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Current Neuropharmacology
ISSN: 1570-159X
Current Neuropharmacology
Volume 6, Number 3, September 2008
Contents
Brain Endothelial Cell-Cell Junctions: How to “Open”
the Blood Brain Barrier Pp. 179-192
S.M. Stamatovic, R.F. Keep and A.V. Andjelkovic
[Abstract]
The TNF-α
System: Functional Aspects in Depression, Narcolepsy and Psychopharmacology
Pp. 193-202
M. Berthold-Losleben and H. Himmerich
[Abstract]
Cellular and Biochemical Actions of Melatonin
which Protect Against Free Radicals: Role in Neurodegenerative
Disorders Pp. 203-214
G.G. Ortiz, G.A. Benítez-King, S.A. Rosales-Corral,
F.P. Pacheco-Moisés and I.E. Velázquez-Brizuela
[Abstract]
Assessing the Neuronal Serotonergic Target-based
Antidepressant Stratagem: Impact of In Vivo Interaction
Studies and Knockout Models Pp. 215-234
R. Rajkumar and R. Mahesh
[Abstract]
Functional Neuroanatomy of the Noradrenergic
Locus Coeruleus: Its Roles in the Regulation of Arousal and
Autonomic Function Part I: Principles of Functional Organisation
Pp. 235-253
E.R. Samuels and E. Szabadi
[Abstract]
Functional Neuroanatomy of the Noradrenergic
Locus Coeruleus: Its Roles in the Regulation of Arousal and
Autonomic Function Part II: Physiological and Pharmacological
Manipulations and Pathological Alterations of Locus Coeruleus
Activity in Humans Pp. 254-285
E.R. Samuels and E. Szabadi
[Abstract]
Role of the Central Cholinergic System in the
Therapeutics of Schizophrenia Pp.
286-292
A.V. Terry, Jr.
[Abstract]
Abstracts
[Back to top]
Brain Endothelial Cell-Cell Junctions: How to “Open”
the Blood Brain Barrier
S.M. Stamatovic, R.F. Keep and A.V. Andjelkovic
The blood-brain barrier (BBB) is a highly specialized
structural and biochemical barrier that regulates the entry
of blood-borne molecules into brain, and preserves ionic homeostasis
within the brain microenvironment. BBB properties are primarily
determined by junctional complexes between the cerebral endothelial
cells. These complexes are comprised of tight and adherens
junctions. Such restrictive angioarchitecture at the BBB reduces
paracellular diffusion, while minimal vesicle transport activity
in brain endothelial cells limits transcellular transport.
Under normal conditions, this largely prevents the extravasation
of large and small solutes (unless specific transporters are
present) and prevents migration of any type of blood-borne
cell. However, this is changed in many pathological conditions.
There, BBB disruption (“opening”) can lead to
increased paracellular permeability, allowing entry of leukocytes
into brain tissue, but also contributing to edema formation.
In parallel, there are changes in the endothelial pinocytotic
vesicular system resulting in the uptake and transfer of fluid
and macromolecules into brain parenchyma. This review highlights
the route and possible factors involved in BBB disruption
in a variety of neuropathological disorders (e.g. CNS inflammation,
Alzheimer’s disease, Parkinson’s disease, epilepsy).
It also summarizes proposed signal transduction pathways that
may be involved in BBB “opening”.
[Back to top]
The TNF-α
System: Functional Aspects in Depression, Narcolepsy and Psychopharmacology
M. Berthold-Losleben and H. Himmerich
Changes of the tumor necrosis factor-alpha (TNF-α)
system have been shown to be involved in the development of
psychiatric disorders and are additionally associated with
changes in body weight as well as endocrine and metabolic
changes in psychiatric patients.
TNF-α
might, for example, contribute to the pathogenesis of depression
by an activation of the hypothalamo-pituitary-adrenocortical
(HPA) axis, an activation of neuronal serotonin transporters
and the stimulation of the indoleamine 2,3-dioxygenase which
leads to tryptophan depletion. On the other hand, during an
acute depressive episode, an elevated HPA axis activity may
suppress TNF-α
system activity, while after remission, when HPA axis activity
has normalized the suppression of the TNF-α
system has been shown not to be apparent any more.
In narcoleptic patients, soluble TNF receptor (sTNF-R) p75
plasma levels have been shown to be elevated, suggesting a
functional role of the TNF-α
system in the development of this disorder.
Additionally, psychotropic drugs influence the TNF-α
system as well as the secretion and the effect of hormones
which counteract or interact with the TNF-α
system such as the intestinal hormone ghrelin. However, only
preliminary studies with restricted sample sizes exist on
these issues, and many open questions remain.
[Back to top]
Cellular and Biochemical Actions of Melatonin which Protect
Against Free Radicals: Role in Neurodegenerative Disorders
G.G. Ortiz, G.A. Benítez-King, S.A. Rosales-Corral,
F.P. Pacheco-Moisés and I.E. Velázquez-Brizuela
Molecular oxygen is toxic for anaerobic organisms but
it is also obvious that oxygen is poisonous to aerobic organisms
as well, since oxygen plays an essential role for inducing
molecular damage. Molecular oxygen is a triplet radical in
its ground-stage (.O-O.) and has two unpaired electrons that
can undergoes consecutive reductions of one electron and generates
other more reactive forms of oxygen known as free radicals
and reactive oxygen species. These reactants (including superoxide
radicals, hydroxyl radicals) possess variable degrees of toxicity.
Nitric oxide (NO•) contains one unpaired electron and
is, therefore, a radical. NO• is generated in biological
tissues by specific nitric oxide synthases and acts as an
important biological signal. Excessive nitric oxide production,
under pathological conditions, leads to detrimental effects
of this molecule on tissues, which can be attributed to its
diffusion-limited reaction with superoxide to form the powerful
and toxic oxidant, peroxynitrite.
Reactive oxygen and nitrogen species are molecular “renegades”;
these highly unstable products tend to react rapidly with
adjacent molecules, donating, abstracting, or even sharing
their outer orbital electron(s). This reaction not only changes
the target molecule, but often passes the unpaired electron
along to the target, generating a second free radical, which
can then go on to react with a new target amplifying their
effects.
This review describes the mechanisms of oxidative damage and
its relationship with the most highly studied neurodegen-erative
diseases and the roles of melatonin as free radical scavenger
and neurocytoskeletal protector.
[Back to top]
Assessing the Neuronal Serotonergic Target-based Antidepressant
Stratagem: Impact of In Vivo Interaction Studies
and Knockout Models
R. Rajkumar and R. Mahesh
Depression remains a challenge in the field of affective
neuroscience, despite a steady research progress. Six out
of nine basic antidepressant mechanisms rely on serotonin
neurotransmitter system. Preclinical studies have demonstrated
the significance of serotonin receptors (5-HT1-3,6,7),
its signal transduction pathways and classical down stream
targets (including neurotrophins, neurokinins, other peptides
and their receptors) in antidepressant drug action. Serotonergic
control of depression embraces the recent molecular requirements
such as influence on proliferation, neurogenesis, plas-ticity,
synaptic (re)modeling and transmission in the central nervous
system. The present progress report analyses the credibility
of each protein as therapeutically relevant target of depression.
In vivo interaction studies and knockout models which
identified these targets are foreseen to unearth new ligands
and help them transform to drug candidates. The importance
of the antidepressant assay selection at the preclinical level
using salient animal models/assay systems is discussed. Such
test batteries would definitely provide antidepressants with
faster onset, efficacy in resistant (and comorbid) types and
with least adverse effects. Apart from the selective ligands,
only those molecules which bring an overall harmony, by virtue
of their affinities to various receptor subtypes, could qualify
as effective antidepressants. Synchronised modulation of various
serotonergic sub-pathways is the basis for a unique and balanced
antidepressant profile, as that of fluoxetine (most exploited
antidepressant) and such a profile may be considered as a
template for the upcoming antidepressants. In conclusion,
5-HT based multi-targeted antidepressant drug discovery supported
by in vivo interaction studies and knock-out models
is advocated as a strategy to provide classic molecules for
clinical trials.
[Back to top]
Functional Neuroanatomy of the Noradrenergic Locus Coeruleus:
Its Roles in the Regulation of Arousal and Autonomic Function
Part I: Principles of Functional Organisation
E.R. Samuels and E. Szabadi
The locus coeruleus (LC) is the major noradrenergic nucleus
of the brain, giving rise to fibres innervating extensive
areas throughout the neuraxis. Recent advances in neuroscience
have resulted in the unravelling of the neuronal circuits
controlling a number of physiological functions in which the
LC plays a central role. Two such functions are the regulation
of arousal and autonomic activity, which are inseparably linked
largely via the involvement of the LC. The LC is a major wakefulness-promoting
nucleus, resulting from dense excitatory projections to the
majority of the cerebral cortex, cholinergic neurones of the
basal forebrain, cortically-projecting neurones of the thalamus,
serotoninergic neurones of the dorsal raphe and cholinergic
neurones of the pedunculopontine and laterodorsal tegmental
nucleus, and substantial inhibitory projections to sleep-promoting
GABAergic neurones of the basal forebrain and ventrolateral
preoptic area. Acti-vation of the LC thus results in the enhancement
of alertness through the innervation of these varied nuclei.
The importance of the LC in controlling autonomic function
results from both direct projections to the spinal cord and
projections to autonomic nuclei including the dorsal motor
nucleus of the vagus, the nucleus ambiguus, the rostroventrolateral
medulla, the Edinger-Westphal nucleus, the caudal raphe, the
salivatory nuclei, the paraventricular nucleus, and the amygdala.
LC activation produces an increase in sympathetic activity
and a decrease in parasympathetic activity via these
projections. Alterations in LC activity therefore result in
complex patterns of neuronal activity throughout the brain,
observed as changes in measures of arousal and autonomic function.
[Back to top]
Functional Neuroanatomy of the Noradrenergic Locus
Coeruleus: Its Roles in the Regulation of Arousal and Autonomic
Function Part II: Physiological and Pharmacological Manipulations
and Pathological Alterations of Locus Coeruleus Activity
in Humans
E.R. Samuels and E. Szabadi
The locus coeruleus (LC), the major noradrenergic nucleus
of the brain, gives rise to fibres innervating most structures
of the neuraxis. Recent advances in neuroscience have helped
to unravel the neuronal circuitry controlling a number of
physiological functions in which the LC plays a central role.
Two such functions are the regulation of arousal and autonomic
activity, which are inseparably linked largely via
the involvement of the LC. Alterations in LC activity due
to physiological or pharmacological manipulations or pathological
processes can lead to distinct patterns of change in arousal
and autonomic function. Physiological manipulations considered
here include the presentation of noxious or anxiety-provoking
stimuli and extremes in ambient temperature. The modification
of LC-controlled functions by drug admini-stration is discussed
in detail, including drugs which directly modify the activity
of LC neurones (e.g., via autoreceptors, storage,
reuptake) or have an indirect effect through modulating excitatory
or inhibitory inputs. The early vulnerability of the LC to
the ageing process and to neurodegenerative disease (Parkinson’s
and Alzheimer’s diseases) is of considerable clinical
significance. In general, physiological manipulations and
the administration of stimulant drugs, α2-adrenoceptor
antagonists and noradrenaline uptake inhibitors increase LC
activity and thus cause heightened arousal and activation
of the sympathetic nervous system. In contrast, the administration
of sedative drugs, including α2-adrenoceptor
agonists, and pathological changes in LC function in neurodegenerative
disorders and ageing reduce LC activity and result in sedation
and activation of the parasympathetic nervous system.
[Back to top]
Role of the Central Cholinergic System in the Therapeutics
of Schizophrenia
A.V. Terry, Jr.
The therapeutic agents currently used to treat schizophrenia
effectively improve psychotic symptoms; however, they are
limited by adverse effects and poor efficacy when negative
symptoms of the illness and cognitive dysfunction are considered.
While optimal pharmacotherapy would directly target the neuropathology
of schizophrenia neither the underlying neurobiological substrates
of the behavioral symptoms nor the cognitive deficits have
been clearly established. Abnormalities in the neurotransmitters
dopamine, serotonin, glutamate, and GABA are commonly implicated
in schizophrenia; however, it is not uncommon for alterations
in the brain cholinergic system (e.g., choline acetyltransferase,
nicotinic and muscarinic acetylcholine receptors) to also
be reported. Further, there is now considerable evidence in
the animal literature to suggest that both first and second
generation antipsychotics (when administered chronically)
can alter the levels of several cholinergic markers in the
brain as well as impair memory-related task performance. Given
the well-established importance of central cholinergic neurons
to information processing and cognition, it is important that
cholinergic function in schizophrenia be further elucidated
and that the mechanisms of the chronic effects of antipsychotic
drugs on this important neurotransmitter system be identified.
A better understanding of these mechanisms would be expected
to facilitate optimal treatment strategies for schizophrenia
as well as the identification of novel therapeutic targets.
In this review, the following topics are discussed: 1) the
central cholinergic system in schizophrenia 2) effects of
antipsychotic drugs on central cholinergic neurons 3) important
neurotrophins in schizophrenia, especially those that support
central cholinergic neurons; 4) novel strategies to optimize
the therapeutics of schizophrenia via the use of
cholinergic compounds as primary (i.e., antipsychotic) treatments
as well as adjunctive, pro-cognitive agents.
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