Neurol Sci (2008) 29:S123S126
DOI 10.1007/s10072-008-0902-9
C U R R E N T R E A L I T Y I N H E A D A C H E T R E AT M E N T S
Central mechanism of action of antimigraine prophylactic drugs
Gerardo Casucci Veronica Villani Fabio Frediani
Springer-Verlag 2008
Abstract The pathogenesis of migraine is obscure. A
hyperexcitable brain state has been postulated. Cortical
spreading depression (CSD) is the most suggestive argu-
ment for the brain hyperexcitability. It has been showed
that valproate, topiramate, amitriptyline and propranolol
inhibit CSD in rats, which suggests that most preventative
treatments of migraine act by normalising neuronal firing
and increasing a genetically lowered and environmentally
modified threshold for neuronal discharge. It has also
been suggested that some antimigraine prophylactic drugs
(i.e., amitriptyline, candesartan and magnesium) may act
by restoring central nociceptive dysmodulation.
Keywords Migraine Cortical spreading depression
Hyperexcitability Central action Prophylactic drugs
G. Casucci ()
Casa di Cura S. Francesco
Viale Europa 21, 82036 Telese Terme (BN), Italy
e-mail: gerardocasucci@tin.it
V. Villani
Neurology Unit
S. Andrea Hospital
La Sapienza University, Rome, Italy
F. Frediani
Neurological Department and Headache Center
Policlinico S. Pietro
Ponte San Pietro (BG), Italy
Introduction
The exact pathogenesis of migraine remains to be deter-
mined. Welch et al. suggested in 1990 that multiple causal
factors for migraine converge onto a common hyperex-
citable brain state, which constitutes the fundamental sus-
ceptibility to migraine attacks [1]. Various causes for
hyperexcitability of the migrainous brain have been sug-
gested. These include low concentrations of glutamate,
mitochondrial abnormalities, dysfunctions related to
nitric oxide or a calcium channelopathy [2, 3]. Cortical
spreading depression (CSD) is a spontaneous neuronal
depolarisation moving slowly (3 mm/min) on the occipi-
tal cortex, which has a clinical counterpart in the scintil-
lating contour (positive scotoma). Neurophysiological
and biochemical studies support the hypothesis that neu-
ronal hyperexcitability is the predisposing factor that
causes the initial cortical event. CSD (or a similar depo-
larising event) activates brainstem and gives rise to depo-
larisation of ascending and descending pathways, peri-
meningeal vasodilatation and neurogenic inflammation
[4, 5]. Therefore, in migraine the excitatory events are
believed to be proximal, whereas the neurovascular
events that lead to pain production are distal [6].
Repeated episodes of hyperexcitability could parallel, or
cause, dysmodulation of nociception pathways, with a
resultant chronic state, potential disease progression and
the refractoriness to therapy that some patients experi-
ence [4]. Central sensitisation, associated with abnormal
neuronal excitability in the trigeminal nucleus caudalis,
may also play a critical role in migraine pathogenesis,
especially in the latter stages of an acute attack, and in the
development of chronic forms of the disorder [7, 8].
Nevertheless, progressive damage to the brains most
powerful antinociceptive centre, the periaqueductal grey
matter, may also explain some aspects of central sensiti-
sation or change in phenotypic expression of episodic to
S124
chronic headache [9]. Recently, Ayata et al. demonstrat-
ed that established preventative drugs, such as valproate,
topiramate (TPM), amitriptyline and propranol, inhibit
CSD in rats, which argues in favour of the hypothesis that
migraine preventive drugs suppress the mechanism of
CSD, the main neurobiological marker for the brain
hyperexcitability [10]. Therefore, most preventive treat-
ments are thought to act, at least in part, by normalising
neuronal firing and increasing a genetically lowered and
environmentally modified threshold for neuronal dis-
charge, by blocking excitatory glutamate-mediated or
inhibiting gamma-aminobutyric acid (GABA)-mediated
central activities [11, 12]. It has also been suggested that
some antimigraine prophylactic drugs (amitriptyline,
candesartan and magnesium) may act by restoring central
nociceptive dysmodulation [13].
Neuromodulators
Numerous neuromodulators (antiepilectic drugs) have
demonstrated efficacy in migraine prophylaxis.
Neuromodulators exhibit multiple mechanisms that may
contribute to reduce the neuronal hyperexcitability in
various areas of the brain, both in epilepsy and migraine.
TPM and valproic acid (VPA) suppress CSD frequency
by 40%80% and longer treatment durations produce
stronger suppression. Direct and indirect effects on inhi-
bition of glutamate release and on blocking NMDA
receptors may be relevant for modulating this migraine
susceptibility [10].
TPM is used in the treatment of partial-onset and pri-
mary generalised tonicclonic seizures [14]. TPM has
emerged recently as a treatment for migraine and is now
approved for migraine prevention in several countries.
Large, multicentre, randomised, double-blind, placebo-
controlled trials have demonstrated the efficacy of TPM
in migraine prophylaxis in adults [1517]. A recent study
showed a significant improvement in health-related qual-
ity of life in a migraine population [18]. Recent studies
showed a significant effect also in paediatric migraine
[19, 20]. Adverse central side effects, generally mild,
include memory impairment, emotional lability and
dysarthria. TPM has multiple mechanisms of action,
including: (1) state-dependent blockade of sodium chan-
nels, (2) enhancement of GABAa receptor-mediated inhi-
bition, (3) antagonism of glutamate at -amino-3-
hydroxy-5-methylisoxazole-4-propionic acid/kainite
(AMPA/kainite) receptors, (4) inhibition of high-voltage-
activated (L-type) calcium channels and (5) weak inhibi-
tion of some isozymes of carbonic anhydrase [21].
VPA is widely used for the treatment of partial and
generalised seizures [22]. The efficacy of VPA in
migraine prevention has been shown in several double-
blind, randomised, placebo-controlled studies [2326].
Its more frequent central side effects are tremor, somno-
Neurol Sci (2008) 29:S123S126
lence, dizziness and headache. VPA increases GABA lev-
els in the brain and potentiates GABA-mediated respons-
es. One possibly important action of VPA is the blockade
of the degradation of GABA by GABA transaminase,
thereby increasing GABA concentrations in both axon
and in glial cells. VPA has been found to block voltage-
dependent sodium ion channels, thereby modulating
release of excitatory amino acids, and to block low
threshold T-type calcium ion channels [22].
Various studies suggest that lamotrigine (LTG) consti-
tutes a specific prophylactic treatment of migraine with
aura [2730]. LTG acts by blocking voltage-sensitive sodi-
um channels, leading to an inhibition of the neural release
of glutamate [31, 32]. Therefore, if high glutamate levels
were responsible for CSD and the clinical symptoms of
migraine aura, LTG might suppress this phenomenon and
thus prevent aura development. LTG also attenuates calci-
um influx via its effect on high-voltage-activated calcium
channels and prevents calcium overload in neurons. The
effective suppression of aura symptoms of LTG may be due
to the potent presynaptic and postsynaptic inhibition of glu-
tamate, indicating that LTG would act as a non-competitive
NMDA antagonist [33].
Amitriptyline
Serotonin (5-HT) and norepinephrine (NE) signalling has
been part of some models of migraine pathophysiology.
Amitriptyline is the prototypical tricyclic antidepressant
that has well demonstrated efficacy in pain and in
migraine [4, 34]. It has mixed serotoninergic and nora-
drenergic reuptake inhibitor (SNRI) properties, which
enhances activity of diffuse noxious inhibitory control.
Amitriptyline has other pharmacological mechanisms.
These include: adenosine-A1 agonism, which would
enhance descending modulation of rostro-ventromedial
nucleus (RVM) neurons; increasing GABA-mediated
inhibition by positively modulating GABAa receptor and
inhibiting the GABA transporter types 1 and 3 (GAT-1
and GAT-3). Recently, it has been shown that amitripty-
line inhibits CSD in rats [10].
Propranolol
Evidence has consistently shown the efficacy of propra-
nolol for the prophylaxis of migraine [35]. Its more fre-
quent central side effects are drowsiness, sleep disorders,
depression and memory disturbance. Its mechanism of
action is not certain. In the rat brainstem, delayed reduc-
tion of the locus coeruleus neuron firing rate has been
demonstrated after propanolol administration [36]. The
central action of propranolol is probably mediated by
inhibition of central -receptors interfering with the vig-
ilance-enhancing adrenergic pathway, interaction with
Neurol Sci (2008) 29:S123S126
5-HT receptors and cross-modulation of the serotoniner-
gic system [37]. Propranolol inhibits CSD in rat by
blocking glutamate release [38].
Flunarizine
Flunarizine (FZ) has proven efficacy in the prevention of
migraine and is commonly used in countries where it is
available. A recent review about the pharmacological
treatment of migraine headache in children and adoles-
cents by the American Academic of Neurology found that,
from 12 anti-migraine preventive drugs evaluated, FZ is
probably the only effective agent, but it is not available in
the USA [39]. It has also been reported that FZ could be a
useful add-on treatment in therapy-resistant forms of
epilepsy [40, 41]. It has been suggested that the FZ effect
on the central nervous system is due to a stabilising action
on the membrane electrical activity of nerve cells close to
firing, the so-called burst neurons. The primary pharmaco-
logical mechanism of FZ on burst potentials has been
attributed to the blockage of calcium/and or sodium ion
channels. Studies showed that the FZ reduces the ampli-
tude of the fast phases of vestibular nystagmus in healthy
volunteers and hypothesised that FZ acts on the vestibular
nystagmus of normal subjects by suppression of reticular
burst neurons or their connections. Because the appear-
ance of abnormal burst activities has been linked to the
pathophysiology of migraine and epilepsy, Casucci et al.
suggested that the therapeutical effect of FZ on both con-
ditions may be due to a stabilising action on abnormal
burst activities of the brainstem [42].
Pizotifen
There is consistent evidence to support pizotifens effica-
cy in migraine prevention. Drowsiness is the most fre-
quent central side effect [43, 44]. Its mechanism of action
is not certain. It has potent 5-HT2 activity but the selec-
tive 5-HT2 receptor antagonist ketanserin (the principal
agent used to identify 5-HT2 receptor-mediated actions)
seems to be ineffective in migraine. These agents have
additional antagonistic effects at histamine H1, mus-
carinic cholinergic, -1-adrenergic, -2-adrenergic and
dopamine receptors, but drugs which are selective for
these non-5-HT receptors appear to be of no benefit in
migraine. An action of pizotifen on 5-HT2 receptors has
also been postulated in migraine [45].
Candesartan
Candesartan is an angiotensin II type-1 inhibitor that has
demonstrated efficacy in migraine prophylaxis. The
S125
mechanism of action in migraine prevention is poorly
understood. It presynaptically inhibits GABA release,
which theoretically would enhance excitation. However,
the co-localisation of AT1, glutamate and GABA recep-
tors on medullary rostral ventromedial neurons suggests
a nociceptive modulatory role [46].
Magnesium (Mg)
The possible mechanism of high-dose oral Mg in migraine
prevention remains elusive. Open-label and clinical trials
have evaluated the role of high-dose oral Mg (up to
600 mg) in migraine prevention, and the results have been
conflicting. Mg has a stabilising role on the sodium potas-
sium pump. Dysfunction of the sodium/potassium pump
may have relevance in terms of increased glutamate in the
synaptic cleft. Low levels of magnesium may also be
responsible for release of NMDA receptors, which may
lead to spontaneous discharge and CSD [47, 48].
Acetazolamide
Acetazolamide response has been described in familial
hemiplegic migraine with associated ataxia and in
migraineurs without cerebellar symptoms [49, 50]. It is
interesting that TPM shares with acetazolamide the prop-
erty of carbonic anhydrase inhibition [51]. Also, it was
recently reported to suppress susceptibility to CSD in
experimental animals [10].
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