Saturday 11 355 PM KEYNOTE Olesen, J

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


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



0

1

2

3

4

5

6

7

8

9

10

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

0

1

2

3

4

5

6

7

8

9

10

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


2

4

6

8

10

12

14

16

18

20

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


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


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


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


Guo et al., Cephalalgia 2016

Migraine after PACAP38 infusion


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


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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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.


PACAP is a potent vasodilator of middle meningeal arteries via PAC1 receptors


Effect of PACAP-38 and VIP on CGRP release in TNC

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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)

**

**

**

***

******

## #

% c

hange fro

m b

aseline

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Mast cell degranulation – dura mater

Glostrup Hospital 1

10-5 M


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


Million dollars question: Is the PAC1 receptor responsible?

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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

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Saturday 11 355 PM KEYNOTE Olesen, J

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