TY - JOUR

T1 - Amylin analog pramlintide induces migraine-like attacks in patients

AU - Ghanizada, Hashmat

AU - Al-Karagholi, Mohammad Al-Mahdi

AU - Walker, Christopher S

AU - Arngrim, Nanna

AU - Rees, Tayla

AU - Petersen, Jakeb

AU - Siow, Andrew

AU - Mørch-Rasmussen, Mette

AU - Tan, Sheryl

AU - O'Carroll, Simon J

AU - Harris, Paul

AU - Skovgaard, Lene Theil

AU - Jørgensen, Niklas Rye

AU - Brimble, Margaret

AU - Waite, Jayme S

AU - Rea, Brandon J

AU - Sowers, Levi P

AU - Russo, Andrew F

AU - Hay, Debbie L

AU - Ashina, Messoud

N1 - This article is protected by copyright. All rights reserved.

PY - 2021

Y1 - 2021

N2 - OBJECTIVE: Migraine is a prevalent and disabling neurological disease. Its genesis is poorly understood and there remains unmet clinical need. We aimed to identify mechanisms and thus novel therapeutic targets for migraine using human models of migraine and translational models in animals, with emphasis on amylin, a close relative of calcitonin gene-related peptide (CGRP).METHODS: Thirty-six migraine without aura patients were enrolled in a randomized, double-blinded, two-way, cross-over, positive-controlled clinical trial study to receive infusion of an amylin analogue pramlintide or human αCGRP on two different experimental days. Furthermore, translational studies in cells and mouse models, and rat and human tissue samples were conducted.RESULTS: Thirty patients (88%) developed headache after pramlintide infusion, compared to thirty-three (97%) after CGRP (p = 0.375). Fourteen patients (41%) developed migraine-like attacks after pramlintide infusion, compared to nineteen patients (56%) after CGRP (p = 0.180). The pramlintide induced migraine-like attacks had similar clinical characteristics to those induced by CGRP. There were differences between treatments in vascular parameters. Human receptor pharmacology studies showed that an amylin receptor likely mediates these pramlintide-provoked effects, rather than the canonical CGRP receptor. Supporting this, preclinical experiments investigating symptoms associated with migraine showed that amylin treatment, like CGRP, caused cutaneous hypersensitivity and light aversion in mice.INTERPRETATION: Our findings propose amylin receptor agonism as a novel contributor to migraine pathogenesis. Greater therapeutic gains could therefore be made for migraine patients through dual amylin and CGRP receptor antagonism, rather than selectively targeting the canonical CGRP receptor. This article is protected by copyright. All rights reserved.

AB - OBJECTIVE: Migraine is a prevalent and disabling neurological disease. Its genesis is poorly understood and there remains unmet clinical need. We aimed to identify mechanisms and thus novel therapeutic targets for migraine using human models of migraine and translational models in animals, with emphasis on amylin, a close relative of calcitonin gene-related peptide (CGRP).METHODS: Thirty-six migraine without aura patients were enrolled in a randomized, double-blinded, two-way, cross-over, positive-controlled clinical trial study to receive infusion of an amylin analogue pramlintide or human αCGRP on two different experimental days. Furthermore, translational studies in cells and mouse models, and rat and human tissue samples were conducted.RESULTS: Thirty patients (88%) developed headache after pramlintide infusion, compared to thirty-three (97%) after CGRP (p = 0.375). Fourteen patients (41%) developed migraine-like attacks after pramlintide infusion, compared to nineteen patients (56%) after CGRP (p = 0.180). The pramlintide induced migraine-like attacks had similar clinical characteristics to those induced by CGRP. There were differences between treatments in vascular parameters. Human receptor pharmacology studies showed that an amylin receptor likely mediates these pramlintide-provoked effects, rather than the canonical CGRP receptor. Supporting this, preclinical experiments investigating symptoms associated with migraine showed that amylin treatment, like CGRP, caused cutaneous hypersensitivity and light aversion in mice.INTERPRETATION: Our findings propose amylin receptor agonism as a novel contributor to migraine pathogenesis. Greater therapeutic gains could therefore be made for migraine patients through dual amylin and CGRP receptor antagonism, rather than selectively targeting the canonical CGRP receptor. This article is protected by copyright. All rights reserved.

U2 - 10.1002/ana.26072

DO - 10.1002/ana.26072

M3 - Journal article

C2 - 33772845

VL - 89

SP - 1157

EP - 1171

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 6

ER -