CGRP in Animal Models of Migraine

Wattiez, Arnaud; Wang, Mengya; Russo, Andrew F.

doi:10.1007/164_2018_187

Cited by 35 publications

(20 citation statements)

References 135 publications

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“…Furthermore, we have only examined aversion to bright light in wild-type mice and while the similar phenotypes of aversion to bright and dim light suggests similar mechanisms (35,36), we cannot rule out the possibility of different mechanisms with different time courses. It will be interesting to see if genetically engineered “migraine mice”, such as hRAMP1 or other migraine models (50) have more prolonged responses to CGRP.…”

Section: Discussionmentioning

confidence: 99%

Vascular actions of peripheral CGRP in migraine-like photophobia in mice

et al. 2020

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Background Calcitonin gene-related peptide is recognized as a key player in migraine, yet the mechanisms and sites of calcitonin gene-related peptide action remain unknown. The efficacy of calcitonin gene-related peptide-blocking antibodies as preventative migraine drugs supports a peripheral site of action, such as the trigeminovasculature. Given the apparent disconnect between the importance of vasodilatory peptides in migraine and the prevailing opinion that vasodilation is an epiphenomenon, the goal of this study was to test whether vasodilation plays a role in calcitonin gene-related peptide-induced light aversive behavior in mice. Methods Systemic mean arterial pressure and light aversive behavior were measured after intraperitoneal administration of calcitonin gene-related peptide and vasoactive intestinal peptide in wild-type CD1 mice. The functional significance of vasodilation was tested by co-administration of a vasoconstrictor (phenylephrine, endothelin-1, or caffeine) with calcitonin gene-related peptide to normalize blood pressure during the light aversion assay. Results Both calcitonin gene-related peptide and vasoactive intestinal peptide induced light aversion that was associated with their effect on mean arterial pressure. Notably, vasoactive intestinal peptide caused relatively transient vasodilation and light aversion. Calcitonin gene-related peptide-induced light aversion was still observed even with normalized blood pressure. However, two of the agents, endothelin-1 and caffeine, did reduce the magnitude of light aversion. Conclusion We propose that perivascular calcitonin gene-related peptide causes light-aversive behavior in mice by both vasomotor and non-vasomotor mechanisms.

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Section: Discussionmentioning

confidence: 99%

Vascular actions of peripheral CGRP in migraine-like photophobia in mice

et al. 2020

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“…Recent studies showing insignificant or no BBB penetration of anti-CGRP-mAbs in animals in which the BBB is intact, versus transient binding in brain parenchyma of animals with compromised BBB, and prolonged binding in brain parenchyma surrounding a stroke site, further support our conclusion (4,5). Difficulty with speculating on how a compromised BBB may explain the outcome seen in this patient after treatment with erenumab stems from the fact that CGRP knockout mice lacking α-CGRP, which is the most dominant CGRP in the cortex, behave normally and show no signs of impairment in cognitive, motor or any other high-order cortical functions (6–12). Nevertheless, evidence for CGRP’s ability to facilitate and inhibit synaptic transmission in different cortical and subcortical regions raises the possibility that accidental introduction of an anti-CGRPr-mAb into a small and well-localized area of the cortex can interfere with proper regulation of (cortical) neuronal firing through two possible mechanisms: The first may be the disruption of facilitation of synaptic transmission that regulates proper firing of inhibitory cortical neurons and the second may be disruption of α-CGRP’s ability to reduce firing (reduce evoked EPSPs) in neurons that facilitate cortical excitability (13–16).…”

Section: Discussionmentioning

confidence: 99%

Adverse effects of erenumab on cerebral proliferative angiopathy: A case report

et al. 2020

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Background Cerebral proliferative angiopathy is a vascular malformation associated with compromised blood-brain barrier and with migraine-like headache. Treating blood-brain barrier-compromised patients with erenumab, an anti-calcitonin gene-related peptide receptor monoclonal antibody, may be risky. Case We describe a case of a 22-year-old chronic migraine patient with cerebral proliferative angiopathy who presented to our hospital in status epilepticus 2 d after his first dose of erenumab. Serial magnetic resonance imaging (MRI) studies demonstrated progressive areas of diffusion restriction including the brain tissue adjacent to the cerebral proliferative angiopathy, bilateral white matter and hippocampi. His 6-month post-presentation magnetic resonance imaging was notable for white matter injury, encephalomalacia surrounding cerebral proliferative angiopathy and bilateral hippocampal sclerosis. He remains clinically affected with residual symptoms, including refractory epilepsy and cognitive deficits. Conclusion The evidence presented in this case supports further investigation into potential deleterious side effects of erenumab in patients with compromised blood-brain barrier, such as individuals with intracranial vascular malformations.

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“…On the other hand, translation does work in some fields of neuroscience. In our opinion, the best examples of this are Experimental Autoimmune Encephalomyelitis (EAE) and Multiple Sclerosis (MS) (t Hart et al, 2018) along with the development of CGRP-targeted drugs for migraine (Wattiez et al, 2019). Despite existing failures (Rolfes et al, 2020), EAE led to the development of multiple drugs for MS that control its inflammatory component, such as INF-β, fingolimod, fumarate, mitoxantrone, cladribine, teriflunomide, glatiramer acetate, siponimod, and antibodies such as ocrelizumab, natalizumab, rituximab, and alemtuzumab (Grzegorski and Losy, 2019;Yamout et al, 2020).…”

Section: Looking At the Bright Side Of Translation: The Successful Examples Of Multiple Sclerosis And Migrainementioning

confidence: 99%

Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

et al. 2021

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Why can we still not translate preclinical research to clinical treatments for acute strokes? Despite > 1000 successful preclinical studies, drugs, and concepts for acute stroke, only two have reached clinical translation. This is the translational block. Yet, we continue to routinely model strokes using almost the same concepts we have used for over 30 years. Methodological improvements and criteria from the last decade have shed some light but have not solved the problem. In this conceptual analysis, we review the current status and reappraise it by thinking “out-of-the-box” and over the edges. As such, we query why other scientific fields have also faced the same translational failures, to find common denominators. In parallel, we query how migraine, multiple sclerosis, and hypothermia in hypoxic encephalopathy have achieved significant translation successes. Should we view ischemic stroke as a “chronic, relapsing, vascular” disease, then secondary prevention strategies are also a successful translation. Finally, based on the lessons learned, we propose how stroke should be modeled, and how preclinical and clinical scientists, editors, grant reviewers, and industry should reconsider their routine way of conducting research. Translational success for stroke treatments may eventually require a bold change with solutions that are outside of the box.

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CGRP in Animal Models of Migraine

Cited by 35 publications

References 135 publications

Vascular actions of peripheral CGRP in migraine-like photophobia in mice

Vascular actions of peripheral CGRP in migraine-like photophobia in mice

Adverse effects of erenumab on cerebral proliferative angiopathy: A case report

Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

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