Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
OPEN ACCESS PLUS
Contents
The Dual Role of Serotonin in Defense and the Mode of Action
of Antidepressants on Generalized Anxiety and Panic Disorders
2010, 10, 207-217
Frederico Guilherme Graeff and Hélio Zangrossi
Jr
[Abstract] [Full
text article]
Brain Senescence and Neuroprotective Dietary Components
2007, 7, 109-114
Keiko Unno and Minoru Hoshino
[Abstract] [Full
text article]
PET Tracers for Mapping Adenosine Receptors as Probes for
Diagnosis of CNS Disorders, 2007, 7, 57-77
K. Ishiwata, Y. Kimura, E.F.J. de Vries and P.H. Elsinga
[Abstract] [Full
text article]
α7
Nicotinic Receptor Agonists as Potential Therapeutic Drugs
for SchizophreniaK, 2005, 5, 171-184
Kenji Hashimoto, Kaori Koike, Eiji Shimizu and Masaomi
Iyo
[Abstract] [Full
text article]
Abstracts
[Back to top]
The Dual Role of Serotonin in Defense and the Mode of Action
of Antidepressants on Generalized Anxiety and Panic Disorders
Frederico Guilherme Graeff and Hélio
Zangrossi Jr
[Full text article]
Antidepressants are widely used to treat several anxiety disorders,
among which generalized anxiety disorder (GAD) and panic disorder
(PD). Serotonin (5-HT) is believed to play a key role in the
mode of action of these agents, a major question being which
pathways and receptor subtypes are involved in each type of
anxiety disorder. The dual role of 5-HT in defense hypothesis
assumes that 5-HT facilitates defensive responses to potential
threat, like inhibitory avoidance, related to anxiety, whereas
it inhibits defensive responses to proximal danger, like one-way
escape, related to panic. The former action would be exerted
at the forebrain, chiefly the amygdala and medial prefrontal
cortex (PFC), while the latter would be exerted at the dorsal
periaqueductal gray (DPAG) matter of the midbrain. The present
review is focused on studies designed to test this hypothesis,
performed in animal models of anxiety and panic, as well as
in human experimental anxiety tests. The reviewed results
suggest that chronic, but not acute, administration of antidepressants
suppress panic attacks by increasing the release of 5-HT and
enhancing the responsivity of post-synaptic 5-HT1A and 5-HT2A
receptors in the DPAG. The attenuation of generalized anxiety,
also caused by the same drug treatment, would be due to the
desensitization of 5-HT2C receptors and, less certainly, to
increased stimulation of 5-HT1A receptors in forebrain structures.
This action would result in less activation of the amygdala,
medial PFC and insula by warning signals, as shown by the
reviewed results obtained with functional neuroimaging in
healthy volunteers and patients with anxiety disorders.
[Back to top]
Brain Senescence and Neuroprotective Dietary Components
Keiko Unno and Minoru Hoshino
[Full
text article]
Senescence is an ageing process characterized by
progressive and irreversible dysfunction of various physiological
systems. Physiological senescence with advancing age is not
a disease, but it affects the life-span and life-quality of
elderly people. Brain functions such as cognition and motor
skills, as with other organ systems, are impaired in almost
all elderly people. Neuroprotective dietary components can
play a key role in ensuring healthy ageing of the brain. Although
the causative mechanisms of senescence are complex and not
yet fully elucidated, enhanced oxidative stress is thought
to be an important contributor. Dietary antioxidants from
fruits and vegetables have preventative effects on oxidative
stress. Catechin, a polyphenol found in green tea, has a potent
antioxidative effect. Recently, catechin has been reported
to protect against reduced ageing-related cognitive functions
such as those associated with learning and memory, and ischemic
brain damage. Catechin may act as a neuroprotective agent
in progressive neurodegenerative disorders such as Parkinson’s
and Alzheimer’s diseases. The neuroprotective effects
and putative mechanisms of action of catechin and other antioxidants
are examined and discussed in this review.
[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.
[Back to top]
α7
Nicotinic Receptor Agonists as Potential Therapeutic Drugs
for SchizophreniaK
Kenji Hashimoto, Kaori Koike, Eiji Shimizu and Masaomi
Iyo
[Full
text article]
Deficient inhibitory processing of the P50 auditory evoked
potential is a measurable marker observed in schizophrenia.
Several lines of evidence suggest that α7
nicotinic receptors (α7
nAChRs) play a critical role in P50 auditory sensory gating
in the human brain. Similar to schizophrenic patients, DBA/2
mice spontaneously exhibit a deficit in inhibitory processing
of the P20-N40 auditory evoked potential, which is a rodent
analogue of the human P50 auditory evoked potential. Agonists
at α7
nAChRs improve deficient inhibitory processing of the P20-N40
auditory gating potential in DBA/2 mice. In this article,
we review the role of α7
nAChRs in the pathophysiology of schizophrenia, and α7
nAChR agonists and indirect agonists (5-hydroxytryptamine-3
(5-HT3) receptor antagonists,
positive allosteric modulators (galantamine, 5-hydroxyindole,
PNU-120596), FK960, FR236924) at α7
nAChRs as potential therapeutic drugs for the treatment of
schizophrenia. In addition, we also discuss the role of kynurenic
acid as an endogenous antagonist of α7
nAChRs in brain.
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