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Current
Neuropharmacology
ISSN: 1570-159X
Current Neuropharmacology
Volume 3, Number 3, July 2005
Contents
Flavonoids and the Brain: Evidences and Putative Mechanisms
for a Protective Capacity Pp.193
F. Dajas, F. Arredondo, C. Echeverry, M. Ferreira, A.
Morquio and F. Rivera
[Abstract]
High-Throughput Screening of Neuronal Cl- Channels:
Why and How? Pp.207
J.W. Lynch
[Abstract]
Pharmacological Characterisation and Modulation of
Neuroplasticity in Humans Pp.217
M.A. Nitsche, D. Liebetanz, W. Paulus and F. Tergau
[Abstract]
The Key Role of Medullary 5-HT3 Receptors
in the
Serotonin-Mediated Neural Control of Cardiovascular Function
Pp.231
C. Sévoz-Couche, B.H. Machado, M. Hamon and R.
Laguzzi
[Abstract]
Iptakalim Hydrochloride and Neuronal Protection Pp.249
J. Wu, M. Wakui, H. Wang and G. Hu
[Abstract]
Abstracts
[Back to top]
Flavonoids and the Brain: Evidences and Putative Mechanisms
for a Protective Capacity
F. Dajas, F. Arredondo, C. Echeverry, M. Ferreira, A.
Morquio and F. Rivera
The origin and/or the evolution of brain diseases of high
morbidity and mortality such as cerebrovascular diseases,
Alzheimer’s Dementia or Parkinson´s disease have
been linked to oxidative stress. Epidemiological or clinical
descriptive studies have shown that diets with predominant
vegetarian composition or popular beverages like green tea
or red wine have beneficial effects on general pathological
markers of oxidative stress. The flavonoids, ubiquitous polyphenols
in plants and vegetables, have been identified as mainly by
responsible for these actions. In apparent agreement with
these data, numerous in vitro and in vivo
studies have demonstrated a neuroprotective capacity of flavonoids
against oxidative or excitotoxic aggressions. Oral flavonoids
undergo several metabolic steps and circulate in the blood
mainly as metabolites. These metabolites by themselves or
after cleavage into non-metabolised flavonoids in the brain
would be the active molecules. The intracellular targets of
flavonoids are multiple, from chelation of iron to homeostasis
of calcium as well as scavenging of free radicals and involvement
through kinase modulation, with key intracellular signalling
cascades. As key regulators of cell reactivity against oxidative
aggressions, the flavonoid molecule can become an ideal template
for compounds therapeutically active in stroke, dementia or
aging.
[Back to top]
High-Throughput Screening of Neuronal Cl- Channels:
Why and How?
J.W. Lynch
Much remains to be learned about the structures, functions
and therapeutic potentials of anion-permeable ion channels
expressed throughout the nervous system. For example, the
molecular identities of Ca2+ - and swelling-activated Cl-
channels are still unknown. Even in well-established neuronal
anion channel families (the CLC and GABA type-A ion channel
receptors), significant gaps exist in our understanding of
the physiological functions and sub-cellular distributions
of particular subtypes. The first part of this review summarises
the current status of this field and discusses how the discovery
of highly-selective pharmacological probes will advance our
understanding of the molecular identities, cellular and sub-cellular
distributions and functional roles of neuronal Cl- channels.
Where relevant, the therapeutic potential of these channels
is also discussed. The review then considers the relative
merits of high-throughput methods that have been employed
to screen anion-permeable channels. It concludes that several
methods are potentially suited to screening homogeneous assays
(such as stably-expressing cell lines), with the choice of
method being governed largely by the detection equipment available.
However, an anion-quenchable yellow fluorescent protein method
is unique in that it retains full dynamic range in assays
comprising transiently-transfected cells where the percentage
of cells expressing recombinant channels is significantly
< 100%. This feature is a significant advantage for screening
the vast range of possible GABA type-A receptor subunit combinations
where the creation of numerous stably-expressing cell lines
would otherwise pose a substantial logistical challenge.
[Back to top]
Pharmacological Characterisation and Modulation of
Neuroplasticity in Humans
M.A. Nitsche, D. Liebetanz, W. Paulus and F. Tergau
Neuroplasticity is defined as enduring modification, both
functional and/or structural, within the central nervous system.
The respective processes are thought to be of crucial importance
for learning, but also for more general adaptive processes
in response to environmental changes or consequences of brain
lesions. Moreover, it is hypothesized that neuroplasticity
is involved in diseases displaying altered central nervous
activity. Exploring its physiological foundations is thus
of crucial importance for understanding the functional properties
of the brain. Until now, research in this area was primarily
restricted to animal research, which has already afforded
important insights into the physiological and pharmacological
foundations of neuroplasticity. In recent years, however,
an arsenal of neurophysiological tools has been developed
which induces or modulates neuroplastic processes, even in
humans. Combining these techniques with pharmacological interventions
has already proved helpful and will, on the one hand, be of
future importance in understanding the mode of action of these
instruments and provide information about the involvement
of neurotransmitters, and neuromodulators in human neuroplasticity
on the other. It has been shown that, like in animal experiments,
NMDA receptor modulation is essential for the induction of
neuroplasticity in the human brain, whereas GABAergic activity
seems to inhibit it. These results, among others, suggest
a similarity between long-term depression and potentiation
as induced in animals and neuroplastic processes in humans.
Moreover, equivalent to studies performed in animals, monoaminergic
and cholinergic neuromodulation controls the consolidation
of human neuroplasticity. Although lots of work has still
to be done to fully understand these processes and their functional
importance, the current state of research already offers important
insights into human brain function and may help in future
to develop appropriate therapeutic regimens, in which neuroplastic
changes are involved or required to treat diseases of the
central nervous system.
[Back to top]
The Key Role of Medullary 5-HT3 Receptors
in the Serotonin-Mediated Neural Control of Cardiovascular
Function
C. Sévoz-Couche, B.H. Machado, M. Hamon1 and R.
Laguzzi
The baroreceptor reflex plays a crucial role in the homeostatic
control of cardiovascular parameters. In the central nervous
system, the nucleus of the tractus solitarius (NTS) is critically
involved in cardiovascular reflex control because it is both
the first site of termination of glutamatergic baroreceptor
afferent fibres and an important integrative area for the
sensory afferent signals reaching the brainstem. In addition
to glutamate, the NTS contains numerous neurotransmitters
that could participate in the modulations of the baroreceptor
reflex sensitivity which occur under various physiological
conditions. In particular, a large body of evidence indicates
that serotonin plays a modulatory role in the central control
of blood pressure, especially at the level of the NTS, which
is innervated by both central and peripheral serotonergic
fibres. Indeed, serotonin exerts multiple cardiovascular influences
through the activation of several receptors in the NTS. Actually,
the NTS is the central area endowed with the highest density
of serotonin3 (5-HT3) receptors whose
stimulation triggers all the adaptive cardiovascular changes
normally associated with behavioural responses to various
stressful conditions.
In this review, we first assess the current knowledge about
the mechanisms underlying the cardiovascular effects of the
specific activation of serotonergic receptors in the NTS.
Secondly, we describe evidence that, in the NTS, 5-HT3
receptors play a key role in one of the crucial homeostatic
responses that characterise the defence reaction: the inhibitory
modulation of the parasympathetic cardiac component of the
baroreceptor reflex. The possible functional interactions
of 5-HT3 receptors with GABAA, NK1 and
NMDA receptors within the NTS are also discussed.
[Back to top]
Iptakalim Hydrochloride and Neuronal Protection
Jie Wu, Makoto Wakui, Hai Wang and Gang Hu
Iptakalim hydrochloride (IPT) is a novel ATP-sensitive potassium
(KATP) channel opener which has a different chemical
structure from any other known KATP channel opener,
and exhibits both blood-brain barrier permeability and little
side effects after systemic administration. Emerging lines
of evidence indicate that IPT effectively protects brain neurons
against glutamate neurotoxicity in in vitro and
in vivo animal ischemic/hypoxic models. In addition,
IPT has also been shown to serve as a potent compound that
protects substantia nigra dopamine neurons against a variety
of chemical stresses (e.g., MPP+, 6-OHDA or rotenone)
in in vitro and in vivo Parkinson’s
disease animal models. Possible pharmacological mechanisms
of neuroprotection induced by IPT involve the opening of cytoplasmic
and mitochondrial KATP channels, diminishing glutamatergic
synaptic transmission by blocking presynaptic glutamate release,
reducing postsynaptic ionotropic glutamate receptor—especially
NMDA receptor—function, enhancing extracellular glutamate
uptake, and reducing Ca2+ release from intracellular
Ca2+ stores. Since it acts on multiple central
targets in order to exert neuroprotective effects, IPT is
a high-potential, promising candidate for the prevention and
treatment of neurodegeneration-relevant disorders. Therefore,
IPT is not only a useful pharmacological tool for KATP channel
investigation, but it also serves as a novel, high-potent,
low-toxic, therapeutic agent that protects brain neurons against
a variety of neurodegenerative diseases.
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