Expression of Pituitary Adenylate Cyclase-activating Peptide, Calcitonin Gene-related Peptide and Headache Targets in the Trigeminal Ganglia of Rats and Humans

Frederiksen, Simona Denise; Warfvinge, Karin; Ohlsson, Lena; Edvinsson, Lars

doi:10.1016/j.neuroscience.2018.10.004

Cited by 31 publications

(32 citation statements)

References 73 publications

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“…In the dura mater, we did not observe any evident PACAP-38 immunoreactivity. Rice et al found no PACAP staining in the dura (45), which contrasts with the data from Frederiksen et al and Eftekhari et al, where some immunopositivity was observed (23,42). We do observe a weak constitutive dural level of PACAP in the hemi-skull model (Figure 1), but this could be an overflow from parasympathetic nerves where PACAP expression is stronger than in sensory fibres (24).…”

Section: Physiology Of Pacap Releasecontrasting

confidence: 90%

Differences in pituitary adenylate cyclase-activating peptide and calcitonin gene-related peptide release in the trigeminovascular system

et al. 2020

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Background Several neurotransmitters are expressed in the neurons of the trigeminal ganglion. One such signalling molecule is the pituitary adenylate cyclase-activating peptide (PACAP). PACAP signalling has been suggested to have a possible role in the pathophysiology of primary headaches. Objective The present study was designed to investigate the relationship between PACAP and calcitonin gene-related peptide, currently the two most relevant migraine peptides. Methods In the current study, we used ELISA to investigate PACAP and calcitonin gene-related peptide release in response to 60 mM K+ or capsaicin using a rat hemi-skull model. We combined this analysis with qPCR and immunohistochemistry to study the expression of PACAP and calcitonin gene-related peptide receptors and ligands. Results Calcitonin gene-related peptide (CGRP) is released from the trigeminal ganglion and dura mater. In contrast, PACAP is only released from the trigeminal ganglion. We observed a weak correlation between the stimulated release of the two neuropeptides. PACAP-38 immunoreactivity was expressed alone and in a subpopulation of neurons in the trigeminal ganglion that also store calcitonin gene-related peptide. The receptor subtype PAC1 was mainly expressed in the satellite glial cells (SGCs), which envelop the neurons in the trigeminal ganglion, in some neuronal processes, inside the Aδ-fibres and in the outermost layer of the myelin sheath that envelopes the Aδ-fibres. Conclusion Unlike CGRP, PACAP is only released within the trigeminal ganglion. This raises the question of whether a migraine therapy aimed at preventing peripheral PACAP signalling would be as successful as the CGRP signalling targeted treatments.

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Section: Physiology Of Pacap Releasecontrasting

confidence: 90%

Differences in pituitary adenylate cyclase-activating peptide and calcitonin gene-related peptide release in the trigeminovascular system

et al. 2020

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“…Immunohistochemical studies in cadavers have shown that PACAP is expressed in trigeminal ganglia neurons ( Frederiksen et al , 2018 ) as well as small-to-intermediate sized DRG neurons and the superficial dorsal horn of the spinal cord ( Dun et al , 1996 ), consistent with expression in sensory afferents. Equally, animal studies have shown that PACAP is expressed in small-to-medium sized DRG neurons ( Moller et al , 1993 ) and upregulated during the regenerative process following nerve injury ( Zhang et al , 1995 , 1996 ; Woodley et al , 2019 ), including nerve compression ( Pettersson et al , 2004 ).…”

Section: Discussionmentioning

confidence: 90%

Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth

Baskozos

Sandy-Hindmarch

Clark

et al. 2020

Brain

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Abstract We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P < 0.0001) and improvements in quantitative sensory testing measures of both small and large nerve fibre function (P < 0.002). Serial biopsies revealed a partial recovery of intraepidermal nerve fibre density [fibres/mm epidermis pre: 4.20 (2.83), post: 5.35 (3.34), P = 0.001], whose extent correlated with symptom improvement (r = 0.389, P = 0.001). In myelinated afferents, nodal length increased postoperatively [pre: 2.03 (0.82), post: 3.03 (1.23), P < 0.0001] suggesting that this is an adaptive phenomenon. Transcriptional profiling of the skin revealed 31 differentially expressed genes following decompression, with ADCYAP1 (encoding pituitary adenylate cyclase activating peptide, PACAP) being the most strongly upregulated (log2 fold-change 1.87, P = 0.0001) and its expression was associated with recovery of intraepidermal nerve fibres. We found that human induced pluripotent stem cell-derived sensory neurons expressed the receptor for PACAP and that this peptide could significantly enhance axon outgrowth in a dose-dependent manner in vitro [neurite length PACAP 1065.0 µm (285.5), vehicle 570.9 μm (181.8), P = 0.003]. In conclusion, carpal tunnel release is associated with significant cutaneous reinnervation, which correlates with the degree of functional improvement and is associated with a transcriptional programme relating to morphogenesis and inflammatory processes. The most highly dysregulated gene ADCYAP1 (encoding PACAP) was associated with reinnervation and, given that this peptide signals through G-protein coupled receptors, this signalling pathway provides an interesting therapeutic target for human sensory nerve regeneration.

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“…Consistent with a role in migraine, PACAP and all three receptors are expressed in anatomic structures within the trigeminovascular system relevant to migraine pathogenesis: dorsal root ganglia, trigeminal ganglion, trigeminal nucleus caudalis, dural nerve fibers and blood vessels, brainstem structures (such as the periaqueductal gray), and ottic and sphenopalatine ganglia (Uddman et al, 1993(Uddman et al, , 1999(Uddman et al, , 2002Mulder et al, 1994;Tajti et al, 1999Tajti et al, , 2001; Fahrenkrug et al, 2000; at ASPET Journals on September 17, 2020 jpet.aspetjournals.org Csati et al, 2012a;Frederiksen et al, 2018) (reviewed by Tajti et al, 2015Jansen-Olesen and Hougaard Pedersen, 2018). CGRP-containing sensory fibers originating from the trigeminal ganglion project to the sphenopalatine ganglion, where CGRP receptors and PACAP and its receptors are expressed; this suggests interaction between sensory and parasympathetic systems.…”

Section: Discussionmentioning

confidence: 93%

“…DMSO, dimethylsulfoxide. pathophysiology, along with the sphenopalatine ganglion are located outside the blood-brain barrier and thus are accessible to antibody therapeutics (Eftekhari et al, 2015;Frederiksen et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic Characterization of ALD1910, a Potent Humanized Monoclonal Antibody against the Pituitary Adenylate Cyclase-Activating Peptide

Loomis

Dutzar

Ojala

et al. 2019

J Pharmacol Exp Ther

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Migraine is a debilitating disease that affects almost 15% of the population worldwide and is the first cause of disability in people under 50 years of age, yet its etiology and pathophysiology remain incompletely understood. Recently, small molecules and therapeutic antibodies that block the calcitonin gene-related peptide (CGRP) signaling pathway have reduced migraine occurrence and aborted acute attacks of migraine in clinical trials and provided prevention in patients with episodic and chronic migraine. Heterogeneity is present within each diagnosis and patient's response to treatment, suggesting migraine as a final common pathway potentially activated by multiple mechanisms, e.g., not all migraine attacks respond to or are prevented by anti-CGRP pharmacological interventions. Consequently, other unique mechanisms central to migraine pathogenesis may present new targets for drug development. Pituitary adenylate cyclase-activating peptide (PACAP) is an attractive novel target for treatment of migraines. We generated a specific, high-affinity, neutralizing monoclonal antibody (ALD1910) with reactivity to both PACAP38 and PACAP27. In vitro, ALD1910 effectively antagonizes PACAP38 signaling through the pituitary adenylate cyclase-activating peptide type I receptor, vasoactive intestinal peptide receptor 1, and vasoactive intestinal peptide receptor 2. ALD1910 recognizes a nonlinear epitope within PACAP and blocks its binding to the cell surface. To test ALD1910 antagonistic properties directed against endogenous PACAP, we developed an umbellulone-induced rat model of neurogenic vasodilation and parasympathetic lacrimation. In vivo, this model demonstrates that the antagonistic activity of ALD1910 is dosedependent, retaining efficacy at doses as low as 0.3 mg/kg. These results indicate that ALD1910 represents a potential therapeutic antibody to address PACAP-mediated migraine.

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Expression of Pituitary Adenylate Cyclase-activating Peptide, Calcitonin Gene-related Peptide and Headache Targets in the Trigeminal Ganglia of Rats and Humans

Cited by 31 publications

References 73 publications

Differences in pituitary adenylate cyclase-activating peptide and calcitonin gene-related peptide release in the trigeminovascular system

Differences in pituitary adenylate cyclase-activating peptide and calcitonin gene-related peptide release in the trigeminovascular system

Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth

Pharmacologic Characterization of ALD1910, a Potent Humanized Monoclonal Antibody against the Pituitary Adenylate Cyclase-Activating Peptide

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