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Current Neuropharmacology
ISSN: 1570-159X
Current Neuropharmacology
Volume 5, Number 1, March 2007
Contents
Synaptic Transmission at Functionally Identified
Synapses in the Enteric Nervous System: Roles for Both Ionotropic
and Metabotropic Receptors Pp. 1-17
R.M. Gwynne and J.C. Bornstein
[Abstract] [Full
text article]
Brain Slices as Models for Neurodegenerative Disease
and Screening Platforms to Identify Novel Therapeutics
Pp. 19-33
S. Cho, A. Wood and M.R. Bowlby
[Abstract] [Full
text article]
Agonism of Peroxisome Proliferator Receptor–Gamma
may have Therapeutic Potential for Neuroinflammation and Parkinson’s
Disease Pp. 35-46
R.L. Hunter and G. Bing
[Abstract] [Full
text article]
GABA and Neuroactive Steroid Interactions in Glia:
New Roles for Old Players? Pp. 47-64
V. Magnaghi
[Abstract] [Full
text article]
Modelling Anxiety in Humans for Drug Development
Pp. 65-72
M. Siepmann and P. Joraschky
[Abstract] [Full
text article]
Abstracts
[Back to top]
Synaptic Transmission at Functionally Identified Synapses
in the Enteric Nervous System: Roles for Both Ionotropic and
Metabotropic Receptors
R.M. Gwynne and J.C. Bornstein
[Full
text article]
Digestion and absorption of nutrients and the secretion and
reabsorption of fluid in the gastrointestinal tract are regulated
by neurons of the enteric nervous system (ENS), the extensive
peripheral nerve network contained within the intestinal wall.
The ENS is an important physiological model for the study
of neural networks since it is both complex and accessible.
At least 20 different neurochemically and functionally distinct
classes of enteric neurons have been identified in the guinea
pig ileum. These neurons express a wide range of ionotropic
and metabotropic receptors. Synaptic potentials mediated by
ionotropic receptors such as the nicotinic acetylcholine receptor,
P2X purinoceptors and 5-HT3 receptors are seen
in many enteric neurons. However, prominent synaptic potentials
mediated by metabotropic receptors, like the P2Y1
receptor and the NK1 receptor, are also seen in
these neurons. Studies of synaptic transmission between the
different neuron classes within the enteric neural pathways
have shown that both ionotropic and metabotropic synaptic
potentials play major roles at distinct synapses within simple
reflex pathways. However, there are still functional synapses
at which no known transmitter or receptor has been identified.
This review describes the identified roles for both ionotropic
and metabotropic neurotransmission at functionally defined
synapses within the guinea pig ileum ENS. It is concluded
that metabotropic synaptic potentials act as primary transmitters
at some synapses. It is suggested identification of the interactions
between different synaptic potentials in the production of
complex behaviours will require the use of well validated
computer models of the enteric neural circuitry.
[Back to top]
Brain Slices as Models for Neurodegenerative Disease
and Screening Platforms to Identify Novel Therapeutics
S. Cho, A. Wood and M.R. Bowlby
[Full
text article]
Recent improvements in brain slice technology have made this
biological preparation increasingly useful for examining pathophysiology
of brain diseases in a tissue context. Brain slices maintain
many aspects of in vivo biology, including functional
local synaptic circuitry with preserved brain architecture,
while allowing good experimental access and precise control
of the extracellular environment, making them ideal platforms
for dissection of molecular pathways underlying neuronal dysfunction.
Importantly, these ex vivo systems permit direct
treatment with pharmacological agents modulating these responses
and thus provide surrogate therapeutic screening systems without
recourse to whole animal studies. Virus or particle mediated
transgenic expression can also be accomplished relatively
easily to study the function of novel genes in a normal or
injured brain tissue context.
In this review we will discuss acute brain injury models in
organotypic hippocampal and co-culture systems and the effects
of pharmacological modulation on neurodegeneration. The review
will also cover the evidence of developmental plasticity in
these ex vivo models, demonstrating emergence of
injury-stimulated neuronal progenitor cells, and neurite sprouting
and axonal regeneration following pathway lesioning. Neuro-
and axo-genesis are emerging as significant factors contributing
to brain repair following many acute and chronic neurodegenerative
disorders. Therefore brain slice models may provide a critical
contextual experimental system to explore regenerative mechanisms
in vitro.
[Back to top]
Agonism of Peroxisome Proliferator Receptor–Gamma
may have Therapeutic Potential for Neuroinflammation and Parkinson’s
Disease
R.L. Hunter and G. Bing
[Full
text article]
Evidence suggests inflammation, mitochondria dysfunction,
and oxidative stress play major roles in Parkinson’s
disease (PD), where the primary pathology is the significant
loss of dopaminergic neurons in the substantia nigra (SN).
Current methods used to treat PD focus mainly on replacing
dopamine in the nigrostriatal system. However, with time these
methods fail and worsen the symptoms of the disease. This
implies there is more to the treatment of PD than just restoring
dopamine or the dopaminergic neurons, and that a broader spectrum
of factors must be changed in order to restore environmental
homeostasis. Pharmacological agents that can protect against
progressive neuronal degeneration, increase the level of dopamine
in the nigrostriatal system, or restore the dopaminergic system
offer various avenues for the treatment of PD. Drugs that
reduce inflammation, restore mitochondrial function, or scavenge
free radicals have also been shown to offer neuroprotection
in various animal models of PD. The activation of peroxisome
proliferator receptor–gamma (PPAR-γ)
has been associated with altering insulin sensitivity, increasing
dopamine, inhibiting inflammation, altering mitochondrial
bioenergetics, and reducing oxidative stress - a variety of
factors that are altered in PD. Therefore, PPAR-γ
activation may offer a new clinically relevant treatment approach
to neuroinflammation and PD related neurodegeneration. This
review will summarize the current understanding of the role
of PPAR-γ
agonists in neuroinflammation and discuss their potential
for the treatment of PD.
[Back to top]
GABA and Neuroactive Steroid Interactions in Glia:
New Roles for Old Players?
V. Magnaghi
[Full
text article]
In recent years it has becoming clear that glial cells of
the central and peripheral nervous system play a crucial role
from the earliest stages of development throughout adult life.
Glial cells are important for neuronal plasticity, axonal
conduction and synaptic transmission. In this respect, glial
cells are able to produce, uptake and metabolize many factors
that are essential for neuronal physiology, including classic
neurotransmitters and neuroactive steroids. In particular,
neuroactive steroids, which are mainly synthesized by glial
cells, are able to modulate some neurotransmitter receptors
affecting both glia and neurons. Among the signaling systems
that are specialized for neuronglial communication, we can
include neurotransmitter GABA.
The main focus of this review is to illustrate the cross-talk
between neurons and glial cells in terms of GABA neurotrans-mission
and actions of neuroactive steroids. To this purpose, we will
review the presence of the different GABA receptors in the
glial cells of the central and peripheral nervous system.
Then, we will discuss their modulation by some neuroactive
steroids.
[Back to top]
Modelling Anxiety in Humans for Drug Development
M. Siepmann and P. Joraschky
[Full
text article]
Animal behavioural profiles are commonly employed to investigate
new therapeutic agents to treat anxiety disorders as well
as to investigate the mechanism of action of anxiolytic drugs.
However, many clinically important symptoms of anxiety can
not be modelled directly in animals. Human models of anxiety
should bridge between animal models and anxiety disorders.
Experimental anxiety states in humans can be induced by either
pharmacological means such as CO2 inhalation or
psychological means such as aversive conditioning of skin
conductance responses to tones. Investigation of these models
may contribute to a better understanding of anxiety disorders,
both from a biological and behavioural point of view. In a
comprehensive review existing models of human experimental
anxiety states are summarized and validity is discussed.
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