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Current Neuropharmacology
ISSN: 1570-159X
Current Neuropharmacology
Volume 6, Number 2, June 2008
Contents
Clearing the Brain’s Cobwebs: The Role of Autophagy
in Neuroprotection Pp. 97-101
B. Bossy, G. Perkins and E. Bossy-Wetzel
[Abstract]
Water and Ion Channels: Crucial in the Initiation
and Progression of Apoptosis in Central Nervous System?
Pp 102-116
M.J. Chen, S. Sepramaniam, A. Armugam, M.S. Choy,
J. Manikandan, A.J. Melendez, K. Jeyaseelan and N.S.
Cheung
[Abstract]
Antipsychotics for the Treatment of Behavioral
and Psychological Symptoms of Dementia (BPSD) Pp.
117-124
R. Liperoti, C. Pedone and A. Corsonello
[Abstract]
The Effects of Maternally Administered Methadone,
Buprenorphine and Naltrexone on Offspring: Review of Human
and Animal Data Pp. 125-150
W.O. Farid, S.A. Dunlop, R.J. Tait and
G.K. Hulse
[Abstract]
TRPV1: A Target for Next Generation Analgesics
Pp. 151-163
L.S. Premkumar and P. Sikand
[Abstract]
Neurodegenerative Diseases of the Retina and Potential for
Protection and Recovery Pp. 164-178
K.-G. Schmidt, H. Bergert and R.H.W. Funk
[Abstract]
Abstracts
[Back to top]
Clearing the Brain’s Cobwebs: The Role of Autophagy
in Neuroprotection
B. Bossy, G. Perkins and E. Bossy-Wetzel
Protein aggregates or inclusion bodies are common hallmarks
of age-related neurodegenerative disorders. Why these aggregates
form remains unclear. Equally debated is whether they are
toxic, protective, or simple by-products. Increasing evidence,
however, supports the notion that in general aggregates confer
toxicity and disturb neuronal function by hampering axonal
transport, synaptic integrity, transcriptional regulation,
and mitochondrial function. Thus, neuroscientists in search
of effective treatments to slow neural loss during neurodegeneration
have long been interested in finding new ways to clear inclusion
bodies. Intriguingly, two studies using conditional neuron-specific
gene ablations of autophagy regulators in mice revealed that
autophagy loss elicits inclusion body formation and a neurodegenerative
cascade. Such studies indicate autophagy may be a built-in
defense mechanism to clear the nervous system of inclusion
bodies. This new finding has implications for our understanding
of aging and neurodegeneration and the development of new
therapies. First, we discuss the pathways underlying autophagy
and its controversial role in cell death and survival regulation.
We then discuss the physiological role of autophagy in the
aging process of the nervous system. In the final portion
of this review, we discuss the therapeutic promise of inducing
autophagy and the potential side effects of such treatments.
[Back to top]
Water and Ion Channels: Crucial in the Initiation
and Progression of Apoptosis in Central Nervous System?
M.J. Chen, S. Sepramaniam, A. Armugam, M.S. Choy,
J. Manikandan, A.J. Melendez, K. Jeyaseelan and N.S.
Cheung
Programmed cell death (PCD), is a highly regulated and
sophisticated cellular mechanism that commits cell to isolated
death fate. PCD has been implicated in the pathogenesis of
numerous neurodegenerative disorders. Countless molecular
events underlie this phenomenon, with each playing a crucial
role in death commitment. A precedent event, apoptotic volume
decrease (AVD), is ubiquitously observed in various forms
of PCD induced by different cellular insults. Under physiological
conditions, cells when subjected to osmotic fluctuations will
undergo regulatory volume increase/decrease (RVI/RVD) to achieve
homeostatic balance with neurons in the brain being additionally
protected by the blood-brain-barrier. However, during AVD
following apoptotic trigger, cell undergoes anistonic shrinkage
that involves the loss of water and ions, particularly monovalent
ions e.g. K+, Na+ and Cl-.
It is worthwhile to concentrate on the molecular implications
underlying the loss of these cellular components which posed
to be significant and crucial in the successful propagation
of the apoptotic signals. Microarray and real-time PCR analyses
demonstrated several ion and water channel genes are regulated
upon the onset of lactacystin (a proteosomal inhibitor)-mediated
apoptosis. A time course study revealed that gene expressions
of water and ion channels are being modulated just prior to
apoptosis, some of which are aquaporin 4 and 9, potassium
channels and chloride channels. In this review, we shall looked
into the molecular protein machineries involved in the execution
of AVD in the central nervous system (CNS), and focus on the
significance of movements of each cellular component in affecting
PCD commitment, thus provide some pharmacological advantages
in the global apoptotic cell death.
[Back to top]
Antipsychotics for the Treatment of Behavioral and
Psychological Symptoms of Dementia (BPSD)
R. Liperoti, C. Pedone and A. Corsonello
Behavioral and psychological symptoms of dementia (BPSD),
i.e. verbal and physical aggression, agitation, psychotic
symptoms (hallucinations and delusions), sleep disturbances,
oppositional behavior, and wandering, are a common and potentially
severe problem complicating dementia. Their prevalence is
very high and it is estimated that up to 90% of patients with
Alzheimer’s disease (AD) may present at least one BPSD.
Beside the obvious impact on the quality of life of people
with dementia, BPSD are responsible for increased risk of
patient institutionalization and increased costs. Furthermore,
they are associated with caregivers’ stress and depression.
Drugs used include antipsychotics, antidepressants, anticonvulsivants,
anxiolytics, cholinesterase inhibitors and N-methyl-D-aspartate
receptor modulators. Among these, the most commonly used are
anti-psychotics. These drugs have been used for many decades,
but in the last years new compounds have been marketed with
the promise of comparable efficacy but less frequent adverse
effects (especially extra-pyramidal side effects). Their safety,
however, has been challenged by data showing a potential increase
in adverse cerebrovascular side effects and mortality. This
review will summarize the pathophysiology and neuropharmacology
of BPSD, it will describe the characteristics of the anti-psychotics
most commonly used focusing on their efficacy and safety in
BPSD.
[Back to top]
The Effects of Maternally Administered Methadone,
Buprenorphine and Naltrexone on Offspring: Review of Human
and Animal Data
W.O. Farid, S.A. Dunlop, R.J. Tait and G.K.
Hulse
Most women using heroin are of reproductive age with
major risks for their infants. We review clinical and experimental
data on fetal, neonatal and postnatal complications associated
with methadone, the current “gold standard”, and
compare these with more recent, but limited, data on developmental
effects of buprenorphine, and naltrexone. Methadone is a μ-opioid
receptor agonist and is commonly recommended for treatment
of opioid dependence during pregnancy. However, it has undesired
outcomes including neonatal abstinence syndrome (NAS). Animal
studies also indicate detrimental effects on growth, behaviour,
neuroanatomy and biochemistry, and increased perinatal mortality.
Buprenorphine is a partial μ-opioid
receptor agonist and a κ-opioid
receptor antagonist. Clinical observations suggest that buprenorphine
during pregnancy is similar to methadone on developmental
measures but is potentially superior in reducing the incidence
and prognosis of NAS. However, small animal studies demonstrate
that low doses of buprenorphine during pregnancy and lactation
lead to changes in offspring behaviour, neuroanatomy and biochemistry.
Naltrexone is a non-selective opioid receptor antagonist.
Although data are limited, humans treated with oral or sustained-release
implantable naltrexone suggest outcomes potentially superior
to those with methadone or buprenorphine. However, animal
studies using oral or injectable naltrexone have shown developmental
changes following exposure during pregnancy and lactation,
raising concerns about its use in humans. Animal studies using
chronic exposure, equivalent to clinical depot formulations,
are required to evaluate safety. While each treatment is likely
to have maternal advantages and disadvantages, studies are
urgently required to determine which is optimal for offspring
in the short and long term.
[Back to top]
TRPV1: A Target for Next Generation Analgesics
L.S. Premkumar and P. Sikand
Transient Receptor Potential Vanilloid 1 (TRPV1) is a
Ca2+ permeant non-selective
cation channel expressed in a subpopulation of primary afferent
neurons. TRPV1 is activated by physical and chemical stimuli.
It is critical for the detection of nociceptive and thermal
inflammatory pain as revealed by the deletion of the TRPV1
gene. TRPV1 is distributed in the peripheral and central terminals
of the sensory neurons and plays a role in initiating action
potentials at the nerve terminals and modulating neurotransmitter
release at the first sensory synapse, respectively. Distribution
of TRPV1 in the nerve terminals innervating blood vessels
and in parts of the CNS that are not subjected to temperature
range that is required to activate TRPV1 suggests a role beyond
a noxious thermal sensor. Presently, TRPV1 is being considered
as a target for analgesics through evaluation of different
antagonists. Here, we will discuss the distribution and the
functions of TRPV1, potential use of its agonists and antagonists
as analgesics and highlight the functions that are not related
to nociceptive transmission that might lead to adverse effects.
[Back to top]
Neurodegenerative Diseases of the Retina and Potential
for Protection and Recovery
K.-G. Schmidt, H. Bergert and R.H.W. Funk
Recent advances in our understanding of the mechanisms
in the cascade of events resulting in retinal cell death in
ocular pathologies like glaucoma, diabetic retinopathy and
age-related macular degeneration led to the common descriptive
term of neurodegenerative diseases of the retina. The final
common pathophysiologic pathway of these diseases includes
a particular form of metabolic stress, resulting in an insufficient
supply of nutrients to the respective target structures (optic
nerve head, retina). During metabolic stress, glutamate is
released initiating the death of neurones containing ionotropic
glutamate (N-methyl-D-aspartat, NMDA) receptors present on
ganglion cells and a specific type of amacrine cells. Experimental
studies demonstrate that several drugs reduce or prevent the
death of retinal neurones deficient of nutrients. These agents
generally block NMDA receptors to prevent the action of glutamate
or halt the subsequent pathophysiologic cycle resulting in
cell death. The major causes for cell death following activation
of NMDA receptors are the influx of calcium and sodium into
cells, the generation of free radicals linked to the formation
of advanced glycation endproducts (AGEs) and / or advanced
lipoxidation endproducts (ALEs) as well as defects in the
mitochondrial respiratory chain. Substances preventing these
cytotoxic events are considered to be potentially neuroprotective.
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