Immunohistochemical characterization of calcitonin gene-related peptide in the trigeminal system of the familial hemiplegic migraine 1 knock-in mouse

Mathew, Robin; Andreou, Anna P.; Chami, L.; Bergerot, A; Maagdenberg, Arn M. J. M. van den; Ferrari, Michel D.; Goadsby, PJ

doi:10.1177/0333102411418847

Cited by 32 publications

(21 citation statements)

References 67 publications

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“…In line with this possibility is the report of apparently lower immunocytochemical expression of CGRP in R192Q KI ganglia [51] together with higher CGRP release [15], [19], suggesting misdirected signaling of CGRP probably toward non-neuronal cells.…”

Section: Discussionmentioning

confidence: 61%

TNFα Levels and Macrophages Expression Reflect an Inflammatory Potential of Trigeminal Ganglia in a Mouse Model of Familial Hemiplegic Migraine

et al. 2013

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Latent changes in trigeminal ganglion structure and function resembling inflammatory conditions may predispose to acute attacks of migraine pain. Here, we investigated whether, in trigeminal sensory ganglia, cytokines such as TNFα might contribute to a local inflammatory phenotype of a transgenic knock-in (KI) mouse model of familial hemiplegic migraine type-1 (FHM-1). To this end, macrophage occurrence and cytokine expression in trigeminal ganglia were compared between wild type (WT) and R192Q mutant CaV2.1 Ca2+ channel (R192Q KI) mice, a genetic model of FHM-1. Cellular and molecular characterization was performed using a combination of confocal immunohistochemistry and cytokine assays. With respect to WT, R192Q KI trigeminal ganglia were enriched in activated macrophages as suggested by their morphology and immunoreactivity to the markers Iba1, CD11b, and ED1. R192Q KI trigeminal ganglia constitutively expressed higher mRNA levels of IL1β, IL6, IL10 and TNFα cytokines and the MCP-1 chemokine. Consistent with the report that TNFα is a major factor to sensitize trigeminal ganglia, we observed that, following an inflammatory reaction evoked by LPS injection, TNFα expression and macrophage occurrence were significantly higher in R192Q KI ganglia with respect to WT ganglia. Our data suggest that, in KI trigeminal ganglia, the complex cellular and molecular environment could support a new tissue phenotype compatible with a neuroinflammatory profile. We propose that, in FHM patients, this condition might contribute to trigeminal pain pathophysiology through release of soluble mediators, including TNFα, that may modulate the crosstalk between sensory neurons and resident glia, underlying the process of neuronal sensitisation.

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Section: Discussionmentioning

confidence: 61%

TNFα Levels and Macrophages Expression Reflect an Inflammatory Potential of Trigeminal Ganglia in a Mouse Model of Familial Hemiplegic Migraine

et al. 2013

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“…A role of CGRP in KI trigeminal ganglia, however, is less obvious. Previously, R192Q KI ganglia were shown to contain less CGRP than WT [39], an observation that may be accounted for by a stronger release of CGRP [19]. Fig.…”

Section: Resultsmentioning

confidence: 81%

The Mechanism of Functional Up-Regulation of P2X3 Receptors of Trigeminal Sensory Neurons in a Genetic Mouse Model of Familial Hemiplegic Migraine Type 1 (FHM-1)

et al. 2013

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A knock-in (KI) mouse model of FHM-1 expressing the R192Q missense mutation of the Cacna1a gene coding for the α1 subunit of CaV2.1 channels shows, at the level of the trigeminal ganglion, selective functional up-regulation of ATP -gated P2X3 receptors of sensory neurons that convey nociceptive signals to the brainstem. Why P2X3 receptors are constitutively more responsive, however, remains unclear as their membrane expression and TRPV1 nociceptor activity are the same as in wildtype (WT) neurons. Using primary cultures of WT or KI trigeminal ganglia, we investigated whether soluble compounds that may contribute to initiating (or maintaining) migraine attacks, such as TNFα, CGRP, and BDNF, might be responsible for increasing P2X3 receptor responses. Exogenous application of TNFα potentiated P2X3 receptor-mediated currents of WT but not of KI neurons, most of which expressed both the P2X3 receptor and the TNFα receptor TNFR2. However, sustained TNFα neutralization failed to change WT or KI P2X3 receptor currents. This suggests that endogenous TNFα does not regulate P2X3 receptor responses. Nonetheless, on cultures made from both genotypes, exogenous TNFα enhanced TRPV1 receptor-mediated currents expressed by a few neurons, suggesting transient amplification of TRPV1 nociceptor responses. CGRP increased P2X3 receptor currents only in WT cultures, although prolonged CGRP receptor antagonism or BDNF neutralization reduced KI currents to WT levels. Our data suggest that, in KI trigeminal ganglion cultures, constitutive up-regulation of P2X3 receptors probably is already maximal and is apparently contributed by basal CGRP and BDNF levels, thereby rendering these neurons more responsive to extracellular ATP.

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“…The peripheral CGRP‐containing neurons (in the trigeminal ganglion and elsewhere) are polymodal nociceptors that innervate essentially all peripheral tissues and send primary afferent input to the dorsal horn, trigeminal nucleus caudalis, or nucleus of the solitary tract (which, in turn, project to the brainstem, amygdala, hypothalamus, and thalamic nuclei) . CGRP‐containing neurons in the trigeminal ganglion project to the trigeminal nucleus caudalis and C1‐C2, where CGRP also acts post‐junctionally on these second‐order neurons to transmit pain signals from the brainstem to the thalamus …”

Section: Role Of Cgrp In Nociception and Neuronal Plasticitymentioning

confidence: 99%

Calcitonin Gene‐Related Peptide (CGRP) and Migraine Current Understanding and State of Development

2013

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Calcitonin gene-related peptide (CGRP) is a ubiquitous neuropeptide found at the very centers of the migraine process, both centrally and peripherally. It has been under careful study for approximately 25 years. Several CGRP-receptor antagonists are being evaluated for acute treatment of episodic migraine. Three monoclonal antibodies are being studied for prevention of episodic migraine, and 1 monoclonal antibody is being studied for prevention of chronic migraine. In this review, we discuss the role of CGRP in normal physiology and the consequences of CGRP inhibition for human homeostasis. We then review the current state of development for CGRP-receptor antagonists and CGRP monoclonal antibodies. We close by speculating on the potential clinical role of CGRP antagonism in the acute and preventive treatment of episodic and chronic migraine.Key words: calcitonin gene-related peptide, antibodies, migraine, chronic migraine (Headache 2013;53:1230-1244 Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide that is derived from the gene encoding calcitonin by alternative splicing of mRNA and proteolytic processing of its precursor. 1,2Despite their common origin, calcitonin and CGRP are involved in totally different physiological processes in humans. While calcitonin is mainly related to calcium homeostasis and bone remodeling, CGRP is involved in vasodilation and sensory transmission.CGRP is found in literally every organ system in the body, 3 occurring in 2 isoforms, a-and b-CGRP. 4,5a-CGRP is the predominant form in the peripheral nervous system, while the b-isoform is mainly present in the enteric nervous system. 6 CGRP is highly conserved across species, 7 suggesting that the neuropeptide is of importance in functions that were established relatively early in mammalian evolution.Immunohistochemistry demonstrated that CGRP is mainly produced in the cell bodies of both ventral and dorsal root neurons.8 Radioimmunology further demonstrated that this molecule is especially common in the trigeminal system, where up to 50% of the neurons produce it.9 Indeed, the potential role of CGRP in migraine pathophysiology was suggested more than 20 years ago, 10,11 and since then, our knowledge of the peptide and its role in the pathophysiology of migraine has increased substantially and has

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Immunohistochemical characterization of calcitonin gene-related peptide in the trigeminal system of the familial hemiplegic migraine 1 knock-in mouse

Abstract: 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.

Cited by 32 publications

References 67 publications

TNFα Levels and Macrophages Expression Reflect an Inflammatory Potential of Trigeminal Ganglia in a Mouse Model of Familial Hemiplegic Migraine

TNFα Levels and Macrophages Expression Reflect an Inflammatory Potential of Trigeminal Ganglia in a Mouse Model of Familial Hemiplegic Migraine

The Mechanism of Functional Up-Regulation of P2X3 Receptors of Trigeminal Sensory Neurons in a Genetic Mouse Model of Familial Hemiplegic Migraine Type 1 (FHM-1)

Calcitonin Gene‐Related Peptide (CGRP) and Migraine Current Understanding and State of Development

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