Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
Central Nervous System Agents
in Medicinal Chemistry
Volume 7, Number 1, March 2007
Contents
Metabotropic Glutamate Receptors Modulate Periaqueductal
Grey Descending Analgesic System Pp. 1-10
E. Palazzo, V. de Novellis, I. Marabese, F. Rossi and S. Maione
[Abstract] [Full
Text Article]
Pathophysiology of Status Epilepticus Induced
by Pilocarpine Pp. 11-15
R.M. Freitas, A.A. Oliveira, F.C.F. Sousa, S.M.M. Vasconcelos,
G.S.B. Viana and M.M.F. Fonteles
[Abstract] [Full
Text Article]
Neuromodulation of Hippocampal Synaptic Plasticity,
Learning, and Memory by Noradrenaline Pp. 17-33
J.N. Gelinas and P.V. Nguyen
[Abstract] [Full
Text Article]
Neurochemistry and Pharmacological Treatments: Where
is the Field of Anorexia Nervosa Heading? Pp. 35-43
N.C. Barbarich-Marsteller
[Abstract] [Full
Text Article]
Kynurenines in the Central Nervous System: Recent
Developments Pp. 45-56
H. Németh, H. Robotka, J. Toldi and L. Vécsei
[Abstract] [Full
Text Article]
PET Tracers for Mapping Adenosine Receptors as Probes
for Diagnosis of CNS Disorders Pp. 57-77
K. Ishiwata, Y. Kimura, E.F.J. de Vries and P.H. Elsinga
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Metabotropic Glutamate Receptors Modulate Periaqueductal Grey
Descending Analgesic System
E. Palazzo, V. de Novellis, I. Marabese, F. Rossi and S. Maione
[Full
Text Article]
Metabotropic glutamate receptors (mGluRs) are a family
of G-protein-coupled receptors which play an important role
in the modulation of nociception transmission and plasticity
[1,2]. In this review we will consider the control of supraspinal
nociception by mGluR ligands in several animal models of pain
through behavioural and biochemical approaches. More specifically,
we will focus our attention on the mGluRs of the midbrain
periaqueductal gray (PAG), which has been recognized as an
antinociceptive area since 1969. The multiplicity of responses
associated with mGluR stimulation is complicated by the localization
of these receptors on a variety of pre- and postsynaptic elements
of either glutamate, GABA and non-GABA containing neurons
that characterize the PAG circuitry. In particular, excitatory-postsynaptic
group I mGlu1/5 subtype receptors produce a preferential
activation of descending excitatory antinociceptive pathways
at the PAG level, while group III mGlu8 receptors
modulate the release of glutamate and GABA conversely. Indeed,
selective stimulation of mGlu8 receptors generates
an increase in glutamate and a decrease in γ-aminobutyric
acid (GABA) extracellular levels. These data, together with
the evidence that these receptors are present presynaptically
on both symmetrical and asymmetrical synapses, justify that
their stimulation relieves hyperalgesia in inflammatory pain.
Unlike mGlu8, the mGlu7 receptors in
the PAG inhibit antinociception via negative modulation of
glutamate release, as they seem expressed mainly on asymmetrical
synapses. In this review we aim to illustrate the role of
mGluRs in controlling nociceptive processes, as well as their
interaction with other neurotransmitters within the PAG, in
the hope that further findings in this field will pave the
way for the development of useful new agents in pain therapy.
[Back to top]
Pathophysiology of Status Epilepticus Induced
by Pilocarpine
R.M. Freitas, A.A. Oliveira, F.C.F. Sousa, S.M.M. Vasconcelos,
G.S.B. Viana and M.M.F. Fonteles
[Full
Text Article]
Status epilepticus (SE) is clinically defined as prolonged
electrical and clinical seizure activity in which the patient
does not regain consciousness to a normal alert state between
repeated tonic-clonic attacks. The disorder is a neurological
emergency associated with a mortality rate of 10-12% and an
even greater morbidity. SE can lead to permanent pathological
damage and altered physiological function in certain brain
regions and induces major changes in membrane phospholipids,
massive increases in arachidonic acid concentrations, diacylglycerol-mediated
activation, of protein kinase C, calcium-mediated changes
in calmodulin kinase II and possibly generation of free radicals
that could play an essential role in the mechanism of oxidative
stress involved in neural damage. SE can be characterized
by a permanent change in neurotransmitter systems and oxidative
stress that it is more facilitated in the brain rather than
in other tissues because it contains large quantities of oxidizable
lipids and metals. The role of monoamines, amino acid and
oxidative stress in pilocarpine-induced SE will be investigated
in hippocampus, striatum and frontal cortex of adult rats.
The SE studied will be induced by pilocarpine (400mg/kg, s.c.)
and the results observed were investigated during acute phase.
The data obtained suggests that pilocarpine induced amino
acid and oxidative stress changes in brain regions that are
similar to the one verified in human temporal lobe epilepsy.
[Back to top]
Neuromodulation of Hippocampal Synaptic Plasticity,
Learning, and Memory by Noradrenaline
J.N. Gelinas and P.V. Nguyen
[Full
Text Article]
Neuromodulators are chemical substances that modify neural
responses without directly triggering synaptic excitation.
They broadly impact multiple brain functions, such as arousal,
sleep, attention, perception, learning, and memory. The noradrenergic
neuromodulatory system widely innervates the mammalian brain,
including the hippocampus. Hippocampal synaptic plasticity
is believed to importantly contribute to the formation and
consolidation of some types of memory. Stimulation of noradrenergic
receptors in the hippocampus alters neuronal excitability
and synaptic plasticity, suggesting a key role for noradrenaline
(NA) in learning and memory. Consistent with this notion,
NA enhances memory for a variety of hippocampus-dependent
tasks. The effects of NA receptor activation on cellular plasticity
may account for NA-dependent modulation of memory in the hippocampus.
Furthermore, dysfunction of the noradrenergic neuromodulatory
system contributes to numerous cognitive and psychiatric disorders.
Determining how NA influences information processing at cellular
and behavioural levels is essential for understanding the
physiology of memory. Such understanding may also reveal new
strategies to improve treatments for human memory disorders.
[Back to top]
Neurochemistry and Pharmacological Treatments: Where
is the Field of Anorexia Nervosa Heading?
N.C. Barbarich-Marsteller
[Full
Text Article]
Anorexia nervosa is a debilitating psychiatric disorder characterized
by severe dietary restriction and life-threatening weight
loss. The onset of the disorder typically occurs during adolescence
with 90-95% of all cases occurring in females. Often characterized
by a chronic and relapsing course, anorexia nervosa has one
of the highest mortality rates of any psychiatric disorder.
Although the etiology is unknown, a complex interplay of genetic,
neurobiological, and environmental variables appear to factor
into the development of the disorder. Accumulating evidence
supports altered serotonin 5-HT1A, 5-HT2A,
and 5-HTT receptor binding in anorexia nervosa, with more
recent studies examining dopamine D2/D3
receptor binding. Despite this increasing knowledge of neurotransmitter
alterations, there are few effective treatment strategies,
with pharmacological treatments having minimal efficacy during
the acute phase of illness. Thus, the goal of this paper is
to provide an overview of neurochemical alterations during
the ill state and following long-term recovery. This will
be followed by a review of pharmacological treatment studies
of anorexia nervosa that will focus on the limited efficacy
of SSRIs and more promising findings from atypical antipsychotics.
Given the combination of receptors targeted by newer generation
atypical antipsychotics, these drugs may provide a more efficient
means for modulating the neurobiological disturbances seen
in anorexia nervosa.
[Back to top]
Kynurenines in the Central Nervous System: Recent
Developments
H. Németh, H. Robotka, J. Toldi and L. Vécsei
[Full
Text Article]
The intermediates of the kynurenine pathway, called kynurenines,
are derived directly or indirectly from the tryptophan metabolism.
This metabolic pathway is responsible for nicotinamide adenine
dinucleotide and nicotinamide adenine dinucleotide phosphate,
which participate in basic cellular processes.
It was discovered some thirty years ago that kynurenines have
neuroactive properties. Kynurenine, the central compound of
this pathway, can be converted to two other important agents:
the neuroprotective kynurenic acid and the neurotoxic quinolinic
acid.
Kynurenic acid is an endogenous broad-spectrum antagonist
of excitatory amino acid receptors, including the N-methyl-D-aspartate
receptors. It can inhibit the overexcitation of these receptors
and reduce the cell damage induced by excitotoxins. Moreover,
kynurenic acid non-competitively blocks the α7-nicotinic
acetylcholine receptors, thereby permitting modulation of
the cholinergic and glutamatergic neurotransmission.
Quinolinic acid is a selective N-methyl-D-aspartate receptor
agonist which can cause lipid peroxidation, the generation
of free radicals and apoptosis via the overexcitation of these
receptors.
Changes in the relative or absolute concentrations of the
kynurenines have been found in several neurodegenerative disorders,
such as Huntington’s disease and Parkinson’s disease,
stroke and epilepsy, in which the hyperactivation of amino
acid receptors could be involved.
Increase of the brain level of kynurenic acid seems to be
a good therapeutic strategy; however, kynurenic acid can cross
the blood-brain barrier only poorly. The latest findings provide
promising opportunities involving the development of the analogues
4-chloro-kynurenine and glucoseamine-kynurenic acid, which
can enter the brain and exert neuroprotective effects. Another
recent possibility is the use of different enzyme inhibitors
which can reduce the production of the neurotoxic quinolinic
acid.
[Back to top]
PET Tracers for Mapping Adenosine Receptors as Probes
for Diagnosis of CNS Disorders
K. Ishiwata, Y. Kimura, E.F.J. de Vries and P.H. Elsinga
[Full
Text Article]
Adenosine is an endogenous modulator of several physiological
functions in the central nervous system (CNS). The effect
is mediated by a receptor family that consists of at least
four subtypes: A1, A2A, A2B
and A3 receptors. The adenosine receptors play
a role in neurological and psychiatric disorders such as Alzheimer’s
disease, Parkinson’s disease, epilepsy and schizophrenia.
Knowledge on adenosine receptor densities and status are important
for understanding the mechanisms underlying the pathogenesis
of diseases and for developing new therapeutics. Positron
emission tomography (PET) offers a non-invasive tool to investigate
these features in vivo, provided that suitable radiopharmaceuticals
are available.
As a consequence of the development of xanthine-type adenosine
receptor antagonists with high affinity and high selectivity,
several PET ligands labeled with carbon-11 (half-life of 20.4
min) and fluorine-18 (half-life of 109.8 min) have been proposed
for mapping the adenosine A1 and A2A
receptors (A1R and A2AR, respectively)
and the adenosine uptake site in the CNS since 1995. Later
non-xanthine-type antagonists for A2AR were radiolabeled.
So far two tracers for A1R, [18F]CPFPX
and [11C]MPDX, and a tracer for A2AR,
[11C]TMSX (also called [11C]KF18446),
have been applied to humans. For the other subtypes and the
adenosine uptake site no suitable radioligands have been developed
yet.
This paper gives an overview of the current status on PET
tracers for mapping adenosine receptors and the development
of new compounds that may lead to new PET tracers.
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