Release of PACAP-38 in episodic cluster headache patients – an exploratory study

Tuka, Bernadett; Szabó, Nikoletta; Tóth, Eszter; Kincses, Zsigmond Tamás; Párdutz, Árpád; Delia, S.; Körtési, Tamás; Bagoly, Teréz; Helyes, Zsuzsanna; Edvinsson, Lars; Vécsei, László; Tajti, János

doi:10.1186/s10194-016-0660-7

Cited by 91 publications

(81 citation statements)

References 36 publications

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“…A recent study in cerebrospinal fluid, in which significantly reduced hypocretin peptide levels were found in cluster headache patients39, further indicates that analysis of other tissues than blood is required to identify all genes and pathways involved in cluster headache. Then again, the worth of blood is supported by the finding that several biomarkers, including PACAP-3840 and methionine-enkephalin41, show altered levels during the course of a cluster headache attack in blood plasma.…”

Section: Discussionmentioning

confidence: 97%

Identifying a gene expression signature of cluster headache in blood

Eising

Pelzer

Vijfhuizen

et al. 2017

Sci Rep

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Cluster headache is a relatively rare headache disorder, typically characterized by multiple daily, short-lasting attacks of excruciating, unilateral (peri-)orbital or temporal pain associated with autonomic symptoms and restlessness. To better understand the pathophysiology of cluster headache, we used RNA sequencing to identify differentially expressed genes and pathways in whole blood of patients with episodic (n = 19) or chronic (n = 20) cluster headache in comparison with headache-free controls (n = 20). Gene expression data were analysed by gene and by module of co-expressed genes with particular attention to previously implicated disease pathways including hypocretin dysregulation. Only moderate gene expression differences were identified and no associations were found with previously reported pathogenic mechanisms. At the level of functional gene sets, associations were observed for genes involved in several brain-related mechanisms such as GABA receptor function and voltage-gated channels. In addition, genes and modules of co-expressed genes showed a role for intracellular signalling cascades, mitochondria and inflammation. Although larger study samples may be required to identify the full range of involved pathways, these results indicate a role for mitochondria, intracellular signalling and inflammation in cluster headache.

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Section: Discussionmentioning

confidence: 97%

Identifying a gene expression signature of cluster headache in blood

Eising

Pelzer

Vijfhuizen

et al. 2017

Sci Rep

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“…PACAP might play a role in migraine having various neurobiological functions such as inhibitory effect on neurogenic inflammation [38]. PACAP has shown to be involved in trigeminovascular activation as PACAP-38 infusion caused headache in healthy volunteers [39] and PACAP-38-like immunoreactivity has proved to be altered in ictal compared to interictal phase of migraine and in cluster headache [40, 41]. It is suggested that the effect of PACAP is biphasic: lower concentration increasing, higher concentration inhibiting the NMDA receptor activation [42].…”

Section: Discussionmentioning

confidence: 99%

Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72)

et al. 2017

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BackgroundMigraine is a debilitating neurological disorder where trigeminovascular activation plays a key role. We have previously reported that local application of Complete Freund’s Adjuvant (CFA) onto the dura mater caused activation in rat trigeminal ganglion (TG) which was abolished by a systemic administration of kynurenic acid (KYNA) derivate (SZR72). Here, we hypothesize that this activation may extend to the trigeminal complex in the brainstem and is attenuated by treatment with SZR72.MethodsActivation in the trigeminal nucleus caudalis (TNC) and the trigeminal tract (Sp5) was achieved by application of CFA onto the dural parietal surface. SZR72 was given intraperitoneally (i.p.), one dose prior CFA deposition and repeatedly daily for 7 days. Immunohistochemical studies were performed for mapping glutamate, c-fos, PACAP, substance P, IL-6, IL-1β and TNFα in the TNC/Sp5 and other regions of the brainstem and at the C1-C2 regions of the spinal cord.ResultsWe found that CFA increased c-fos and glutamate immunoreactivity in TNC and C1-C2 neurons. This effect was mitigated by SZR72. PACAP positive fibers were detected in the fasciculus cuneatus and gracilis. Substance P, TNFα, IL-6 and IL-1β immunopositivity were detected in fibers of Sp5 and neither of these molecules showed any change in immunoreactivity following CFA administration.ConclusionThis is the first study demonstrating that dural application of CFA increases the expression of c-fos and glutamate in TNC neurons. Treatment with the KYNA analogue prevented this expression.

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“…Notably, PACAP administration in healthy subjects induces migraine-like headache [31]. PACAP, through PACAP receptor, induces activation of neurons in the superior salivatory nucleus, sphenopalatine and Gasser ganglion [32], that is thought to be a crucial event in CH pathophysiology, and higher PACAP plasma levels were detected during ictal phase than during inter-bout periods in CH patients [33]. …”

Section: Discussionmentioning

confidence: 99%

A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants

et al. 2016

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BackgroundCluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; however, no confirmed gene associations have been identified. The aim of this study is to identify genetic variants influencing risk to CH and to explore the potential pathogenic mechanisms.MethodsWe have performed a genome-wide association study (GWAS) in a clinically well-defined cohort of 99 Italian patients with CH and in a control sample of 360 age-matched sigarette smoking healthy individuals, using the Infinium PsychArray (Illumina), which combines common highly-informative genome-wide tag SNPs and exonic SNPs. Genotype data were used to carry out a genome-wide single marker case-control association analysis using common SNPs, and a gene-based association analysis focussing on rare protein altering variants in 745 candidate genes with a putative role in CH.ResultsAlthough no single variant showed statistically significant association at the genome-wide threshold, we identified an interesting suggestive association (P = 9.1 × 10−6) with a common variant of the PACAP receptor gene (ADCYAP1R1). Furthermore, gene-based analysis provided significant evidence of association (P = 2.5 × 10−5) for a rare potentially damaging missense variant in the MME gene, encoding for the membrane metallo-endopeptidase neprilysin.ConclusionsOur study represents the first genome-wide association study of common SNPs and rare exonic variants influencing risk for CH. The most interesting results implicate ADCYAP1R1 and MME gene variants in CH susceptibility and point to a role for genes involved in pain processing. These findings provide new insights into the pathogenesis of CH that need further investigation and replication in larger CH samples.Electronic supplementary materialThe online version of this article (doi:10.1186/s10194-016-0705-y) contains supplementary material, which is available to authorized users.

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Release of PACAP-38 in episodic cluster headache patients – an exploratory study

Cited by 91 publications

References 36 publications

Identifying a gene expression signature of cluster headache in blood

Identifying a gene expression signature of cluster headache in blood

Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72)

A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants

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