Current
Drug Targets, Volume 5, No. 7, 2004
Contents
Ion Channels as Important Targets for
Antiepileptic Drug Design Pp.589-602
Neuroprotection Against Ischemic/Hypoxic
Brain Damage: Blockers of Ionotropic Glutamate Receptor and Voltage Sensitive
Calcium Channels Pp.603-618
A. Schurr
Microglia-Targeted Pharmacotherapy in Retinal
Neurodegenerative Diseases Pp.619-627
Erik Schuetz and Solon
Thanos
In Vivo MRI in Different Models of Experimental
Epilepsy Pp.629-636
P.F. Fabene and A.
Sbarbati
Clinical Pharmacotherapy for Obesity: Current
Drugs and Those in Advanced Development Pp.637-646
Jason C.G. Halford
Traumatic Injury to CNS Fiber Tracts - What
are the Genes Telling Us? Pp.647-654
Daniel Abankwa and
Patrick Kury
Psychosocial Conditions and the Efficacy of
Clinically Available Anxiolytics Pp.655-664
Jozsef Haller, Jozsef
Halasz and Eszter Majercsik
Abstracts
[Back to top] Ion Channels as Important Targets for
Antiepileptic Drug Design
P. Yogeeswari, J.
Vaigunda Ragavendran, R. Thirumurugan, A. Saxena, D. Sriram
Ion
channels have a critical role in the function of the nervous system, where they
instigate and conduct nerve impulses by asserting control over the voltage
potential across the plasma membrane. Propagation of electrical impulses occurs
by opening of voltage-gated ion channels. Ion channel blockers prevent this
from occurring, and can therefore be used in the treatment of central nervous
system disorders and neuropathic pain. Recent identification of ion channel
gene mutations in Mendelian epilepsies suggests that genetically driven
neuronal hyperexcitability plays an important role in epileptogenesis. Studies
with animal seizure models have indicated that changes in temporal and spatial
expression of voltage-gated sodium channels may be important in the pathology
of epilepsy. This paper is aimed at elucidating the organization of the ion
channels and covers a review on the antiepileptic drugs, both established and
currently under development targeted to the ion channels in order to bring
about effective seizure control.
[Back to top] Neuroprotection Against Ischemic/Hypoxic
Brain Damage: Blockers of Ionotropic Glutamate Receptor and Voltage Sensitive
Calcium Channels
A. Schurr
The
growing number of cellular and molecular pathways believed to be involved in
mechanisms of ischemic cell death in the brain has spurred a similar growth in
the number of potential neuroprotective modalities, the majority of which are
pharmacological in nature. Preventing or minimizing the first few steps in the
cascade of events leading to ischemic cell death would have a more profound
effect on the postischemic outcome than intervention at later steps in that
cascade. This logic is, of course, at the heart of the urgency in providing the
stroke or cardiac arrest patient with the earliest possible neuroprotective
treatment. For the purpose of assessing potential neuroprotective modalities,
the use of a well-established cerebral hypoxic/ischemic model system is a
prerequisite. In our studies, we have used two major approaches, in vitro
and in vivo. We evaluated both agonists and antagonists of ionotropic
glutamate receptor channels (IGRC) and their effects in exacerbating and
attenuating, respectively, the posthypoxic/ischemic outcome. Other drugs were
tested for their ability to block the L-type voltage-sensitive calcium channels
(VSCC), which are responsible for calcium influx and overload upon
hypoxia/ischemia. These two membrane protein entities, the IGRC and the VSCC,
are believed to be involved in the early stages of the cellular cascade that
leads to the demise of neurons posthypoxia/ischemia. Some of the drugs were
also tested for possible interaction with each other searching for possible
synergy. These and other published studies in the field are reviewed here.
[Back to top]
Microglia-Targeted Pharmacotherapy in Retinal
Neurodegenerative Diseases
Erik Schuetz and Solon
Thanos
Microglial
cells, members of the monocytic lineage, represent the resident immunocompetent
cells of the central nervous system including the retina with its peculiarities
like a double blood retinal barrier. Microglial cells invade the retina in
response to naturally occurring neuronal death during embryonic development and
remodelling. Resident microglial cells are extremely sensitive to changes in
their microenvironment arising from either traumatic or chronic
neurodegeneration, inproper wiring, hereditary diseases or infection and become
rapidly activated. In their activated state, the cells undergo drastic
morphological changes, upregulate a variety of receptors and secrete soluble
factors, which contribute to recognition and phagocytotic cleareance of dying
or malfunctioning neurons.
In this
review, we aim to summarise the current knowledge of microglial involvement in
experimentally induced or naturally occurring retinal neurodegenerations with
emphasising on mechanisms of microglia activation. Expanding on the mechanisms,
we shall discuss on approaches to pharmacologically interfere with the
microglial activation and neurophagy. The protagonistic role of these cells in
the outcome of certain diseases may help designing microglial targeted
treatments with potential benefit for neuronal survival and regeneration in
clinically relevant conditions.
[Back to top] In Vivo MRI in Different Models of
Experimental Epilepsy
P.F. Fabene and A.
Sbarbati
In order
to investigate epilepsy, that is one of the most common neurological disorders,
in the last decades different animal models have been proposed. Prevention,
diagnosis, treatment and basic knowledge have been improved by the mean of
these models.
Numerous
animal models have been developed in epilepsy research, both for generalized
and for simple/complex partial seizures. Animal models for generalized seizures
include sensory (light, noise, movement, etc) or electrical stimulations and
genetic models. Models for focal seizures include topical or systemic
application of pro-convulsive compounds or electrical stimulation. Baboons,
mice, rats, rabbits, and Fayoumi chicken have been extensively used in this
regard.
Since
1983, when magnetic resonance spectroscopy was used to evaluate for the first
time in vivo alterations induced by status epilepticus in rabbit,
an increasing interest for the neuroimaging perspective has led to new insights
in the study of epileptic disorders. In the early 1990s experimental studies
provided evidence for the feasibility of magnetic resonance imaging analysis
and detection of tissue damage in kainic acid-induced epilepsy in rat. In the
following years a wealth of data has been obtained by the mean of functional
MRI and/or by diffusion-weighted images.
The
studies reported in the literature of the last decades indicate in vivo
magnetic resonance of epilepsy model as valuable and extremely informative
tool.
[Back to top] Clinical Pharmacotherapy for Obesity: Current
Drugs and Those in Advanced Development
Jason C.G. Halford
The
current obesity pandemic imposes a major global disease burden. Levels of
non-communicable diseases such as type 2 diabetes, cardiovascular disease and
some cancers will continue to rise unless an effective approach to treat
obesity is found. Sustained weight loss of between 5-10% in the obese, by
various means, confers marked health benefits. The currently available
pharmacotherapies, orlistat and sibutramine, can induce weight loss of between
5-10% over 2 years or more. In trials, orlistat and sibutramine induced weight
loss tends to be only between 2-4 kg greater than that produced by placebo
control. However, this additional placebo subtracted weight loss produces
marked additional improvements in diabetes and cardiovascular risk factors.
Moreover, in the 4 year long XENDOS trial, the modest placebo subtracted weight
loss produced by orlistat (2.8 kg) reduced the incidence of diabetes by over a
third in those with normal glucose tolerance, and by nearly half in those with
impaired glucose tolerance. Despite this, prescription sales of sibutramine in
the US have apparently remained static and those of orlistat have fallen, with
the drug now entering the global over-the-counter medication market. Recent
data on potential anti-obesity drugs currently under going phase III trials,
such as Rimonabant and Topiramate, demonstrate these drugs produce greater and
more prolonged weight loss. Wider use of pharmacotherapy and enhanced efficacy
for the next generation of anti-obesity drugs certainly promise to reduce
obesity related illness if not halt the rise in obesity per se.
[Back to top] Traumatic Injury to CNS Fiber Tracts - What
are the Genes Telling Us?
Daniel Abankwa and
Patrick Kury
In
contrast to the peripheral nervous system (PNS) nerve fiber tracts of the adult
central nervous system (CNS) cannot spontaneously regenerate in response to
lesions. As a result injured individuals suffer from chronically impaired
neuronal connections leading to major motor-, sensory- and cognitive deficits.
It is generally assumed that combinatorial effects account for this
regeneration failure including a growth non-permissive environment within CNS
lesion zones as well as incomplete activation of axonal growth programmes. In
order to design CNS repair strategies it is, therefore, imperative to address
the molecular mechanisms responsible for this abortive growth behaviour by
means of large scale screening techniques. This review summarizes the outcome
of recent gene expression profiling studies investigating local and remote
molecular reactions following CNS axotomy.
[Back to top] Psychosocial Conditions and the Efficacy of
Clinically Available Anxiolytics
Jozsef Haller, Jozsef
Halasz and Eszter Majercsik
The
treatment of anxiety cannot be considered a solved problem, therefore, efforts
are directed towards the development of novel treatment approaches. Increasing
evidence suggests, however, that the efficacy of available treatments can be
improved by taking into account the yet poorly known interactions between
psychosocial conditions and the efficacy of pharmacological treatments. We
review here evidence demonstrating that psychosocial factors affect the
properties and function of receptors that mediate the effects of clinically
available anxiolytics. Such neuronal changes affect the efficacy of
anxiolytics, which consequently depends largely on psychosocial factors. We
show that the interaction between psychosocial factors and drug responsiveness
is clinically relevant. Laboratory studies predict that (i) the frequent
exposure of subjects to acute stressors lowers the efficacy of benzodiazepines
and buspirone, but increases the efficacy of selective serotonin reuptake
inhibitors (SSRIs); (ii) the anxiolytic efficacy of buspirone is largely
affected by social support and stability, whereas (iii) the efficacy of SSRIs
is larger in subjects experiencing early maltreatment. Laboratory studies also
show that the side effects of compounds decrease under certain conditions.
Disparate human studies suggest that such predictions are clinically valid.
Thus, further research on the relationship between psychosocial (Axis-IV)
factors and drug efficacy would lead to substantial therapeutic progress with
the available anxiolytic compounds. This interaction should be in focus also
when new therapeutic approaches are developed.