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CURRENT LITERATURE
CURRENT PREVENTIVE THERAPY: WHAT WE KNOW ABOUT
MECHANISM(S) OF ACTION?
Migraine Prophylactic Drugs Work via Ion Channels
Cohen GK
Medical Hypotheses 2005;65:114–122
In recent decades, the concept of a vascular origin of mi-
graine has been replaced by theories based on neuronal
pathophysiology. These theories involve rapid changes
in the functioning of the brain, particularly the brain-
stem, and the trigeminal nerves. While such paroxysmal
changes in function could be the result of altered synaptic
transmission, or other physiological changes, the author
hypothesizes that they could also be due to changes in
the function of voltage-regulated sodium and calcium ion
channels. Support for this view of migraine as a chan-
nelopathy comes from an examination of the likely mech-
anism of action of migraine prophylactic drugs, as most
of the widely used drugs for migraine prevention work by
inhibiting the function of one or both of these ion chan-
nels. This review of the laboratory research done on most
of the commonly used migraine prophylactic drugs, di-
vided into five classes, reveals that they all may work on
sodium channels, calcium channels, or both. If this is the
common mechanism of action of migraine prophylactics,
it should lead toward the development of more effective
prophylactic drugs.
COMMENTARY
T he efficacy of some β-blockers, flunarizine, some
antiepileptics, and amitriptyline in migraine prevention
has been demonstrated, both in controlled clinical trials and
in clinical practice. Their mechanisms of action, however, are
unknown. Curiously, none of these medications were devel-
oped specifically for the prophylaxis of migraine, but for the
treatment of other diseases. Recent genetic discoveries in the
familial hemiplegic variant of migraine, together with many
of its clinical characteristics, support the hypothesis that mi-
graine should be considered as one channelopathy. A gain of
function of sodium and calcium channels has been proposed
as the abnormality responsible. These two channels have much
in common, as they may be evolved from a common gene.
In this complete and highly recommendable paper, the au-
thor proposes the idea that migraine preventatives have as their
mechanism of action an inhibition of voltage-regulated sodium
and/or calcium channels and reviews the available experimental
evidence in this regard. Beginning with antidepressants, all tri-
cyclics block sodium channels, but with varying potencies. In
fact, amitriptyline is a very effective blocker, while imipramine
and other tricyclics are less effective. SSRIs were developed with
the idea of saving some of the adverse events of tricyclics by
avoiding any blockage of sodium channels. Interestingly, fluox-
etine, the only SSRI with some efficacy in migraine prevention,
appears to be the only compound in this group showing any in-
hibition on sodium channels. Finally, there is limited evidence
that tricyclics may also inhibit calcium channels. With regard
to β-blockers, propranolol not only inhibits sodium channels
(membrane-stabilizing effect), but does so more potently than
other β-blockers. Propranolol has also shown, in slices of cor-
tical synaptosomes, calcium-channel blocking properties. Flu-
narizine, and in a lesser degree, verapamil are the most effec-
tive “calcium channel blockers” for migraine prophylaxis. The
two drugs work nonspecifically on different calcium channels.
They also block voltage-regulated sodium channels, which may
distinguish them from other members of the class, such as ni-
modipine, nonefficacious for migraine prevention. The same
is true for classical antiepileptics: like verapamil and flunar-
izine, valproic acid might be more potent in migraine as com-
pared to other older anticonvulsants because it blocks both
sodium and calcium channels. Among the new antiepileptics,
topiramate is the only one with demonstrated efficacy in mi-
graine prevention. Topiramate’s ability to block both sodium
and calcium channels is well demonstrated. Gabapentin, an-
other “new” antiepileptic with low-grade efficacy in migraine
prevention, blocks calcium channels but not sodium channels.
The author sensibly concludes that, even though these drugs
could also work in migraine via multiple mechanisms, it seems
more than a coincidence that most of the commonly used drugs
in migraine prophylaxis act as blockers of sodium or calcium
channels, or both. It seems logical to propose that inhibition of
sodium channels would be especially useful in a migraine pro-
phylactic, as it is the ability to block both sodium and calcium
channels.
Clinical Science 121
The Role of Dopamine in a Model of Trigeminovascular
Nociception
Akerman S, Goadsby PJ
J Pharmacol Exp Therapeutics 2005;314:162–169
In animal studies, dopamine has been found to cause
vasodilation of cranial arteries at very low doses. Using
a model of intravital microscopy, the authors examined
the effect of dopamine receptor agonists on dural blood
vessel calibre and the effect of dopamine on trigemi-
novascular neurogenic dural vasodilation. Dopamine hy-
drochloride caused a significant vasoconstriction (p <
0.05) and increase in arterial blood pressure (p < 0.05) that
was reversed by an α2-adrenoceptor antagonist, yohim-
bine, rather than specific dopamine receptor antagonists.
The D1 receptor agonist caused vasoconstriction (p <
0.05) and blood pressure increase (p < 0.05), which were
reversed by yohimbine and therefore α2-adrenoceptor-
mediated. None of the specific dopamine receptor antag-
onists were able to attenuate neurogenic dural vasodila-
tion. Dopamine hydrochloride infusion (p < 0.05) and a D1
receptor agonist were able to attenuate vasodilation (p <
0.05), which maximal dilation returning after cessation of
the dopamine agonist infusion. The authors conclude that
this response may be due to the vasoconstrictor effects
of the α2-adrenoceptor and an action at the D1 receptor.
In addition, in the intravital model of trigeminal activa-
tion, it seems that dopamine receptors do not play a ma-
jor role and may not present an acute treatment option.
Their data, however, do not exclude a role for dopamine
receptor modulators in short- or long-term prevention.
COMMENTARY
D opaminergic mechanisms seem to be involved in mi-
graine pathophysiology, especially in its premonitory
phase, which is characterized by symptoms such as nausea, vom-
iting, drowsiness, tiredness, yawning, or mood changes. Given
that these changes may be a result of monoamine, and specifi-
cally dopaminergic neurotransmission, dopamine has been im-
plicated in migraine. Migraine patients seem to show hyper-
sensitivity to dopamine agonists and preliminary studies have
shown domperidone can prevent the occurrence of migraine if
taken during the premonitory phase. These observations have
led to a dopamine theory of migraine.
To examine whether dopamine is involved in the patho-
physiology of the headache phase of migraine, this work tests the
effect of dopamine on the dural vasculature. The authors make
use of the intravital microscopy model of trigeminovascular ac-
tivation, which has proven to be an excellent model in predict-
ing antimigraine efficacy. Dopamine receptors are present in the
trigeminovascular system. The infusion of dopamine attenuated
neurogenic dural vasodilation, possibly due to its vasoconstric-
tive effects. This attenuation was also seen with A68930, a D1
receptor agonist, but not with a D2 agonist and was partially
reversed by the D1 receptor antagonist SCH-23390. The data
obtained by Akerman and Goadsby support the fact that D1
receptors may be involved in the control of the central vascu-
lature on trigeminal nerve endings. All the effects of dopamine
and the D1 agonist were clearly antagonized by yohimbine,
an α2-adrenoceptor antagonist. The same authors, however,
have previously shown that the α2-adrenoceptor is not involved
in neurogenic vasodilation. Significant blood pressure changes
were caused by dopamine receptor antagonists, and these were
accompanied by a change in dural vessel diameter. Dopamine
acts as a precursor to the catecholamines noradrenaline and
adrenaline, which mediate vasoconstriction and blood pressure
increase via the α1- and α2-adrenoceptors. It is possible that the
effect of dopamine antagonists on blood pressure is a response
to inhibition of the precursor to adrenergic synthesis, namely
dopamine and that the dural blood vessel diameter changes are
a response to the change in blood pressure.
What would the theoretical implications of these findings
for migraine pathophysiology and treatment be? As only the D1
receptor was able to slightly tone down the activation of dural
blood vessels or trigeminal neurons, the role of dopamine and
D1 receptors in the acute phase of migraine seems small. There-
fore the involvement of dopamine and its receptors in migraine
may dominate other aspects of the attack, such as the initia-
tion, this providing a potential role for dopamine modulation
in prevention.
Noradrenergic Agonists and Antagonists Influence Mi-
gration of Cortical Spreading Depression in Rat—a Pos-
sible Mechanism of Migraine Prophylaxis and Preven-
tion of Postischemic Neuronal Damage
Richter F, Milulik O, Ebersberger A, Schaible HG
J Cereb Blood Flow Metab 2005;25:1225–1235
The authors analyze the effect of adrenergic agonists and
antagonist on cortical spreading depression (CSD). They
applied different drugs topically to an area of the exposed
cortex to anesthetized adult rats and observed the mi-
gration of CSD-related DC potential deflections across
the treated area. The adrenergic agonist norepinephrine
(1 mmol/L) and the α2-agonist clonidine (0.56 mmol/L)
blocked reversibly the migration of CSD. The β-blocker
122 Clinical Science
propranolol dose dependently diminished migration ve-
locity or even blocked CSD migration. The CSD blockade
by the α2-antagonist yohimbine (1.75 mmol/L) was be-
cause of its action on inhibitory 5-HT1A receptors. None
of the substances in the concentrations used had influ-
ence on regional cerebral blood flow or systemic arterial
blood pressure. The data suggest that the interference
of these compounds with CSD may contribute to their
beneficial therapeutic effect. The effect of β-receptor an-
tagonists in human migraine needs further exploration,
because these drugs also work in migraine without aura.
COMMENTARY
S urprisingly, both (α and β) adrenergic agonists and an-
tagonists have shown efficacy in migraine prevention. For
instance, tizanidine (an α2-adrenoceptor agonist), clonidine (an
α2-agonist) and mainly β-blockers have been reported as suc-
cessful preventatives. How these drugs, including β-blockers,
exert their antimigraine actions is not known. In this paper,
Ritcher et al. test the effect of adrenergic drugs on a CSD model
in rats. Even though the role of CSD in the pathophysiology
of migraine without aura is debatable, CSD epiphenomenon is
crucial in the pathophysiology of migraine aura.
The authors elegantly showed that CSD can be inhibited by
the topical application of norepinephrine, the α2-adrenoceptor
agonist clonidine, the α2-adrenergic antagonist yohimbine and
propranolol, a β-adrenergic receptor antagonist, which suggests
a role of both α2 and β-adrenoceptors in CSD propagation.
How can drugs with opposite actions in the same receptors have
identical final effects in CSD? The inhibition of CSD induced
by noradrenaline and clonidine is probably due to an action on
presynaptic neuronal α2-adrenoceptors. These receptors inhibit
adenylate-cyclase via G-proteins, which in turn inhibits calcium
currents necessary for the release of glutamate. Inhibition of glu-
tamate release could thus explain why α2-adrenoceptor agonists
reverse CSD. The authors of this paper show that the inhibi-
tion of α2-adrenoceptor antagonists on CSD is mainly because
of their agonistic action at the inhibitory 5-HT1A receptors,
which are known to regulate cAMP levels and glutamate release.
Finally, the inhibition of CSD propagation by propranolol is
very likely due to a reduction of glutamate release via an an-
tagonism of adenylate cyclase that activates P/Q-type calcium
channels. These results suggest that CSD inhibition can be a
novel explanation for the preventive effects of β-blockers and
also of adrenergic agonists. These findings open new approaches
in the preventive treatment of migraine with future drugs reg-
ulating presynaptic cAMP concentration and its consequence,
glutamate release.
Cortical Spreading Depression Activates and Upregu-
lates MMP-9
Gursoy-Ozdemir Y, Chu J, Matsuoka N, Bolay H,
Bermpohl D, Jin H, Wang X, Rosenberg GA, Lo EH,
Moskowitz MA
J Clin Invest 2004;113:1447–1455
In this study, Gursoy-Ozdemir et al. demonstrate that
CSD alters blood-brain barrier (BBB) permeability by
activating brain metalloproteases (MMPs). Beginning at
3–6 hours, MMP-9 levels increased within cortex ipsi-
lateral to the CSD, reaching a maximum at 24 hours
and persisting for at least 48 hours. Gelatinolytic activity
was detected earliest within the matrix of cortical blood
vessels and later within neurons and pia-arachnoid (>3
hours), particularly within piriform cortex; this activity was
suppressed by injection of the metalloprotease inhibitor
GM6001 or in vitro by the addition of a zinc chelator (1,10-
phenanthroline). At 3–24 hours, immunoreactive laminin,
endothelial barrier antigen, and zona occludens-1 dimin-
ished in the ipsilateral cortex, suggesting that CSD al-
tered proteins critical to the integrity of BBB. At 3 hours
after CSD, plasma protein leakage and brain edema de-
veloped contemporaneously. Albumin leakage was sup-
pressed by the administration of GM6001. Protein leak-
age was not detected in MMP-9-null mice, implicating
the MMP-9 isoform in barrier disruption. They conclude
that intense neuronal and glial depolarization initiates a
cascade that disrupts the BBB via an MMP-9-dependent
mechanism.
COMMENTARY
I n this excellent and extensive work, Gursoy-Ozdemir et al.
study the relationship between CSD and a metalloprotease
protein, MMP-9. MMPs are important for BBB breakdown
and for edema formation and leakage in several neurological
disorders, such as stroke, multiple sclerosis or Guillain-Barre.
MMPs are able to disrupt the BBB, which comprises endothe-
lial tight junctions, astrocytic end feet and basal lamina. The
basal lamina contains extracellular matrix collagen, laminin and
fibronectin, which are substrates for MMPs, namely MMP-2
and MMP-9.
These authors were able to detect MMP-9 activation at as
early as 15–30 minutes, coincidental with changes in vascular
permeability. This MMP-9 activation was long-lasting, still ob-
served 48 hours after CSD induction. At 3 hours most MMP-9
activity was localized within neurons. Even though the method
Clinical Science 123
of activation of MMP-9 needs to be studied further, oxygen
radicals, nitric oxide and proteases, such as stromelysin-1 and
plasmin, have been implicated in MMP activation. CSD, in ad-
dition, stimulates molecules that bind to the promoter region of
MMP-9, that is, c-fos, tumor necrosis factor-α and interleukin-
1β. MMP activation cleaves a broad range of substrates, includ-
ing components of basal lamina, like laminin, type IV collagen,
and brain ECM components such as elastin, fibronectin, tenas-
tin, and collagen. Gursoy-Ozdemir et al.’s findings open a vari-
ety of new potential targets for the preventive treatment of mi-
graine. One obvious question is whether the MMP-9 increase
is a specific consequence of CSD (and not an epiphenomenon)
causing BBB dysfunction. By using several clever experimental
approaches, such as an MMP-9-null mice model, the authors
were able to demonstrate that BBB breakdown develops as a
true consequence of MMP-9 activation. It is clear that drugs
able to prevent MMP-9 upregulation are one of the future con-
ceptually new promises to test for the preventive treatment of
migraine.
by Julio Pascual, M.D., Ph.D.
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