has been demonstrated that calcitonin gene-related peptide receptor antagonists act in the central nervous system, their effects in preclinical migraine models have been investigated in only the trigeminocervical complex. Migraine is a complex neurological disorder; sites in the brainstem and forebrain are clearly involved in its expression. We have performed electrophysiological recordings in thalamic neurons of rats responding to nocioceptive trigeminovascular inputs and tested the effect of olcegepant, a calcitonin gene-related peptide receptor antagonist (1 mg/kg, intravenously), on cell firing. We further tested the effect of microiontophoresed calcitonin gene-related peptide and the receptor antagonists calcitonin gene-related peptide 8-37 and olcegepant on thalamic cell firing, elicited by stimulation of the superior sagittal sinus or by microiontophoretic application of l-glutamate. Additionally, we used immunofluorescent staining to demonstrate the presence of functional calcitonin gene-related peptide receptors in the ventroposteromedial thalamic nucleus by specifically co-staining for the calcitonin gene-related peptide receptor subunits calcitonin receptor-like receptor and receptor activity modifying protein 1. Intravenously administered olcegepant significantly inhibited cell firing evoked by stimulation of the superior sagittal sinus as well as the background activity. Microiontophoresis of calcitonin gene-related peptide 8-37 also showed a significant inhibition of l-glutamate-evoked cell firing and firing evoked by stimulation of the superior sagittal sinus. Immunofluorescent staining confirmed the presence of the components of a functional calcitonin gene-related peptide receptor, the calcitonin receptor-like receptor and the receptor activity modifying protein 1, within the area of the ventroposteromedial thalamic nucleus. This is the first report on the efficacy of calcitonin gene-related peptide receptor antagonists at the level of third-order neurons in the migraine pathway, showing that the central effects of calcitonin gene-related peptide receptor antagonists extend beyond the trigeminocervical complex at least to the sensory thalamus.
Brain 09/2010; 133(9):2540-8. · 9.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In recent years bench-based studies have greatly enhanced our understanding of headache pathophysiology, while facilitating the development of new headache medicines. At present, established animal models of headache utilize activation of pain-producing cranial structures, which for a complex syndrome, such as migraine, leaves many dimensions of the syndrome unstudied. The focus on modeling the central nociceptive mechanisms and the complexity of sensory phenomena that accompany migraine may offer new approaches for the development of new therapeutics. Given the complexity of the primary headaches, multiple approaches and techniques need to be employed. As an example, recently a model for trigeminal autonomic cephalalgias has been tested successfully, while by contrast, a satisfactory model of tension-type headache has been elusive. Moreover, although useful in many regards, migraine models are yet to provide a more complete picture of the disorder.
Expert Review of Neurotherapeutics 03/2010; 10(3):389-411.
-
[show abstract]
[hide abstract]
ABSTRACT: Migraine is a common and disabling neurological disorder. Although the pharmacotherapy of migraine has advanced in parallel with our understanding of the pathophysiology of the disease, there is still a considerable unmet need to find more effective treatments. Migraine pathophysiology involves activation or the perception of activation of the trigeminovascular system. Glutamate, the major excitatory neurotransmitter in the CNS, is implicated in elements of the pathophysiology of the disorder, including trigeminovascular activation, central sensitization and cortical spreading depression.
The aim of this article is to review the potential use of glutamate receptor antagonists as innovative neuronally targeted treatments of migraine.
A systematic search of peer-reviewed publications was performed in PubMed on glutamate and migraine/trigeminovascular activation, and important references providing an insight into migraine pathophysiology are included. The results of unpublished trials were obtained from presentations at national and international meetings.
The preclinical and clinical data argue strongly for a role of glutamatergic receptor activation in migraine. The pharmacology of glutamatergic trigeminovascular responses in brain areas involved in migraine pathophysiology is relevant to the development of new therapies for this disabling condition. Glutamate receptors represent a promising target for a valuable, non-vasoconstrictor, and perhaps more importantly neuronal-specific therapeutic approach to the treatment of migraine.
Expert Opinion on Investigational Drugs 06/2009; 18(6):789-803. · 5.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Objective: To study the role of GABA receptors in thalamic relay neurons in the ventroposteromedial (VPM) nucleus of the rat activated by a trigeminovascular nociceptive stimulus in relationship to migraine, and the potential modulation of nociceptive transmission by GABA acting anti-convulsants.Methods: Trigeminovascular nociceptive afferents were identified in the VPM by electrical stimulation of the superior sagittal sinus (SSS), and cell bodies identified by activation with l-glutamate. The effect of GABA, valproate and gabapentin ejection during SSS stimulation and microiontophoresis of l-glutamate was studied. GABA responses were characterized with the selective GABAA and GABAB agonists muscimol and baclofen, respectively, and the antagonists bicuculline (GABAA) and hydroxysaclofen (GABAB).Results: GABA inhibited the response to SSS stimulation and l-glutamate ejection. Both the selective GABAA receptor agonist muscimol, and the GABAB agonist baclofen strongly inhibited the post-synaptic response to l-glutamate. This inhibition could be antagonised by co-ejection of the appropriate antagonist. The post-synaptic inhibitory action of GABA on the cell bodies of third order neurons could be partially antagonised by co-ejection of bicuculline but not by hydroxysaclofen. Valproate inhibited the responses to SSS stimulation and l-glutamate ejection. Bicuculline, but not hydroxysaclofen, was able to antagonise the effect of valproate on both responses to l-glutamate and SSS stimulation. Gabapentin did not alter the responses to l-glutamate and SSS stimulation.Interpretation: These results indicate that GABAA and GABAB receptors on thalamic neurons can modulate trigeminovascular nociceptive transmission in the VPM nucleus. Sodium valproate can inhibit trigeminovascular nociception at the level of VPM through GABAA receptor mechanisms, whereas gabapentin does not alter trigeminovascular nociception.
Neurobiology of Disease.
