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Current Neuropharmacology
ISSN: 1570-159X
Current Neuropharmacology
Volume 6, Number 1, March 2008
Contents
GABAA Receptors in Normal Development and Seizures: Friends
or Foes? Pp.1-20
A.S. Galanopoulou
[Abstract]
ThermoTRP Channels in Nociceptors: Taking a Lead
from Capsaicin Receptor TRPV1 Pp. 21-38
S. Mandadi and B.D. Roufogalis
[Abstract]
Alcohol Related Changes in Regulation of NMDA
Receptor Functions Pp. 39-54
J. Nagy
[Abstract]
Pharmacodynamics of Memantine: An Update
Pp. 55-78
G. Rammes, W. Danysz and C.G. Parsons
[Abstract]
Herbal Compounds and Toxins Modulating TRP Channels
Pp. 79-96
J. Vriens, B. Nilius and R. Vennekens
[Abstract]
Abstracts
[Back to top]
GABAA Receptors in Normal Development and Seizures:
Friends or Foes?
A.S. Galanopoulou
GABAA receptors have
an age-adapted function in the brain. During early development,
they mediate excitatory effects resulting in activation of
calcium sensitive signaling processes that are important for
the differentiation of the brain. In more mature stages of
development and in adults, GABAA
receptors transmit inhibitory signals. The maturation of GABAA
signaling follows sex-specific patterns, which appear to also
be important for the sexual differentiation of the brain.
The inhibitory effects of GABAA
receptor activation have been widely exploited in the treatment
of conditions where neuronal silencing is necessary. For instance,
drugs that target GABAA receptors
are the mainstay of treatment of seizures. Recent evidence
suggests however that the physiology and function of GABAA
receptors changes in the brain of a subject that has epilepsy
or status epilepticus.
This review will summarize the physiology of and the developmental
factors regulating the signaling and function of GABAA
receptors; how these may change in the brain that has experienced
prior seizures; what are the implications for the age and
sex specific treatment of seizures and status epilepticus.
Finally, the implications of these changes for the treatment
of certain forms of medically refractory epilepsies and status
epilepticus will be discussed.
[Back to top]
ThermoTRP Channels in Nociceptors: Taking a Lead from Capsaicin
Receptor TRPV1
S. Mandadi and B.D. Roufogalis
Nociceptors with peripheral and central projections express
temperature sensitive transient receptor potential (TRP) ion
channels, also called thermoTRP’s. Chemosensitivity
of thermoTRP’s to certain natural compounds eliciting
pain or exhibiting thermal properties has proven to be a good
tool in characterizing these receptors. Capsaicin, a pungent
chemical in hot peppers, has assisted in the cloning of the
first thermoTRP, TRPV1. This discovery initiated the search
for other receptors encoding the response to a wide range
of temperatures encountered by the body. Of these, TRPV1 and
TRPV2 encode unique modalities of thermal pain when exposed
to noxious heat. The ability of TRPA1 to encode noxious cold
is presently being debated. The role of TRPV1 in peripheral
inflammatory pain and central sensitization during chronic
pain is well known. In addition to endogenous agonists, a
wide variety of chemical agonists and antagonists have been
discovered to activate and inhibit TRPV1. Efforts are underway
to determine conditions under which agonist-mediated desensitization
of TRPV1 or inhibition by antagonists can produce analgesia.
Also, identification of specific second messenger molecules
that regulate phosphorylation of TRPV1 has been the focus
of intense research, to exploit a broader approach to pain
treatment. The search for a role of TRPV2 in pain remains
dormant due to the lack of suitable experimental models. However,
progress into TRPA1’s role in pain has received much
attention recently. Another thermoTRP, TRPM8, encoding for
the cool sensation and also expressed in nociceptors, has
recently been shown to reduce pain via a central
mechanism, thus opening a novel strategy for achieving analgesia.
The role of other thermoTRP’s (TRPV3 and TRPV4) encoding
for detection of warm temperatures and expressed in nociceptors
cannot be excluded. This review will discuss current knowledge
on the role of nociceptor thermoTRPs in pain and therapy and
describes the activator and inhibitor molecules known to interact
with them and modulate their activity.
[Back to top]
Alcohol Related Changes in Regulation of NMDA Receptor Functions
J. Nagy
Long-term alcohol exposure may lead to development of
alcohol dependence in consequence of altered neurotransmitter
functions. Accumulating evidence suggests that the N-methyl-D-aspartate
(NMDA) type of glutamate receptors is a particularly important
site of ethanol’s action. Several studies showed that
ethanol potently inhibits NMDA receptors (NMDARs) and prolonged
ethanol exposition leads to a compensatory “up-regulation”
of NMDAR mediated functions. Therefore, alterations in NMDAR
function are supposed to contribute to the development of
ethanol tolerance, dependence as well as to the acute and
late signs of ethanol withdrawal.
A number of publications report alterations in the expression
and phosphorylation states of NMDAR subunits, in their interaction
with scaffolding proteins or other receptors in consequence
of chronic ethanol treatment. Our knowledge on the regulatory
processes, which modulate NMDAR functions including factors
altering transcription, protein expression and post-translational
modifications of NMDAR subunits, as well as those influencing
their interactions with different regulatory proteins or other
downstream signaling elements are incessantly increasing.
The aim of this review is to summarize the complex chain of
events supposedly playing a role in the up-regulation of NMDAR
functions in consequence of chronic ethanol exposure.
[Back to top]
Pharmacodynamics of Memantine: An Update
G. Rammes, W. Danysz and C.G. Parsons
Memantine received marketing authorization from the European
Agency for the Evaluation of Medicinal Products (EMEA) for
the treatment of moderately severe to severe Alzheimer´s
disease (AD) in Europe on 17th
May 2002 and shortly thereafter was also approved by the FDA
for use in the same indication in the USA. Memantine is a
moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA)
receptor antagonist with strong voltage-dependency and fast
kinetics. Due to this mechanism of action (MOA), there is
a wealth of other possible therapeutic indications for memantine
and numerous preclinical data in animal models support this
assumption. This review is intended to provide an update on
preclinical studies on the pharmacodynamics of memantine,
with an additional focus on animal models of diseases aside
from the approved indication. For most studies prior to 1999,
the reader is referred to a previous review [196].
In general, since 1999, considerable additional preclinical
evidence has accumulated supporting the use of memantine in
AD (both symptomatic and neuroprotective). In addition, there
has been further confirmation of the MOA of memantine as an
uncompetitive NMDA receptor antagonist and essentially no
data contradicting our understanding of the benign side effect
profile of memantine.
[Back to top]
Herbal Compounds and Toxins Modulating TRP Channels
J. Vriens, B. Nilius and R. Vennekens
Although the benefits are sometimes obvious, traditional
or herbal medicine is regarded with skepticism, because the
mechanism through which plant compounds exert their powers
are largely elusive. Recent studies have shown however that
many of these plant compounds interact with specific ion channels
and thereby modulate the sensing mechanism of the human body.
Especially members of the Transient Receptor Potential (TRP)
channels have drawn large attention lately as the receptors
for plant-derived compounds such as capsaicin and menthol.
TRP channels constitute a large and diverse family of channel
proteins that can serve as versatile sensors that allow individual
cells and entire organisms to detect changes in their environment.
For this family, a striking number of empirical views have
turned into mechanism-based actions of natural compounds.
In this review we will give an overview of herbal compounds
and toxins, which modulate TRP channels.
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