the pacap receptor: a novel target for migraine treatment · guo et al., cephalalgia 2016. danish...
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D A N I S H H E A D A C H E
C E N T E R
The PACAP Receptor: A Novel Target for
Migraine Treatment
Faculty of Health and Medical Sciences
DEPARTMENT OF NEUROLOGY & DANISH HEADACHE CENTER
Glostrup Hospital, the Capital Region of Denmark
Messoud Ashina, MD, PhD, DMSc
Professor of Neurology
Rigshospitalet Glostrup
DANISH HEADACHE CENTER
Disclosures
Personal fees from Alder BioPharmaceuticals, Allergan, Amgen,
Autonomic Technologies Inc. (ATI), and Eli Lilly Autonomic Technologies Inc. (ATI), and Eli Lilly
Principal investigator for Amgen trials 20120178, 20120295,
20130255, and 20120297, and GM-11 gammaCore®-R trial
DANISH HEADACHE CENTER
PACAP belongs to the secretin/glucagon/Vasoactive
intestinal polypeptide (VIP) familyintestinal polypeptide (VIP) family
Arimura et al. Jpn J Physiol. 1998
DANISH HEADACHE CENTER
CNS and PNSNeurotransmission, neuromodulation, regulation of cicardian clock, behavioral actions, learning and memory procession
Immune systemRegulation of immune reponses
Vascular systemVasodilation
Endocrine systemRegulation of pituitary, adrenal
and pacreatic secretion
Respiratory systemBronchodilation
Urogenital systemRegulation of micturation
pathways
Gastrointestinal systemRegulator of lipid/carbohydrate mebolism, liver cell proliferation
PACAP38 VIP
Diané et al., J Metabolic Synd 2014Vaudry et al. Pharmacol Rev. 2009
DANISH HEADACHE CENTER
Pain-sensitive structures
Wolff 1963 Olesen et al, Lancet Neurology 2009
Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38)
Vasoactive intestinal peptide (VIP) Uddman et al. J Cereb Blood Flow Metab. 1993; Jansen-Olesen et al. J Auton Nerv Syst. 1994; Baun et al. Eur J Pharmacol. 2011
DANISH HEADACHE CENTER
What triggers migraines?
DANISH HEADACHE CENTER
Human model of migraine
PACAP & VIPModified from Olesen et al. Cephalalgia 2009
DANISH HEADACHE CENTER
10
0
1
2
3
4
5
6
7
8
9
10
0 40 80 120 4 6 8 12
Hea
dach
e in
ten
sity
(V
RS
) VIP
Migraine-like attacks (n=0/12)
Rahmann et al. Cephalalgia 2008
0
1
2
3
4
5
6
7
8
9
10
0 40 80 4 8 12
Hea
da
che
inte
nsi
ty (
VR
S)
PACAP38
Migraine-like attacks (7/12)
Schytz et al. Brain 2009
min hoursVIP
min hoursPACAP
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Recruited (n=34)
Drop outs (n=10)
STUDY FLOW CHARTSTUDY DESIGN
Baseline
Infusion
MEASUREMENTS
Clinical dataHeadache interviewsMigraine symptomsOther symptoms
Physiological dataHeart rate
Blood pressureRespiratory freq.
Double blind randomized crossover study
Included (n=24)
Completed (n=22)
Drop outs (n=2)
In-hospital phase(0-5 h)
Post-hospital phase(6-24 h)
InfusionPACAP38 / VIP
Respiratory freq.End-tidal CO2 pressure
Biochemical dataPlasma PACAP38 conc.
Plasma VIP conc.Plasma tryptase conc.
Neuroimaging dataMR-angiographyFunctional MRIAnatomical MRIMR-venography
DANISH HEADACHE CENTER
16
18
20
22
Headache
Migraine
91%
73%
82%
Headache/migraine after PACAP38 and VIP
2
4
6
8
10
12
14
PACAP VIP
Migraine
18%
Amin et al, Brain 2014Intravenous PACAP38 (10 pmol/kg/min) infusion over 20 min
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MRI angiographyMRI angiographyMRI angiographyMRI angiographyBaseline
PACAP-38
Amin et al., Brain 2014
2 hours after
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An axial view of a 3D reconstruction of the time-of-flight MR-angiography scan
Before (A) and after (B) subcutaneous injection of 6 mg
sumatriptan, showing marked extracranial vasoconstriction
A B
Amin et al., Brain 2014
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RestingRestingRestingResting----statestatestatestate functionalfunctionalfunctionalfunctional connectivityconnectivityconnectivityconnectivity MRIMRIMRIMRI
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RestingRestingRestingResting----state functional connectivity MRIstate functional connectivity MRIstate functional connectivity MRIstate functional connectivity MRI
PACAP-38
Amin et al., Neurology 2016
DANISH HEADACHE CENTER
DANISH HEADACHE CENTER
PACAP38PACAP38PACAP38PACAP38----induced induced induced induced migrainemigrainemigrainemigraine attacksattacksattacksattacksSalience Network
Sensorimotor Network
Default Mode NetworkINCREASED CONNECTIVITYR+L inferior frontal gyrus INCREASED CONNECTIVITYR premotor cortex INCREASED CONNECTIVITYL primary auditory cortexL somatosensory cortex IIL somatosensory cortex IIL premotor cortexL visual cortex V4DECREASED CONNECTIVITYNone DECREASED CONNECTIVITYL visual cortex V1, V2, V3 DECREASED CONNECTIVITYR frontal lobeR cerebellumCognitive functions
EmotionsSpeech/languageWorking memory
Motor function in faceCognitive affected
Photophobia
Phono/photophobiaPain perception
Cognitive functionsPain modulation
Amin et al., Neurology 2016
DANISH HEADACHE CENTER
PACAP38 induced more migraine than VIP
Conclusions
PACAP38-induces marked dilation of extracerebral arteries blocked by sumatriptan
The pre-ictal phase is associated with change of functional connectivity of core brain networks
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No migraine
25 %
PACAP38 induced migraine
Genetics? Biochemical markers?
CGRP
75 %
Migraine
Schytz et al. Brain 2009; Amin et al. Brain 2014
TNF alfa
Premonitory symptoms?
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Migraine after PACAP38 infusion
Guo et al., Cephalalgia 2016
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No attacks (n=9)
VIPPACAP38
Attack (n=23)
P=0.363 P=0.819
CGRP TNFaP=0.792 P=0.448
Guo et al., Cephalalgia 2016
DANISH HEADACHE CENTER
11 out of 23 patients (48%) with induced attack had PS after PACAP
Results – PACAP38
Guo et al., Cephalalgia 2016
DANISH HEADACHE CENTER
Familial predisposition has no effect on migraine response
Conclusions
Changes in plasma CGRP or TNF alfa have no effect on migraine response
PACAP38 induces premonitory symptoms in 48% of patients
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PACAP & VIP receptors
Drug target?
PACAP38 has 1000 times higher affinity for the PAC1-R than VIP
Dickinson & Fleetwood-Walker. TIPS 1999
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