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doi:10.1111/j.1468-2982.2009.01954.

Matrix metalloproteinases during and outside of migraine


attacks without aura ceph_1954 1..9

M Ashina1, JF Tvedskov1, K Lipka1, J Bilello2,3, M Penkowa4 & J Olesen1


1
Danish Headache Centre and Department of Neurology, Glostrup Hospital and 4Section of Neuroprotection, The Panum Institute, Faculty of
Health Sciences, University of Copenhagen, Copenhagen, Denmark
2
GlaxoSmithKline R&D, Research Triangle Park and 3Precision Human Biolaboratory, Durham, NC, USA

Ashina M, Tvedskov JF, Lipka K, Bilello J, Penkowa M & Olesen J. Matrix


metalloproteinases during and outside of migraine attacks without aura. Ceph-
alalgia 2009. London. ISSN 0333-1024
To test the hypothesis that permeability of the blood–brain barrier (BBB) is
altered during migraine attack due to enhanced activation of matrix metallo-
proteinases (MMPs), we investigated MMP-3, MMP-9 and tissue inhibitor of
metalloproteases (TIMP)-1 in the external jugular vein during and outside of
migraine attacks in 21 patients with migraine without aura. In addition, we
measured plasma levels of several other proteins including MMP-7, -8, -10 and
TIMP-2. We used Rules-Based Medicine multi-analyte profiling and protein array
technologies to study plasma concentration of MMPs. There was no difference
in MMP-9 and TIMP-1 levels between ictal and interictal periods. We found
significantly decreased plasma levels of MMP-3 in the external jugular (P = 0.002)
and cubital (P = 0.008) vein during attacks compared with outside of attacks.
We found no correlation of ictal or interictal MMP-3, MMP-9 and TIMP-1 to
migraine duration and frequency analysed in 21 patients (P > 0.05). There was
no difference between ictal and interictal plasma levels of MMP-7, -8, -10 and
TIMP-2 (P > 0.05). Our data suggest that plasma MMP-9 cannot be used as a
biomarker of BBB disruption in migraine without aura. Decreased MMP-3 levels
are an interesting and unexpected finding warranting further investigation.
䊐Matrix metalloproteinases, migraine, blood–brain barrier, tissue inhibitor of metallo-
proteases, external jugular vein, plasma, concentration
Messoud Ashina MD, PhD, Danish Headache Centre and Department of Neurology,
Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Nordre
Ringvej 57, Building 23-24, DK-2600 Glostrup, Copenhagen, Denmark. Tel.
+ 45-4323-2062, fax + 45-4323-3960, e-mail: ashina@dadlnet.dk Received 2 October
2008, revisions 15 March 2009, 19 May 2009, accepted 4 June 2009

aberrant production or activation of MMPs, or a


Introduction lack of their natural tissue inhibitors, the TIMPs
Matrix metalloproteinases (MMPs) are a family of (1, 2, 4).
zinc- and calcium-dependent enzymes that are col- Migraine is a neurovascular disorder with a
lectively responsible for remodelling of connective complex pathophysiology (5). The migraine attack
tissue (1, 2). MMPs are regulated at the transcrip- consists of different phases that may include aura
tional level by cytokines and growth factors that and headache. There is general agreement that the
stimulate the synthesis and secretion of pro-MMPs aura is caused by a cortical spreading depression
and also endogenous tissue inhibitors of metallo- (CSD), a propagating wave of neuronal and glial
proteases (TIMPs) (3). The human MMP system is depolarization (6–8). A ‘silent’ CSD may occur
comprised of at least 24 proteases and four TIMPs during migraine attack without aura (9). In animal
(3). It has been suggested that diseases involving models of migraine, CSD may trigger nociception
pathological tissue destruction are associated with (10) and CSD alters blood–brain barrier (BBB)

© Blackwell Publishing Ltd Cephalalgia, 2009 1


2 M Ashina et al.

permeability by activating brain MMPs, in particu- breast-feeding women were excluded from the
lar MMP-9 (11). MMP-9 is capable of degrading study. Patients kept a headache diary to ensure the
proteins found in the extracellular matrix (ECM) frequency of migraine and tension-type headache.
(12) and has been implicated in cerebral ischaemia Approvals were obtained from the Scientific Ethical
(13) and neural inflammation (14). Furthermore, it Committee for the County of Copenhagen. Signed
has been shown that MMP-3 may contribute to a informed consent was obtained from each patient.
breakdown of the BBB in relapsing–remitting mul- The study was undertaken in accordance with
tiple sclerosis (15). the Helsinki Declaration of 1964, as revised in
Two studies have reported elevated ictal and Edinburgh in 2000.
interictal plasma levels of pro-MMP-9 (a latent
form) (16) and interictal plasma MMP-9 (17) in the
Clinical study design
peripheral circulation of migraine sufferers. In
the present study we tested these hypotheses: first, After inclusion, all migraine patients were given the
that MMPs in the cranial circulation, in particular number of a pager and instructed to call when they
MMP-9 and MMP-3, are increased during migraine experienced a migraine attack. Patients could call
attacks; second, that increased MMPs in the cranial daily between 06.00 and 22.00 h, including week-
circulation would be detectable in the external ends and holidays. A physician would personally
jugular blood during migraine attacks. To test these return their call and as soon as possible come to the
hypotheses we analysed MMP-3, MMP-9 and patient’s home, workplace, or wherever the patient
TIMP-1 in the external jugular vein during and was at the time to take blood samples during the
outside of migraine attacks in patients with migraine attack. Because of the short distances in
migraine without aura (MoA). In addition, we mea- the Copenhagen area, all patients could be reached
sured plasma levels of several other proteins within 40 min, and all blood samples during
including MMP-7, -8, -10 and TIMP-2, where no migraine attack could be taken within 60 min from
significant changes related to migraine were noted the patient’s initial contact. Patients agreed not to
(data not shown). treat their migraine until after the blood samples
had been taken; therefore, treatment was delayed
by up to 60 min. Blood samples during attacks were
Material and methods
taken only if all of the following could be con-
firmed: the attack fulfilled IHS criteria for MoA and
Subjects
according to the patient was a usual attack; the
Blood samples were obtained in 21 patients (17 attack had started < 6 h ago (if the patient awoke
women, four men, mean age 39 years, range 26–53 with a migraine attack, this time was considered the
years) fulfilling International Headache Society start time); the migraine was not a recurrent attack
(IHS) criteria 1.1 for MoA (18), during as well as (migraine free for at least 72 h); and the patient had
outside of an attack. Patients were enrolled from not taken 5-HT1B/D agonists within 48 h, ergotamine
the out-patient headache clinic at the Danish Head- or similar medication within 72 h, and no form of
ache Centre (Glostrup Hospital, Denmark). Inclu- analgesics had been taken within 24 h. Blood pres-
sion criteria were MoA fulfilling migraine criteria of sure and heart rate were measured before blood
IHS 1.1 for at least 1 year; one to six attacks per sampling. Samples were taken after a minimum
month for the last 3 months; age between 18 and 65 of 15 min of rest in the supine position with legs
years; good general health determined by medical slightly elevated. Samples were taken on the same
history, normal physical examination, neurological side as the headache; if the migraine headache was
examination, and electrocardiogram. Exclusion cri- bilateral, samples were taken on the patient’s domi-
teria included more than six migraine attacks or 10 nant side. Headache characteristics and accompa-
days with migraine per month, use of migraine or nying symptoms were recorded. Blood samples
headache medication > 12 days/month, > 6 days/ were taken with a cannula (Venflon or butterfly) in
month with tension-type headache, migraine pro- the external jugular vein and the antecubital vein.
phylaxis within 6 weeks of inclusion, alcohol or With a minimum interval of 7 days, the control
drug overuse, regular use of prescribed or over-the- samples were taken on the same side and in the
counter medication except oral contraceptive pills same way as during an attack, but on a day without
and usual acute migraine medication, use of weak migraine or other headache. The patients were con-
analgesics exceeding the equivalent of 18 g para- tacted by telephone 24 h after the control samples
cetamol (acetaminophen) per month. Pregnant or were taken to ensure that an attack had not

© Blackwell Publishing Ltd Cephalalgia, 2009


Matrix metalloproteinases and migraine 3

developed after blood sampling. One patient had calibrators were run in the first and last columns of
new control samples taken because of the deve- each plate and three-level controls were included
lopment of migraine within 24 h after the initial in duplicate. Testing results were determined first
control samples were taken. All blood samples were for the high, medium and low controls for each
taken by two physicians, both with extensive prac- multiplex to ensure proper assay performance.
tice in puncturing the external jugular vein and at Unknown values for each of the analytes localized
least 1 year of anaesthesiology training. The blood in a specific multiplex were determined using four-
samples were collected into cooled 10-ml tubes and five-parameter, weighted and non-weighted
(BD vacutainer™; Becton Dickinson, Plymouth, curve fitting algorithms included in the data analy-
UK) prepared with 15% ethylenediamine tetraaceti- sis package.
cacid (EDTA) (0.12 ml/0.369 M) and 500 ml EDTA
10 000 IU Trasylol (Bayer, Leverkusen, Germany).
Protein microarray
They were immediately put on ice water, trans-
ported to the laboratory, centrifuged at 2.000 g A rolling cell amplification (RCA) immunoassay
for 15 min at 6°C, and plasma was transferred to was performed by Molecular Staging Inc. (MSI,
polypropylene tubes (Nunc Cryotube™ vials; Nunc New Haven, CT, USA) utilizing a protein microar-
A/S, Roskilde, Denmark) and stored at -80°C until ray platform that measured levels of 143 analytes
tested. on five separate arrays (19, 20). After the incubation
Plasma samples were coded, and MMPs and and washing of the plasma samples on microarrays,
TIMPs were measured blindly with respect to the captured proteins were detected by specific,
patient identity, attack status, and sampling site. biotinylated second antibodies, and a universal
Plasma samples from attack and outside of attack antibiotin antibody was bound to the secondary
were measured at the same time, and MMP-9 and antibodies. The antibiotin antibody contained an
TIMP-1 samples were measured with two different oligonucleotide DNA primer used for amplification.
assays. During the process, a circular DNA hybridizes to
the oligonucleotide DNA primer in the presence
of DNA polymerase and fluorescent nucleotides to
Rules-Based Medicine multi-analyte profiling
generate a signal. Following RCA, the slides were
The samples were thawed at room temperature, scanned (L200 scan; TECAN, Durham, NC, USA)
vortexed, spun at 13 000 g for 5 min for clarification using a proprietary software. The fluorescence
and 150 ml was removed for multi-analyte profiling intensity of microarray spots was analysed and
(MAP) antigen analysis into a master microtitre the resulting mean intensity values were measured.
plate. Using automated pipetting, an aliquot of Dose–response curves for the biomarkers were
each sample was introduced into one of the determined with increasing intensity indicating
capture microsphere multiplexes of the Human increasing analyte concentration.
Antigen MAP (http://www.rulesbasedmedicine.
com). These mixtures of sample and capture micro-
Statistical analysis
spheres were thoroughly mixed and incubated at
room temperature for 1 h. Multiplexed cocktails of Given that MMP and TIMP variables were not
biotinylated, reporter antibodies for each multiplex normally distributed, data are presented as median
were then added robotically and after thorough and quartiles. Samples with less than the detection
mixing were incubated for an additional hour at level were excluded from statistical analysis. To
room temperature. Multiplexes were developed test the differences between variables (including
using an excess of streptavidin–phycoerythrin baseline variables) we used the Wilcoxon signed
solution, which was thoroughly mixed into each rank test.
multiplex and incubated for l h at room tempe- All analyses were performed with SPSS for
rature. The volume of each multiplexed reaction Windows 14.0 (SPSS Inc., Chicago, IL, USA). Five
was reduced by vacuum filtration and the volume percent (P < 0.05) was accepted as the level of
increased by dilution into matrix buffer for analysis. significance.
Analyte measurements were performed in a
Luminex 100 instrument. We analysed the data
Results
separately from an Excel spreadsheet of the data.
For each multiplex, both calibrators and controls In 21 patients, blood samples were obtained during
were included on each microtitre plate. Eight-point a migraine attack fulfilling IHS criteria 1.1 for MoA,

© Blackwell Publishing Ltd Cephalalgia, 2009


4 M Ashina et al.

Table 1 Patient characteristics either jugular or cubital vein (P > 0.05). There was
no difference between ictal and interictal plasma
Migraine attack frequency per month 2.3 (1–5)
levels of MMP-7, -8, -10 and TIMP-2 (P > 0.05) (data
(mean and range)
Tension-type headache frequency 1.4 (0–4)
not shown).
per month
Oral contraception 5 of 17 female Correlation to migraine duration and frequency
Menstrual-related migraine 7 of 17 female
Migraine history (year, mean and range) 16 (2–40) We analysed a group of subjects (n = 11) whose
Smoker/non-smoker 2/18 blood samples were collected > 3 h after onset
Migraine duration at blood sampling 201 (95–305) (range 3.3–5.1 h). While MMP-3 levels were also
(min) decreased during attack, we found no changes
between ictal or interictal levels of MMP-9 and
TIMP-1 (P > 0.05). No correlation was found of
Table 2 Migraine attack characteristics (n = 21) ictal or interictal MMP-3, MMP-9 and TIMP-1 to
migraine duration or frequency analysed in 21
Number of
patients (P > 0.05).
Characteristic patients

Migraine as usual migraine All Discussion


Headache intensity
Mild 1 The major result from the present study is
Moderate 13 that plasma levels of MMP-9 and TIMP-1 were
Severe 7 unchanged during MoA attacks. An additional sur-
Localization prising and interesting finding was decreased ictal
Unilateral 19 levels of plasma MMP-3 in the cranial and peri-
Bilateral 2 pheral circulation during MoA attacks.
Quality
Pulsating 12 Blood–brain barrier in migraine
Pressing 9
Aggravation by physical activity 20 In spite of considerable interest in the BBB in
Nausea 17 the aetiology of migraine, few human studies have
Phonophobia 15 addressed the underlying physiological changes in
Photophobia 17 migraine. Two pathophysiological mechanisms may
cause alteration of BBB in migraine: CSD and acti-
vation of trigeminal sensory fibres with leakage of
as well as outside of attacks (Tables 1 and 2). In 17 substance P and other messenger molecules. CSD
patients, both external jugular and cubital venous has been implicated in stroke (21), and cerebral
blood was obtained. In four patients, only cubital ischaemia is associated with increased BBB perme-
venous blood was obtained. This was due to ability (22, 23). Inflammatory mediators are known
patients not accepting external jugular puncture, or modulators of BBB permeability (24), and animal
because no suitable external jugular vein could be models of inflammatory pain (formalin, Freund’s
found for puncture during a migraine attack. adjuvant and carrageenan injected in hind paw)
cause increased permeability of BBB (25–27). Given
that CSD (28) and possibly neurogenic inflamma-
Plasma levels of MMP-3, MMP-9 and TIMP-1
tion (29) play a key role in migraine, it would be
Rules-Based Medicine MAP analysis revealed no plausible to suggest that the BBB may be opened to
difference in MMP-9 and TIMP-1 levels between the same extent during migraine with or without
ictal and interictal periods (Table 3 and Fig. 1). aura. Neuroimaging is the only tool to examine this.
There were significantly decreased plasma levels of Cutrer et al. (30) used diffusion-weighted magnetic
MMP-3 in the external jugular (P = 0.002) and resonance imaging and observed no changes dur-
cubital (P = 0.008) veins during attacks compared ing migraine aura. Furthermore, no gadolinium
with outside of attacks (Table 3 and Fig. 2). Using enhancement was reported in patients with and
protein microarray technology, we found no differ- without migraine aura. However, these data should
ence in mean fluorescence intensity of MMP-9 and be interpreted with caution because of possible
TIMP-1 between ictal and interictal periods in methodological issues. What if BBB openings vary

© Blackwell Publishing Ltd Cephalalgia, 2009


Matrix metalloproteinases and migraine 5

Table 3 Median (quartiles) plasma levels of MMP-3, MMP-9 and TIMP-1 in the external jugular and cubital veins
measured by Rules-Based Medicine Multi-analyte Profiling analysis

MMPs (ng/ml) Ictal Interictal P-values

MMP-3 (jugular) 7.6 (5.0–9.0) 10.0 (6.7–13.5) 0.002


MMP-3 (cubital) 8.1 (6.3–9.5) 11.0 (7.2–14.5) 0.008
MMP-9 (jugular) 56.8 (31.1–146.0) 107.5 (58.5–147.0) 0.45
MMP-9 (cubital) 93.3 (45.6–145.0) 84.3 (46.5–152.0) 0.90
TIMP-1 (jugular) 82.0 (71.0–90.3) 84.0 (78.3–92.3) 0.08
TIMP-1 (cubital) 84.0 (76.9–90.6) 88.5 (78.0–95.5) 0.37

Plasma MMP-9 in the jugular vein (n=18) Plasma TIMP-1 (n=18) in the jugular vein

250 120

100
200
80
150

ng/ml
ng/ml

60
100
40
50
20

0 0
Ictal Interictal Ictal Interictal
* Two samples during and 3 samples outside attacks were under the detection level.
* Two samples outside attacks were under the detection level.

Plasma MMP-9 (n=18) in the cubital vein


Plasma TIMP-1 (n=21) in the cubital vein
300
150
250
120
200
ng/ml

90
ng/ml

150

100 60

50
30
0
0
Ictal Interictal
Ictal Interictal
* Two samples during attacks were under the detection level.
* One sample during attacks was under the detection level.

Figure 1 Individual plasma levels of MMP-9 and TIMP-1 in the cranial and peripheral circulation in patients with
migraine without aura. There was no difference in MMP-9 and TIMP-1 levels between ictal and interictal periods
(P > 0.05). *Samples under the detection level. Thick line shows median values.

in size during migraine aura or pain, or it depends studies. Furthermore, it is known that gadolinium-
on the severity of aura? Thus, two studies have induced enhancement may be dose dependent as
reported gadolinium enhancement over the symp- shown in multiple sclerosis plaques (33). Collec-
tomatic cerebral hemisphere during severe and pro- tively, there is no firm evidence of significant BBB
longed attacks of familial hemiplegic migraine disruptions in migraine. Besides, slight changes in
(31, 32). This indicates that the severity and dura- permeability of BBB could be missed due to meth-
tion of CSD may influence outcome in imaging odological limitations in neuroimaging techniques.

© Blackwell Publishing Ltd Cephalalgia, 2009


6 M Ashina et al.

Plasma MMP-3 (n=17) in the jugular vein is specific for the BBB disruption or pathological
24 states such as CSD per se. In an animal model of
20
epileptic seizures, significantly increased intracere-
bral expression levels of MMP-3 and -9 without any
16
simultaneous BBB disruption or changes in the BBB
ng/ml

12 properties were reported (38). Another question is


8 to what extent intracerebral alterations of MMPs
may reach plasma and be detected in blood samples
4
of patients and used as biomarkers? Circulating
0
Ictal Interictal
MMPs are derived from leucocytes, which are also
recruited to the brain during pathological and/or
* Three samples outside of attacks were under the detection level. inflammatory conditions (38–41). In fact, this
recruitment of peripheral leucocytes such as mono-
Plasma MMP-3 (n=21) in the cubital vein
cytes, macrophages and lymphocytes to the brain
24 parenchyma is highly contributory to the BBB dis-
20 ruptions seen in most neuropathological disorders,
16 as the leucocytic cells secrete tissue-degrading
ng/ml

12 enzymes including MMPs during their invasion of


8 the cerebral vascular endothelium and perivascular
4 space. Hence, when peripheral leucocytes or the
0 bone marrow homeostasis are suppressed, it will
Ictal Interictal lead to deficient brain inflammatory responses due
* One sample during and one sample outside of attacks were under the detection level. to a lack of recruitment of haematopoietic (periph-
eral) cells. In such cases the BBB was shown to be
Figure 2 Individual plasma levels of MMP-3 in the cranial
intact, indicating that leucocytic invasion of the
and peripheral circulation in patients with migraine
without aura. Plasma MMP-3 levels were significantly cerebral endothelium and leucocytic secretion of
decreased during attack compared with outside of attack enzymes (including MMPs) are major contributors
in the external (P = 0.002) and cubital (P = 0.008) vein. to BBB disruption.
Thick line shows median values. These data indicate that plasma MMP fluctua-
tions in migraine patients are likely to be associated
with ongoing BBB pathology, although the timing
Can plasma MMPs be used as biomarkers of
and degree of BBB damage probably affect the
altered permeability of BBB?
outcome. However, the BBB disruption is a local
The anatomical substrate of the BBB is the cerebral pathology, which mainly works (transports mol-
microvascular endothelium, astrocytes, pericytes, ecules) in a one-way manner (from blood vessel
neurons and ECM (23). Of particular relevance lumen and into brain parenchyma). Accordingly,
for migraine is the disruption of the ECM that is there are so far no reliable and specific factors
strongly associated with increased BBB permeabil- (biomarkers of BBB damage) that are released from
ity in pathological states (34). Thus, the ECM mol- the central nervous system into the blood vessel
ecules constitute the basement membrane around lumen and into circulation. Therefore, it is unclear
the vasculature and play a critical role in maintain- whether fluctuations of brain MMPs may be
ing the integrity of the BBB (23). detected in the plasma of migraineurs.
MMPs regulate ECM degradation during tissue
remodelling and can influence the expression
Present findings
of endothelial tight junction proteins (35, 36). In
an animal model of stroke, MMP-9 expression The present study focused upon a carefully charac-
increased progressively over time after stroke (37). terized and monitored population, and had shown
Gursoy-Ozdemir et al. (11) reported that CSD ini- that plasma levels of MMP-9 are unchanged dur-
tiates a cascade that disrupts the BBB via an MMP- ing attacks compared with outside of attacks. All
9-dependent mechanism. The authors showed that samples were assessed blindly in respect of ictal
MMP-9 levels increased within the cortex ipsilateral and interictal periods. These data are in contrast to
to the CSD beginning at 3–6 h, reaching a maxi- two previous studies showing elevated plasma
mum at 24 h and persisting for at least 48 h (11). MMP-9 in the first 3–6 h from onset of migraine
However, it is unclear whether increased MMP attack (16) and the highest plasma MMP-9 levels in

© Blackwell Publishing Ltd Cephalalgia, 2009


Matrix metalloproteinases and migraine 7

subjects from whom blood samples were taken 2–4 and peripheral circulation during attack. Could
days after their latest attack (42). Leira and col- decreased plasma concentrations of MMP-3 indicate
leagues (16) also found increased interictal plasma increased ECM degradation and thereby possibly
levels of MMP-9 in the peripheral circulation in increased permeability of BBB in migraine? It has
patients with (n = 14) and without aura (n = 20) been reported that MMP-3 knockout (KO) mice have
compared with controls. Given that up-regulation less disruption of the BBB after lipopolysaccharide-
of MMP-9 is a hallmark indicating nociception in induced opening of the BBB than WT mice (43).
trigeminal sensory afferents (11), it is difficult to Interestingly, MMP-9 mRNA levels were increased
interpret these data because one would expect no to a similar level in both the MMP-3 KO and WT. The
difference between patients outside of attacks and authors suggested that MMP-3 may attack the basal
controls. Furthermore, Leira and colleagues (16) lamina and tight junction proteins, opening the BBB
did not register the time from migraine attack to and facilitating neutrophil influx (43). Interestingly,
pain-free period, or the time from the last migraine MMP activation is often the result of a complex
attack to the current attack. Furthermore, it is proteinase cascade, and some of the activated MMPs
unclear whether ictal levels in patients with aura can activate other pro-MMPs, e.g. MMP-3 can acti-
were examined during attacks with or without aura vate pro-MMP-9 (44). It was recently demonstrated
(16). In the present study the patients had been that serum MMP-3 concentration is significantly
migraine free for at least 72 h, and ictal samples lower in the acute phase of myocardial infarction
were collected between 1.6 and 5.1 h after onset than during recovery (45). In contrast MMP-3 brain
of migraine pain. We did not collect samples in tissue levels could not be detected between 6 and
healthy controls, and it is therefore unknown 24 h after focal stroke in the rat (37). However, the
whether baseline levels in patients differ from those authors reported increased MMP-9 expression in
without migraine. It has been suggested that CSD endothelial cells and infiltrating neutrophils. It
initiates a cascade that disrupts the BBB via an is possible that this study was unable to identify
MMP-9-dependent mechanism. This would lead to transient expression of MMP-3 in the early phase of
release of inflammatory mediators and subsequent the time course (37). Based on these data, it would be
sensitization of meningeal nociceptors and head plausible to suggest that MMP-3 decreases during
pain. In the present study all patients reported the early phase of acute migraine attacks. However,
moderate to severe pain. If one assumes that all of these data should be interpreted with caution and
them experienced a ‘silent’ CSD, we would expect should be replicated before any firm conclusions
increased MMP-9 levels during ongoing nocicep- are drawn.
tion. We found no changes in plasma MMP-9 even
in the group of subjects whose blood samples were
collected > 3 h after onset (range 3.3–5.1 h). This Conclusions
is in contrast to Leira et al. (16), who reported MMP-9 and TIMP-1 levels in the external jugular
up-regulation of pro-MMP-9 in the first 3–6 h from vein are unchanged during migraine attacks
onset of migraine attack compared with outside of without aura 1.6–5.1 h after onset of migraine pain.
attacks. We have no satisfactory explanation for this However, it is possible that delayed up-regulation
discrepancy. In the present study plasma samples of MMP-9 might occur, but this would hardly be
were measured with two different assays. Quanti- relevant for migraine pain. Our data suggest that
tative measurements were made by Rules-Based plasma MMP-9 cannot be used as a biomarker of
Medicine, a US Clinical Laboratory Improvement BBB disruption in MoA. Decreased MMP-3 levels
Amendments-certified biomarker testing laboratory are an interesting and unexpected finding warrant-
delivering reproducible, quantitative, multiplexed ing further investigation.
immunoassay data. For these measurements im-
munobead technology was used, which, unlike
microarray or enzyme-linked immunosorbent assay, References
performs assays in a fluidic phase. Fluid phase
assays allow greater availability for antibody 1 Yong VW, Krekoski CA, Forsyth PA, Bell R, Edwards DR.
Matrix metalloproteinases and diseases of the CNS.
binding due to the three-dimensional nature of the
Trends Neurosci 1998; 21:75–80.
microparticle. 2 Yong VW, Agrawal SM, Stirling DP. Targeting MMPs in
MMP-3 levels have not previously been examined acute and chronic neurological conditions. Neurothera-
in patients with migraine. In the present study, we peutics 2007; 4:580–9.
found decreased levels of MMP-3 in both cranial 3 Ethell IM, Ethell DW. Matrix metalloproteinases in brain

© Blackwell Publishing Ltd Cephalalgia, 2009


8 M Ashina et al.

development and remodeling: synaptic functions and occur in human ischemic stroke with high incidence. Ann
targets. J Neurosci Res 2007; 85:2813–23. Neurol 2008; 63:720–8.
4 Yong VW. The potential use of MMP inhibitors to treat 22 Kempski O. Cerebral edema. Semin Nephrol 2001;
CNS diseases. Expert Opin Investig Drugs 1999; 8:255–68. 21:303–7.
5 Goadsby PJ. Migraine pathophysiology. Headache. 2005; 23 Hawkins BT, Davis TP. The blood–brain barrier/
45 (Suppl. 1):S14–24. neurovascular unit in health and disease. Pharmacol Rev
6 Lauritzen M, Skyhøj Olsen T, Lassen NA, Paulson OB. 2005; 57:173–85.
Changes in regional cerebral blood flow during the 24 Abbott NJ. Inflammatory mediators and modulation
course of classic migraine attacks. Ann Neurol 1983; of blood–brain barrier permeability. Cell Mol Neurobiol
13:633–41. 2000; 20:131–47.
7 Leão AAP. Spreading depression of activity in the cere- 25 Huber JD, Witt KA, Hom S, Egleton RD, Mark KS,
bral cortex. J Neurophysiol 1944; 7:359–90. Davis TP. Inflammatory pain alters blood–brain barrier
8 Olesen J, Larsen B, Lauritzen M. Focal hyperemia permeability and tight junctional protein expression. Am
followed by spreading oligemia and impaired activation J Physiol Heart Circ Physiol 2001; 280:H1241–8.
of rCBF in classic migraine. Ann Neurol 1981; 9:344–52. 26 Huber JD, Hau VS, Borg L, Campos CR, Egleton RD,
9 Sanchez-del-Rio M, Reuter U, Moskowitz MA. New Davis TP. Blood–brain barrier tight junctions are altered
insights into migraine pathophysiology. Curr Opin during a 72-h exposure to lambda-carrageenan-induced
Neurol 2006; 19:294–8. inflammatory pain. Am J Physiol Heart Circ Physiol 2002;
10 Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Mosk- 283:H1531–7.
owitz MA. Intrinsic brain activity triggers trigeminal 27 Brooks TA, Hawkins BT, Huber JD, Egleton RD,
meningeal afferents in a migraine model. Nat Med 2002; Davis TP. Chronic inflammatory pain leads to increased
8:136–42. blood–brain barrier permeability and tight junction
11 Gursoy-Ozdemir Y, Qiu J, Matsuoka N, Bolay H, protein alterations. Am J Physiol Heart Circ Physiol 2005;
Bermpohl D, Jin H et al. Cortical spreading depression 289:H738–43.
activates and upregulates MMP-9. J Clin Invest 2004; 28 Lauritzen M. Cerebral blood flow in migraine and cortical
113:1447–55. spreading depression. Acta Neurol Scand Suppl 1987;
12 Shapiro SD. Matrix metalloproteinase degradation of 113:1–40.
extracellular matrix: biological consequences. Curr Opin 29 Moskowitz MA. Neurogenic inflammation in the patho-
Cell Biol 1998; 10:602–8. physiology and treatment of migraine. Neurology 1993;
13 del Zoppo GJ, Milner R, Mabuchi T, Hung S, Wang X, 43:S16–20.
Berg GI, Koziol JA. Microglial activation and matrix 30 Cutrer FM, Sorensen AG, Weisskoff RM, Ostergaard L,
protease generation during focal cerebral ischemia. Stroke Sanchez del Rio M, Lee EJ et al. Perfusion-weighted
2007; 38:646–51. imaging defects during spontaneous migrainous aura.
14 Yong VW, Power C, Forsyth P, Edwards DR. Metallo- Ann Neurol 1998; 43:25–31.
proteinases in biology and pathology of the nervous 31 Crawford JS, Konkol RJ. Familial hemiplegic migraine
system. Nat Rev Neurosci 2001; 2:502–11. with crossed cerebellar diaschisis and unilateral
15 Kanesaka T, Mori M, Hattori T, Oki T, Kuwabara S. meningeal enhancement. Headache 1997; 37:590–3.
Serum matrix metalloproteinase-3 levels correlate with 32 Arnold G, Reuter U, Kinze S, Wolf T, Einhäupl KM.
disease activity in relapsing-remitting multiple sclerosis. Migraine with aura shows gadolinium enhancement
J Neurol Neurosurg Psychiatry 2006; 77:185–8. which is reversed following prophylactic treatment.
16 Leira R, Sobrino T, Rodriguez-Yáñez M, Blanco M, Arias Cephalalgia 1998; 18:644–6.
S, Castillo J. Mmp-9 immunoreactivity in acute migraine. 33 Filippi M, Yousry T, Campi A, Kandziora C, Colombo B,
Headache 2007; 47:698–702. Voltz R et al. Comparison of triple dose versus standard
17 Imamura K, Takeshima T, Fusayasu E, Nakashima K. dose gadolinium-DTPA for detection of MRI enhancing
Increased plasma matrix metalloproteinase-9 levels in lesions in patients with MS. Neurology 1996; 46:379–84.
migraineurs. Headache 2008; 48:135–9. 34 Rosenberg GA, Estrada E, Kelley RO, Kornfeld M.
18 Headache Classification Committee of the International Bacterial collagenase disrupts extracellular matrix and
Headache Society. Classification and diagnostic criteria opens blood–brain barrier in rat. Neurosci Lett 1993;
for headache disorders, cranial neuralgias and facial pain, 160:117–19.
2nd edn. Cephalalgia 2004; 24(Suppl. 1):9–160. 35 Savettieri G, Di Liegro I, Catania C, Licata L, Pitarresi GL,
19 Perlee L, Christiansen J, Dondero R, Grimwade B, Lejnine D’Agostino S et al. Neurons and ECM regulate occludin
S, Mullenix M et al. Development and standardization of localization in brain endothelial cells. Neuroreport 2000;
multiplexed antibody microarrays for use in quantitative 11:1081–4.
proteomics. Proteome Sci 2004; 2:9. 36 Tilling T, Korte D, Hoheisel D, Galla HJ. Basement mem-
20 Schweitzer B, Wiltshire S, Lambert J, O’Malley S, Kukan- brane proteins influence brain capillary endothelial
skis K, Zhu Z et al. Inaugural article: immunoassays with barrier function in vitro. J Neurochem 1998; 71:1151–7.
rolling circle DNA amplification: a versatile platform for 37 Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone
ultrasensitive antigen detection. Proc Natl Acad Sci USA FC. Matrix metalloproteinase expression increases after
2000; 97:10113–19. cerebral focal ischemia in rats: inhibition of matrix
21 Dohmen C, Sakowitz OW, Fabricius M, Bosche B, Rei- metalloproteinase-9 reduces infarct size. Stroke 1998;
thmeier T, Ernestus RI et al. Spreading depolarizations 29:1020–30.

© Blackwell Publishing Ltd Cephalalgia, 2009


Matrix metalloproteinases and migraine 9

38 Penkowa M, Florit S, Giralt M, Quintana A, Molinero A, after 6-aminonicotinamide treatment. Exp Neurol 2002;
Carrasco J, Hidalgo J. Metallothionein reduces central 176:308–21.
nervous system inflammation, neurodegeneration, and 42 Imamura K, Takeshima T, Fusayasu E, Nakashima K.
cell death following kainic acid-induced epileptic sei- Increased plasma matrix metalloproteinase-9 levels in
zures. J Neurosci Res 2005; 79:522–34. migraineurs. Headache 2008; 48:135–9.
39 Penkowa M, Giralt M, Moos T, Thomsen PS, Hernández 43 Gurney KJ, Estrada EY, Rosenberg GA. Blood–brain
J, Hidalgo J. Impaired inflammatory response to glial cell barrier disruption by stromelysin-1 facilitates neutrophil
death in genetically metallothionein-I- and -II-deficient infiltration in neuroinflammation. Neurobiol Dis 2006;
mice. Exp Neurol 1999; 156:149–64. 23:87–96.
40 Penkowa M, Hidalgo J. IL-6 deficiency leads to reduced 44 Ogata Y, Enghild JJ, Nagase H. Matrix metalloproteinase
metallothionein-I+II expression and increased oxidative 3 (stromelysin) activates the precursor for the human
stress in the brain stem after 6-aminonicotinamide treat- matrix metalloproteinase 9. J Biol Chem 1992; 267:3581–4.
ment. Exp Neurol 2000; 163:72–84. 45 Samnegard A, Silveira A, Tornvall P, Hamsten A, Erics-
41 Penkowa M, Poulsen C, Carrasco J, Hidalgo J. M-CSF son CG, Eriksson P. Lower serum concentration of matrix
deficiency leads to reduced metallothioneins I and II metalloproteinase-3 in the acute stage of myocardial
expression and increased tissue damage in the brain stem infarction. J Intern Med 2006; 259:530–6.

© Blackwell Publishing Ltd Cephalalgia, 2009

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