The fifth cranial nerve in headaches

Edvinsson, Jacob C A; Viganò, Alessandro; Алексеева, Анна; Alieva, E.; Arruda, R. P.; Luca, Ciro De; D’Ettore, N.; Frattale, Ilaria; Kurnukhina, M. Yu.; Macerola, Noemi; Malenkova, E.; Maiorova, M.; Novikova, A.; Řehulka, Pavel; Rapaccini, V.; Roshchina, O.; Vanderschueren, Geraldine; Zvaune, Linda; Andreou, Anna P.; Haanes, Kristian Agmund

doi:10.1186/s10194-020-01134-1

Cited by 104 publications

(82 citation statements)

References 201 publications

(250 reference statements)

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“…Calcitonin gene-related peptide (CGRP) has a strong position in migraine pathophysiology [12]. Thus, monoclonal antibodies and gepants are examples of the rapidly growing body of medications designed to modify CGRP mechanisms in the trigeminovascular system [13] (TVS); these are successful drugs for acute and prophylactic treatments of migraine in all age groups and in both sexes [14]. However, new targets are needed [15].…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects

et al. 2020

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Background Migraine occurs 2–3 times more often in females than in males and is in many females associated with the onset of menstruation. The steroid hormone, 17β-estradiol (estrogen, E2), exerts its effects by binding and activating several estrogen receptors (ERs). Calcitonin gene-related peptide (CGRP) has a strong position in migraine pathophysiology, and interaction with CGRP has resulted in several successful drugs for acute and prophylactic treatment of migraine, effective in all age groups and in both sexes. Methods Immunohistochemistry was used for detection and localization of proteins, release of CGRP and PACAP investigated by ELISA and myography/perfusion arteriography was performed on rat and human arterial segments. Results ERα was found throughout the whole brain, and in several migraine related structures. ERβ was mainly found in the hippocampus and the cerebellum. In trigeminal ganglion (TG), ERα was found in the nuclei of neurons; these neurons expressed CGRP or the CGRP receptor in the cytoplasm. G-protein ER (GPER) was observed in the cell membrane and cytoplasm in most TG neurons. We compared TG from males and females, and females expressed more ER receptors. For neuropeptide release, the only observable difference was a baseline CGRP release being higher in the pro-estrous state as compared to estrous state. In the middle cerebral artery (MCA), we observed similar dilatory ER-responses between males and females, except for vasodilatory ERβ which we observed only in female arteries. Conclusion These data reveal significant differences in ER receptor expression between male and female rats. This contrasts to CGRP and PACAP release where we did not observe discernable difference between the sexes. Together, this points to a hypothesis where estrogen could have a modulatory role on the trigeminal neuron function in general rather than on the acute CGRP release mechanisms and vasomotor responses.

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Section: Introductionmentioning

confidence: 99%

Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects

et al. 2020

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“…4). Pertinently, BoNT/A was suggested to attenuate the release of CGRP from nociceptors and also to inhibit the release of glutamate [27], the main excitatory neurotransmitter of trigeminal fibers, and a major sensitizing molecule [67]. It will be important to investigate in future experiments how BiTox/AA could affect glutamatergic excitation during nociceptive stimuli which was shown to be exacerbated in the presence of CGRP [68].…”

Section: Discussionmentioning

confidence: 99%

Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine

Andreou

Leese

Greco³

et al. 2021

Neurotherapeutics

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With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene–related peptide–targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain—binary toxin-AA (BiTox/AA)—cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ- and C-fiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine.

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“…CGRP is involved in trigeminovascular activation and it is likely to play a role in migraine chronification [21]. CGRP contributes to the release of pro-nociceptive substances from trigeminovascular terminals and to the enhancement of neuronal activity leading to central sensitization [22,23]. Peripheral levels of CGRP have been proposed as a potential marker of CM, based on the higher values observed interictally, in the absence of symptomatic medications [24].…”

Section: Discussionmentioning

confidence: 99%

Plasma levels of CGRP and expression of specific microRNAs in blood cells of episodic and chronic migraine subjects: towards the identification of a panel of peripheral biomarkers of migraine?

et al. 2020

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Background Migraine can manifest with an episodic or a chronic pattern in a continuum of disease severity. Multiple factors are associated with the progression of the pattern from episodic to chronic. One of the most consistently reported factors is the overuse of medications (MO) for the acute treatment of migraine attacks. The mechanisms through which MO facilitates the transformation of episodic migraine (EM) into chronic migraine (CM) are elusive. In order to provide insights into these mechanisms, the present study aims to identify possible peripheral biomarkers associated with the two forms of migraine, and with the presence of MO. Methods We evaluated the plasma levels of calcitonin gene-related peptide (CGRP) and the expression of miR-34a-5p and miR-382-5p in peripheral blood mononuclear cells of subjects with EM (n = 27) or CM-MO (n = 28). Subjects in the CM-MO group were also tested 2 months after an in-hospital detoxification protocol. Results CGRP, miR-382-5p, and miR-34a-5p levels were significantly higher in CM-MO subjects when compared to EM patients (p = 0.003 for all comparisons). After correcting for age, sex, and disease duration, miRNAs expression was still significantly associated with migraine phenotype (EM vs. CM-MO: p = 0.014 for miR-382-5p, p = 0.038 for miR-34a-5p), while CGRP levels were not (p = 0.115). CGRP plasma levels significantly and positively correlated with miR-382-5p (Spearman’s rho: 0.491, p = 0.001) and miR-34a-5p (Spearman’s rho: 0.303, p =0.025) in the overall population. In the CM-MO group, detoxification significantly decreased CGRP levels and miRNAs expression (p = 0.001). When comparing responders and non-responders to the detoxification, the former group (n = 23) showed significantly higher levels of CGRP at baseline, and significantly lower expression of miR-382-5p after the detoxification. Conclusions Our findings identify a potential panel of peripheral markers associated with migraine subtypes and disease severity. CGRP levels as well as miRNAs expression were influenced by MO, and modulated by detoxification in subjects with CM-MO. Trial registration The study protocol was registered at www.clinicaltrials.gov (NCT04473976).

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The fifth cranial nerve in headaches

Cited by 104 publications

References 201 publications

Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects

Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects

Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine

Plasma levels of CGRP and expression of specific microRNAs in blood cells of episodic and chronic migraine subjects: towards the identification of a panel of peripheral biomarkers of migraine?

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