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CNS &
Neurological Disorders -Drug Targets
ISSN: 1871-5273
CNS & Neurological Disorders
- Drug Targets
Volume 6, Number 4, August 2007
Contents
Migraine
Guest Editor: Dimos D. Mitsikostas
Editorial Pp. 234
5HT1F- and 5HT7-Receptor Agonists for the Treatment
of Migraines Pp. 235-237
Reto M. Agosti
[Abstract]
Pathophysiology of Tension-Type Headache: Potential
Drug Targets Pp. 238-239
Messoud Ashina
[Abstract]
CGRP-Receptor Antagonism in Migraine Treatment
Pp. 240-246
Lars Edvinsson and Kenneth Ahrend Petersen
[Abstract]
GABAergic Drugs for the Treatment of Migraine
Pp. 247-250
Anja Puppe and Volker Limmroth
[Abstract]
The Role of Glutamate and its Receptors in Migraine
Pp. 251-257
Michail Vikelis and Dimos D. Mitsikostas
[Abstract]
Nitric Oxide in Migraine Pp. 258-264
L. Neeb and U. Reuter
[Abstract]
General Articles
Novel Targets for Drugs in Schizophrenia Pp. 265-272
J.M. Stone and L.S. Pilowsky
[Abstract]
Chinese Herbs and Herbal Extracts for Neuroprotection
of Dopaminergic Neurons and Potential Therapeutic Treatment
of Parkinson’s Disease Pp. 273-281
Liang-Wei Chen, Yan-Qin Wang, Li-Chun Wei, Mei Shi and
Ying Shing Chan
[Abstract]
Therapeutic Potential of 3-Hydroxy-3-Methylglutaryl
Coenzyme A Reductase Inhibitors for the Treatment of Retinal
and Eye Diseases Pp. 282-287
Christian Schmeer, Alexandra Kretz and Stefan Isenmann
[Abstract]
Extrasynaptic GABA and Glutamate Receptors in Epilepsy
Pp. 288-300
Germán Sierra-Paredes and Germán Sierra-Marcuño
[Abstract]
Abstracts
[Back to top]
Editorial
Although less frequent among men, migraine affects almost
one third of reproductive women, transforming this disorder
into a significant public health problem with enormous socioeconomic
impact. The last decade however, has seen a great improvement
within both the scientific and the clinical fields: the 1988
international classification of headache disorders followed
by the release of sumatriptan into the market opened novel
avenues. For the first time, clear diagnostic criteria were
established, and for the first time a drug targeting migraine,
became available. After sumatriptan several other agonists
at 5-HT1B and 5-HT1D receptors have been developed constituting
a new antimigraine drug class, the so-called triptans. Limitations
in their use, mainly due to vascular contraindications keep
the field, searching for new potential targets that modulate
pain neurotransmission exclusively within the trigeminovascular
system. The recently cloned serotonin receptor subtypes 5-HT1F
and the 5-HT7 have been shown to exert little or no vasoactive
properties, and therefore are considered potential targets
for antimigraine drugs with an improved safety profile. Apart
from serotonin, other trigeminal and brainstem neurotransmission
systems have been investigated. CGRP literature is probably
the largest, following by reports implicating the glutamate
receptors. CGRP receptor antagonists showed efficacy not only
in animal models of migraine but in clinical trials as well.
Adenosine and NO pathways are more recent targets. In addition
to brain neurotransmission, modulation of cortical spreading
phenomenon may influence migraine headache. Neuroimaging and
genetic data shows promising results. Drugs with already proven
prophylactic efficacy in migraine after well designed clinical
trials analyses have also been found to modulate the cortical
spreading depression in laboratory animals, suggesting that
inhibition of cortical spreading depression phenomenon is
an important pathway to control the migraine frequency and
severity.
Scientists working within the migraine field report in this
issue the most recent achievements in their field. Undoubtedly,
cephalic pain and migraine in particular, will be less resistant
in the near future and patients suffering from these disorders
will have the opportunity to get their lost quality of life
back.
Dimos D. Mitsikostas
Athens Naval Hospital
Neurology Department
77ª Vas. Sofias Avenue
11521 Athens, Greece
E-mail: dmitsikostas@ath.forthnet.gr
[Back to top]
5HT1F- and 5HT7-Receptor Agonists for the Treatment
of Migraines
Reto M. Agosti
Serotonin was the first neurotransmitter believed to be involved
in cephalic pain transfer forward to the cortex, but the precise
mechanism was confirmed only after sumatriptan, a 5-HT1B/1D
high affinity agonist, was introduced in the acute treatment
of migraine. Although very efficient for migraine relief,
activation of 5-HT1B receptor
may also cause vasoconstriction outside brain, within the
heart arteries for example. Unlike 5-HT1B,
the 5-HT1D receptor is not
located in vascular tissues but exclusively within neuronal,
but high affinity agonists for 5-HT1D
failed to prove clinical significance in randomized trials.
The recent clone of 5-HT1F
receptor together with data showing that sumatriptan exerts
high affinity for this receptor subtype generated high expectations.
Potent agonists for 5-HT1F
receptors were effective in animal models for migraine and
later clinical trials showed efficacy even in humans, introducing
the first line future anti-migraine drugs. Apart from 5-HT1F,
another new cloned 5-HT subtype receptor, the 5-HT7
also attracts attention. Recently developed and clinically
tested selective 5HT7 antagonists
SB-269970-A and SB-656104-A suggest that the receptor may
play a role in other CNS disorders including anxiety and cognitive
disturbances, suggesting a potential role for the migraine
prophylaxis. These data and speculations are discussed in
details in this paper with special references.
[Back to top]
Pathophysiology of Tension-Type Headache: Potential
Drug Targets
Messoud Ashina
The pathophysiology of tension-type headache is still far
from clear, although recent advances in basic and clinical
research have increased our knowledge about mechanisms underlying
this disorder. Experimental studies suggest that increased
excitability of the CNS generated by repetitive and sustained
pericranial myofascial input may be responsible for transformation
of episodic tension-type headache into chronic form. Future
studies should focus on the identification of the source of
peripheral nociception in patients with tension-type headache
and the development of more effective and specific treatment
modalities.
[Back to top]
CGRP-Receptor Antagonism in Migraine Treatment
Lars Edvinsson and Kenneth Ahrend Petersen
Primary headaches are among the most prevalent neurological
disorders, afflicting up to 16% of the adult population. Associated
pain originates from intracranial blood vessels that are innervated
by sensory nerves storing several neurotransmitters. In primary
headaches, there is a clear association between the headache
and the release of calcitonin gene-related peptide (CGRP)
but not with other neuronal messengers. The specific purpose
of this review is to describe CGRP in the human cranial circulation
and to elucidate a possible role for a specific antagonist
in the treatment of primary headaches. Acute treatment by
administration of a triptan (5-HT1B/1D
agonist) results in alleviation of the headache and normalization
of the elevated CGRP level. The mechanism of action of triptans
involves vasoconstriction of intracranial vessels and a presynaptic
inhibitory effect of the trigeminal sensory nerves. The central
role of CGRP in migraine and cluster headache pathophysiology
has led to the search for small molecule CGRP antagonists,
which would predictably have less cardiovascular side effects
as compared to the triptans. The initial pharmacological profile
of such a group of compounds has recently been disclosed.
These compounds have high selectivity for human CGRP receptors
and are reported to be efficacious in the relief of acute
attacks of migraine.
[Back to top]
GABAergic Drugs for the Treatment of Migraine
Anja Puppe and Volker Limmroth
Within the last decades significant progress has been made
in the understanding of the underlying pathophysiological
mechanisms of migraine. There is a general agreement now that
migraine is not only a vascular phenomenon but also a genetically
determined heterogenic ion-channelopathy resulting in cortical-spreading-depression-like
events, the temporary impairment of antinociceptive structures
of the brainstem and the activation of the trigeminal-vascular
system. The development and use of drugs targeting ion-channels
and subsequently reducing cortical excitability appears as
a promising avenue for both the acute treatment of migraine
and migraine prevention. This review summarizes the current
knowledge and evidence for GABAergic drugs in the treatment
of migraine.
[Back to top]
The Role of Glutamate and its Receptors in Migraine
Michail Vikelis and Dimos D. Mitsikostas
Glutamate (Glu) is the principal excitatory neurotransmitter
in the central nervous system. Its receptors are classified
into ionotropic receptors, which are ion channels and include
NMDA, AMPA and kainate receptors, named after the agonists
that selectively bind to them, and metabotropic receptors,
which are G-protein coupled receptors. The trigeminal system
is considered to play a key role in migraine pathophysiology,
trafficking pain signals from the head and face to the trigeminal
nucleus caudalis. The role of glutamate in the pathophysiology
of migraine is implicated by data from animal and human studies.
Animal studies include experiments of cortical spreading depression,
studies of c-fos protein expression in trigeminal nucleus
caudalis, studies of plasma protein extravasation and electrophysiological
studies. Human studies investigating the role of Glu in migraine
pathogenesis measured the levels of Glu in plasma, platelets
and cerebrospinal fluid, studied its effect on migraine symptoms
and examined the effect of Glu in modulating sensitization.
Findings from both the animal and the human studies suggest
a link between glutamate and migraine and further suggest
that glutamate plays a key role in migraine mechanisms. In
the future, efforts should be made to further investigate
the role of glutamate in migraine pathogenesis and, subsequently,
in migraine treatment.
[Back to top]
Nitric Oxide in Migraine
L. Neeb and U. Reuter
The potent vasodilatator and messenger molecule nitric oxide
(NO) is believed to play a key role in migraine pathogenesis.
NO donors such as glyceryl trinitrate (GTN) can cause headache.
Infusion of GTN leads to a migraine attack in migraineurs
with a latency of 4 to 6 hours. In this review we focus in
the role of nitric oxide and the transcription factor nuclear
factor-κB
(NF-κB)
in migraine pathophysiology in humans and animal models. NO
is involved in pain transmission, hyperalgesia, chronic pain,
inflammation and central sensitization mostly in a cyclic
guanosinemono-phosphate (cGMP) dependent way. We aim to illustrate
how NO is implicated in the induction of a migraine attack
in migraineurs and how experimental animal models may help
to elucidate the mechanisms of the human GTN response. Because
of the role of NO in migraine we try to assess if and how
the action of preventative migraine drugs involves the NO
pathways. More knowledge about the involvement of NO in the
genesis of migraine headache may also provide possible future
therapeutic targets for acute migraine therapy.
[Back to top]
Novel Targets for Drugs in Schizophrenia
J.M. Stone and L.S. Pilowsky
Since the discovery of the first antipsychotic drug, chlorpromazine,
in the early 1950s, all effective antipsychotic drugs have
been found to share the common property of dopamine D2 receptor
antagonism. There has been some suggestion that simple D2
receptor antagonism may not confer optimal antipsychotic efficacy.
Currently available antipsychotic drugs leave many symptoms
of the illness untreated and cause unacceptable side effects.
Recent research in schizophrenia suggests a number of potential
new non-D2 targets for pharmacotherapy including glutamate,
acetylcholine and serotonin neurotransmitter systems. This
review summarises the main neurochemical theories of schizophrenia,
and, in the light of these, examines possible therapeutic
targets for new antipsychotic drugs.
[Back to top]
Chinese Herbs and Herbal Extracts for Neuroprotection
of Dopaminergic Neurons and Potential Therapeutic Treatment
of Parkinson’s Disease
Liang-Wei Chen, Yan-Qin Wang, Li-Chun Wei, Mei Shi and
Ying Shing Chan
Parkinson’s disease (PD) is a common and debilitating
degenerative disease resulting from massive degenerative loss
of dopamine neurons, particularly in the substantia nigra.
The most classic therapy for PD is levodopa administration,
but the efficacy of levodopa treatment declines as the disease
progresses. The neuroprotective strategies to rescue nigral
dopamine neurons from progressive death are currently being
explored, and among them, the Chinese herbs and herbal extracts
have shown potential clinical benefit in attenuating the progression
of PD in human beings. Growing studies have indicated that
a range of Chinese herbs or herbal extracts such as green
tea polyphenols or catechins, panax ginseng and ginsenoside,
ginkgo biloba and EGb 761, polygonum, triptolide from tripterygium
wilfordii hook, polysaccharides from the flowers of nerium
indicum, oil from ganoderma lucidum spores, huperzine and
stepholidine are able to attenuate degeneration of dopamine
neurons and sympotoms caused by the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) and 6-hydroxydopamine (6-OHDA) in vitro and
in vivo conditions. In addition, accumulating data
have suggested that Chinese herbs or herbal extracts may promote
neuronal survival and neurite growth, and facilitate functional
recovery of brain injures by invoking distinct mechanisms
that are related to their neuroprotective roles as the antioxidants,
dopamine transporter inhibitor, monoamine oxidase inhibitor,
free radical scavengers, chelators of harmful metal ions,
modulating cell survival genes and signaling, anti-apoptosis
activity, and even improving brain blood circulation. New
pharmaceutical strategies against PD will hopefully be discovered
by understanding the various active entities and valuable
combinations that contribute to the biological effects of
Chinese herbs and herbal extracts.
[Back to top]
Therapeutic Potential of 3-Hydroxy-3-Methylglutaryl
Coenzyme A Reductase Inhibitors for the Treatment of Retinal
and Eye Diseases
Christian Schmeer, Alexandra Kretz and Stefan Isenmann
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
inhibitors, generically termed statins, are widely prescribed
for their cholesterol-lowering properties. In addition to
lipid-lowering properties, statins have pleiotropic effects
including anti-inflammatory, anti-apoptotic, and antiproliferative
effects. Recently, data from experimental and observational
studies have indicated that statins could also become a treatment
option for diseases of the central nervous system (CNS). Many
neurodegenerative diseases particularly affect the retina
and other ocular structures and are the cause for blindness.
This review, focused on recent clinical and experimental data,
discusses known and putative mechanisms of statin actions
underlying neuroprotective effects in relevant retinal and
eye diseases. In addition, it presents evidence for the role
of heat shock proteins (Hsps) as target of statin-mediated
neuroprotective effects in ocular diseases.
[Back to top]
Extrasynaptic GABA and Glutamate Receptors in Epilepsy
Germán Sierra-Paredes and Germán Sierra-Marcuño
Epilepsy is a neurological disorder in which normal brain
function is disrupted as a consequence of intensive and synchronous
burst activity from neuron assemblies. Epilepsies result from
long-lasting plastic changes in the brain affecting neurotransmitter
release, the properties of receptors and channels, synaptic
reorganization and astrocyte activity. There is considerable
evidence for alterations in glutamatergic and GABAergic synaptic
transmission in the origin of the paroxysmal depolarization
shifts that initiate epileptic activity. However, recent studies
on non-synaptic transmission, re-ceptor mobility and glia-neuron
signaling pathways suggest that extrasynaptic GABA and glutamate
receptors may play an important role in seizure initiation,
maintenance and arrest. Extracellular aminoacids such as glutamate,
aspartate, gly-cine and GABA seem to communicate neurons and
glial cells acting primarily on extrasynaptic receptors. Synaptic
and extrasynaptic glutamate and GABA receptors have been show
to play different roles in neuronal excitability. NMDA and
GABAA receptors expressed in a single neuron can be differentially
regulated based on subcellular localization, and it has been
proposed that distinct regulation of synaptic versus extrasynaptic
receptors provides a mechanism for receptor adaptation in
response to a variety of stimuli. Furthermore, glutamate and
GABA receptors are highly mobile, and the number and composition
of extrasynaptic receptors can be modulated by several factors.
This review addresses recent advances in our understanding
of the role of extrasynaptic receptors in epilepsy, suggesting
that extrasynaptic receptors and their mechanisms of regulation
are expected to be important pharmacological targets.
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