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1/25/2018
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D A N I S H H E A D A C H E
C E N T E R
Glostrup Hospital, the Capital Region of Denmark
Pituitary adenylate cyclase-activating polypeptide 38
(PACAP38). New hot-spot in migraine
Jes Olesen, MD
Professor of Neurology
Danish Headache Center
Rigshospitalet Glostrup
Faculty of Health and Medical Sciences
DEPARTMENT OF NEUROLOGY & DANISH HEADACHE CENTER
DANISH HEADACHE CENTER
PACAP belongs to the secretin/glucagon/Vasoactive
intestinal polypeptide (VIP) family
Arimura et al. Jpn J Physiol. 1998
DANISH HEADACHE CENTER
PACAP distribution
CEREBELLUMGhatei, 1993; Mikkelsen, 1994; Takahashi,
1994; Hannibal, 1995; Nielsen, 1998.
CINGULATE CORTEXMikkelsen, 1994
FRONTAL CORTEXMikkelsen, 1994 OCCIPITAL CORTEX
Nonaka, 2012.
SUP CERV GANGLIONMikkelsen, 1994
TRIG GANGLIONMoller, 1993; Mulder, 1994;
Dun, 1996.
HYPOTHALAMUSKöves, 1990, 1991; Kivipelto,
1992; Tamada, 1994; Hannibal,
1995a,b; Mikkelsen, 1995
THALAMUSKöves, 1991; Masuo, 1993; Takahashi, 1994;
Palkovits, 1995; Hannibal, 2002.
PAGDas, 2007
PONTINE NUCLEITajti, 2001; Hannibal, 2002;
Farnham, 2008.
Vollesen et al. In preparation
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PACAP receptor
distribution
CEREBELLUM
PAC1: Hashimoto, 1996; Shioda, 1997;
Zhou, 1999, 2000; Basille, 2000.
CINGULATE CORTEX
PAC1: Hashimoto, 1996; Shioda, 1997;
Zhou, 1999.
FRONTAL CORTEX
PAC1: Shioda, 1997, 1999.
SUP CERV GANGLION
PAC1: Nogi, 1997; Braas and
May, 1999.
CRANIAL ARTERIES
VPAC1 & VPAC2: Baun, 2013.
THALAMUS
PAC1: Usdin, 1994; Hashimoto, 1996;
Shioda, 1997.
PONTINE NUCLEI
PAC1: Sheward, 1995; Hashimoto, 1996, Shioada, 1997.
HYPOTHALAMUS
PAC1 & VPAC2: Usdin, 1994;
Hashimoto, 1996;
Shioda, 1997.
TRIG GANGLION
PAC1 & VPAC2: Chaudhary and Baumann, 2002.
Vollesen et al. In preparation
DANISH HEADACHE CENTER
DANISH HEADACHE CENTER
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0 40 80 4 8 12
Hea
da
ch
e in
ten
sity
(V
RS
)
PACAP38Migraine-like attacks (7/12)
Schytz et al. Brain 2009
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0 40 80 120 4 6 8 12
Hea
da
che
inte
nsi
ty (
VR
S) VIP
Migraine-like attacks
(n=0/12)
Rahmann et al. Cephalalgia 2008
min hours
VIP
min hours
PACAP
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Recruited (n=34)
Included (n=24)
Completed (n=22)
Drop outs (n=10)
Drop outs (n=2)
STUDY FLOW CHARTSTUDY DESIGN
Baseline
In-hospital phase(0-5 h)
Post-hospital phase(6-24 h)
InfusionPACAP38 / VIP
MEASUREMENTS
Clinical data
Headache interviews
Migraine symptomsOther symptoms
Physiological data
Heart rate
Blood pressureRespiratory freq.
End-tidal CO2 pressure
Biochemical data
Plasma PACAP38 conc.
Plasma VIP conc.Plasma tryptase conc.
Neuroimaging data
MR-angiography
Functional MRIAnatomical MRI
MR-venography
Double blind randomized crossover study
Amin et al, Brain 2014
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4
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12
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22
PACAP VIP
Headache
Migraine
91%
73%
82%
18%
Amin et al, Brain 2014
Headache/migraine after PACAP38 and VIP
Intravenous PACAP38 (10 pmol/kg/min) infusion over 20 min
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Head to head comparison of PACAP and VIP
Amin F et al Brain 2014
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PACAP-38
MRI angiography
Amin et al., Brain 2014
4 h 15 min2 h
STA - MMA - MCA
Baseline
2 hours after
DANISH HEADACHE CENTER
Before (A) and after (B) subcutaneous injection of 6 mg
sumatriptan, showing marked extracranial vasoconstriction
A B
An axial view of a 3D reconstruction of the time-of-flight
MR-angiography scan
Amin et al., Brain 2014
DANISH HEADACHE CENTER
Salience
Network
Sensorimotor
Network
Default Mode
Network
Cognitive functions
Emotions
Speech/language
Working memory
Motor function in face
Cognitive affected
Photophobia
Phono/photophobia
Pain perception
Cognitive functions
Pain modulation
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11 out of 23 patients (48%) with induced attack had premonitory symptoms after PACAP
PACAP38- premonitory symptoms
Guo et al., Pain 2016
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Guo et al., Cephalalgia 2016
Migraine after PACAP38 infusion
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No attacks (n=9)
VIP
CGRP TNFa
PACAP38
Attack (n=23)
P=0.363 P=0.819
P=0.792 P=0.448
Guo et al., Cephalalgia 2016
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Familial predisposition has no effect on migraine response
Changes in plasma CGRP or TNF alfa have no effect on migraine response
Conclusions
DANISH HEADACHE CENTERGlostrup Hospital .
• Partially sharing receptors:
• VIP: VPAC1 + VPAC2
• PACAP: VPAC1 + VPAC2+ PAC1
• G-protein coupled receptors from the secretin/glucagon superfamily
• No splice variants for VPAC1 or VPAC2, multiple splice variants for PAC1.
VIP and PACAP receptors
VPAC1 VPAC2 PAC1
PACAPVIP
VPAC1VPAC1 VPAC2VPAC2 PAC1PAC1
PACAPPACAPVIPVIP
DANISH HEADACHE CENTER
The key questions…
• Why can PACAP-38 trigger migraine attacks, while VIP can not?
• What is the mechanism and site of action of PACAP-induced migraine?
• In which part of the trigeminovascular system is PACAP but not VIP
acting?
• Is it related to the PAC1 receptor?
Glostrup Hospital 1
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DANISH HEADACHE CENTER
PACAP and VIP cause relaxation via VPAC1 receptors
VPAC1
VPAC2
RIGSHOSPITALET GLOSTRUP, DEPARTMENT OF NEUROLOGY & DANISH HEADACHE CENTER
Baun, et al. 2011. Eur. J. Pharmacol. 670, 186–194.
DANISH HEADACHE CENTER
PACAP is a potent vasodilator of middle meningeal arteries via PAC1 receptors
DANISH HEADACHE CENTER
Effect of PACAP-38 and VIP on CGRP release in TNC
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DANISH HEADACHE CENTER
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Skull model – dural mast cell degranulation
Glostrup Hospital 1
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Effect of antihistamine on PACAP-38 induced dilation of dural artery
0 10 20 30 40 500
25
50
75
100
125
PACAP-38-AH pretreated rats (n=9)
Time (min)
Infusion Post-infusion
PACAP-38-Control rats (n=13)
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PACAP-38-MCD rats (n=7)
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## #
% c
hange fro
m b
aseline
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Mast cell degranulation – dura mater
Glostrup Hospital 1
10-5 M
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Summary basic science
• PACAP induced dilation of cerebral and dural arteries is mainly via VPAC1
receptors
• PACAP co-localizes with CGRP in the trigeminal ganglion neurons and in
lamina I/II of the spinal trigeminal nucleus caudalis
• PACAP-38, but not PACAP-27 and VIP cause CGRP release in the spinal
trigeminal nucleus caudalis that with a great probability is not mediated via
PAC1 receptors.
• In addition to the neuronal location of PACAP it is also located to satellite
glial cells in the trigeminal ganglion
• PACAP-38, but not PACAP-27 and VIP cause mast cell degranulation in
dura that with a great probability is not mediated via PAC1 receptors
DANISH HEADACHE CENTER
Million dollars question: Is the PAC1 receptor responsible?
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DANISH HEADACHE CENTER
Invitation to Master in Headache Disorders Join us for the 2. Master course starting in September 2018
WWW. MHD.KU.DK
Endorsed by
International Headache Society; European Headache Federation;
European Academy of Neurology; Lifting The Burden; European
Headache Alliance; Migraine Trust; Danish Headache Society;
Patient Organizations