| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 20, 2006
Contents
Drugs Promoting Wakefulness and Performance
Executive Editor: J.G. Ramaekers
Editorial Pp. 2455-2456
Effects of Modafinil on Cognitive Performance and Alertness
During Sleep Deprivation Pp. 2457-2471
N.J. Wesensten
[Abstract]
Serotonin and Human Cognitive Performance
Pp. 2473-2486
J.A.J. Schmitt, M. Wingen, J.G. Ramaekers, E.A.T. Evers
and W.J. Riedel
[Abstract]
Dopaminergic Enhancement of Cognitive Function
Pp. 2487-2500
M.A. Mehta and W.J. Riedel
[Abstract]
Stimulating Effects of H1-Antagonists
Pp. 2501-2509
E.L. Theunissen, A. Vermeeren, E.F.P.M. Vuurman and J.G.
Ramaekers
[Abstract]
Improving Memory: A Role for Phosphodiesterases
Pp. 2511-2523
A. Blokland, R. Schreiber and J. Prickaerts
[Abstract]
Human Cognition Assessment in Drug Research
Pp. 2525-2539
W.J. Riedel, M.A. Mehta and P.J. Unema
[Abstract]
Therapeutics for Protein Misfolding Diseases
Executive Editor: Claudio Soto
Editorial Pp. 2541-2542
Therapeutic Approaches to Polyglutamine Diseases:
Combating Protein Misfolding and Aggregation Pp.
2543-2555
M. Herbst and E.E. Wanker
[Abstract]
Inhibition of Protein Misfolding and Aggregation
by Small Rationally-Designed Peptides Pp. 2557-2567
L.D. Estrada and C. Soto
[Abstract]
Immunotherapy for Conformational Diseases
Pp. 2569-2585
E.M. Sigurdsson
[Abstract]
Role of Copper in Prion Diseases: Deleterious
or Beneficial Pp. 2587-2595
L. Varela-Nallar, A. González and N.C. Inestrosa
[Abstract]
Abstracts
[Back
to top]
Editorial
Drugs Promoting Wakefulness and Performance
In modern society the market for drugs to enhance human performance
is large. Health-food stores and Internet sites already offer
a large variety of ‘smart drugs’ or ‘nootropics’
that are claimed to improve intelligence in humans of all
age categories. Such products usually include multivitamins
or herbal extracts from ginseng, ginko biloba or other substances
derived from non-Western cultures. Most of these claims are
largely unsubstantiated but there is growing evidence that
some of these substances can actually mildly improve overall
cognitive functioning in healthy subjects as indicated by
composite neuropsychological measures of cognitive performance
[1].
Similarly, drugs are being used that sustain or increase arousal
to help stimulate human performance, particularly during periods
of fatigue or sleepiness. The classical examples being amphetamine
use in long-haul truck drivers, students, athletes and the
military at times of war. Though amphetamines when given in
low doses have been repeatedly shown to improve performance
and cognitive function the drugs are also associated with
a range of psychological en physical side effects, particularly
after repeated use. When the drugs wear off, a long period
of sleep ensues, often followed by hunger and depression,
which can lead to further use of amphetamines. Amphetamine
addiction has been common among those who have used the drugs
for increased energy, alertness, or endurance.
Side effects that are associated with amphetamine use are
believed to be absent or relative minor with modafinil as
reviewed in the paper by Wesensten [2]. Modafinil is a schedule
IV drug promoting wakefulness that has been approved for the
treatment of narcolepsy, sleep apnea syndrome, and shift work
sleep disorder. Modafinil’s performance enhancing effects
were quickly discovered by the military as a means to keep
military personnel at work for 40 hours straight, without
feeling "wired" and without crashing afterward [3].
Also, elite athletes were quick to discover modafinil. In
November 2004, the U.S. Olympic gold medal for the 1600 meter
relay was revoked and given to France because US athlete Calvin
Harrison tested positive for modafinil.
Discovering molecules that enhance cognition and performance
comprises one of the most exciting areas in drug development.
At present the psychopharmacology of wakefulness has focused
primarily on 2 parallel pathways that activate the cortex.
The first pathway includes monominergic projections from the
brainstem to the cortex via the ascending reticular formation.
Stimulation of this pathway may be mediated by dopamine, serotonine,
noradrenaline and acetylcholine and result in increased levels
of ‘external’ vigilance or hypervigilance. Stimulants
such as amphetamines and caffeine are supposed to activate
this system. Stimulation of the second pathway is believed
to increase levels of another form of arousal: i.e. ‘internal’
vigilance. Internal vigilance may be mediated by the ascending
histaminergic neurons and stimulation of this pathway should
lead to enhanced problem solving and cognitive function without
producing any of the side effects associated with ‘external’
vigilance as in the case of amphetamines. The papers by Smitt
and coworkers [4], Mehta and Riedel [5] and Theunissen and
coworkers [6] provide a detailed review of the association
between serotonin, dopamine, histamine and human performance
enhancement.
Interestingly, the search for a ‘viagra for the brain’
also comprises studies on the association between cognition
enhancement and PDE5 inhibitors, a drug class of which viagra
is a distinguished member. PDE5 inhibitors have been repeatedly
shown to improve recognition memory in animals. The mechanism
underlying the nootropic effect of PDE5 inhibitors however
is largely unknown. PDE5 has been implicated to play a role
in memory formation in animals through long-term potentiation.
It is hypothesized that presynaptic cGMP stimulates the release
of glutamate that in turn will bind to postsynaptic NMDA receptors.
Human studies demonstrating memory enhancing effects of PDE5
inhibitors are presently lacking but will offer an interesting
challenge for researchers in the near future. The article
by Blokland and coworkers [7] nicely analyzes and reviews
the present data on cognition enhancements and PDE5 inhibitors.
This special issue on “Drugs promoting wakefulness and
performance” encompasses psychopharmacological research
related to the issues outline above. Key concepts include
1) the pharmacological pathways and substrates underlying
cognition and performance enhancement as indicated above and
2) methods and measures for assessing human performance in
drug development. The latter aspect is primarily covered in
the paper by Riedel and coworkers [8] that provides a thorough
and insightful review of contemporary measures of human performance
that are being used in drug development and drug evaluation
today.
References
[1] Scholey A, Kennedy D, Wesnes K. The psychopharmacology
of herbal extracts: issues and challenges. Psychopharmacology
(Berl) 2005; 179: 705-707.
[2] Wesensten N. Modafinil effects on cognitive performance
and alertness during sleep deprivation. Curr Pharm Design
2006; 12(20): 2457-2471.
[3] Caldwell JA, Caldwell JL. Fatigue in military aviation:
an overview of US military-approved pharmacological countermeasures.
Aviat Space Environ Med 2005; 76: C39-51.
[4] Schmitt JAJ, Wingen M, Ramaekers JG, Evers L, Riedel WJ.
Serotonin and human cognitive performance. Curr Pharm Design
2006; 12(20): 2473-2486.
[5] Mehta MA, Riedel WJ. Dopaminergic enhancement of cognitive
function. Curr Pharm Design 2006; 12(20): 2487-2500.
[6] Theunissen EL, Vermeeren A, Vuurman EFPM, Ramaekers JG.
Stimulant effects of H1 antagonists. Curr Pharm Design 2006;
12(20): 2501-2509.
[7] Blokland A, Schreiber R, Prickaerts J. Improving memory:
a role for fosfodiesterase. Curr Pharm Design 2006; 12(20):
2511-2523.
[8] Riedel WJ, Mehta MA, Unema PJ. Human cognition assessment
in drug research. Curr Pharm Design 2006; 12(20): 2525-2539.
J.G. Ramaekers
Experimental Psychopharmacology Unit
Faculty of Psychology
Maastricht University
The Netherlands
[Back to top]
Effects of Modafinil on Cognitive Performance and Alertness
During Sleep Deprivation
N.J. Wesensten
The performance- and alertness-sustaining/restoring
effects of modafinil during sleep deprivation in normal, healthy
adults were reviewed. Results indicate that modafinil is efficacious
for sustaining/restoring objective performance and alertness
during sleep deprivation with few adverse effects. At appropriate
dosages, modafinil restores performance and alertness to non-sleep
deprived levels. Modafinil also impairs post-sleep deprivation
recovery sleep, but from the few studies available addressing
this issue, it is unclear whether these sleep impairments
translate into post-sleep performance impairments. Further
research is needed to determine whether modafinil restores
performance on simple cognitive tasks only or whether modafinil
additionally restores executive functions (e.g., abstract
thought, critical reasoning, planning, decision-making, situational
awareness, and effective judgment) which are critical in most
modern operational settings. In addition, studies are needed
to determine whether modafinil use during sleep deprivation
is preferable to that of other available controlled stimulants
(such as dextroamphetamine) or non-controlled stimulants (such
as caffeine). Such studies would be comprised of direct, head-to-head
comparisons among various stimulants across a range of dosages.
[Back to top]
Serotonin and Human Cognitive Performance
J.A.J. Schmitt, M. Wingen, J.G. Ramaekers, E.A.T. Evers
and W.J. Riedel
In the past decade, experimental studies involving healthy
human volunteers have revealed that manipulations of the central
serotonin (5-HT) system can produce quite specific changes
in cognitive functioning, independent of overt mood changes.
Reduced 5-HT turnover is consistently associated with impaired
long-term memory functioning. Low 5-HT function may also impair
cognitive flexibility and improve focused attention. On the
other hand, stimulation of central 5-HT has repeatedly been
found to impair performance in a true vigilance task. Currently,
there is little evidence for mirrored cognitive changes due
to opposite 5-HT manipulations in healthy volunteers. Given
the mounting evidence for a role of 5-HT in human cognition,
reduced 5-HT function could be directly linked to cognitive
disturbances in certain conditions, such as in depression
and Alzheimer’s Disease (AD). There is evidence that
stimulating (i.e. normalizing) 5-HT activity in depression
may have specific beneficial effects on cognition, independent
of a general relief of depressive symptoms, but this premise
needs to be confirmed by larger-scale clinical studies. Recently,
a potential role of 5-HT in the cognitive symptoms in AD has
been identified, but there is insufficient data to evaluate
the effects of 5-HT stimulation on cognitive symptoms in AD.
It is concluded that serotonin is a potential target for pharmacological
cognition enhancement, particularly for restoration of impaired
cognitive performance due to 5-HT dysfunction. Further differentiation
of the role of 5-HT in normal and disturbed cognition and
evaluation of the effects of 5-HT manipulations in various
populations is required to establish the full potential of
5-HT drugs as cognition enhancers.
[Back to top]
Dopaminergic Enhancement of Cognitive Function
M.A. Mehta and W.J. Riedel
The ascending dopamine system of the mammalian brain
has been associated with motor, mnemonic and goal-directed
or reward-related behaviour. The most progress in understanding
the cortical mechanisms of dopaminergic modulation of function
has been made with regards to short-term mnemonic (or working
memory) function. Research in experimental animals strongly
suggests that stimulation of dopamine D1 receptors in the
prefrontal cortex can ameliorate spatial working memory related
cognitive deficits, and may even enhance cognitive function
in healthy animals. Research in humans has not been able to
clearly replicate these findings, partly due to the lack of
available agents that can safely be used. Low doses of dopamine
D2 receptor agonists such as bromocriptine and pergolide may
be able to enhance working memory and executive functions,
but these effects may be dependent on the nature of the tasks
used and the baseline performance levels of the subjects.
Thus, the effects of dopaminergic cognitive enhancers may
not be simple, or uniform across subjects. Systematic studies
in humans carefully controlling task parameters are needed
in order to specify the potential cognitive processes open
to enhancement with dopaminergics. However, since the DA receptor
subtypes in different brain regions appear to differentially
influence similar functions, carefully defining the cognitive
processes to be tested against potential therapeutics is an
equally important goal. Studies in patients groups using selective
dopaminergics are rather restricted, but show promise for
designing large-scale clinical trials into the cognitive enhancing
properties of potential therapeutic agents that act through
the dopamine system.
[Back to top]
Stimulating Effects of H1-Antagonists
E.L. Theunissen, A. Vermeeren, E.F.P.M. Vuurman and J.G.
Ramaekers
Whereas antihistamines are generally known for their
sedative side effects, this review shows that several studies
also found mild stimulating effects on performance for the
H1-antagonists terfenadine, ebastine, fexofenadine and desloratadine.
These stimulating effects were mostly demonstrated in tasks
involving high levels of attention, e.g. divided attention
tasks, vigilance tasks and driving tasks. The stimulating
effects of these antihistamines were often dependent of the
given dose; however the relation was not always linear. The
mechanism responsible for the stimulating effects of these
four antihistamines is still unclear, though it is hypothesized
that it involves other neurotransmitters like dopamine and
GABA, or that it acts through the H3 histamine receptor. Further
research is needed to clarify the ambiguous role of histamine
in processes of arousal. In addition, it would be useful to
determine whether terfenadine, ebastine, fexofenadine and
desloratadine can return allergic patient’s performance
back to their preclinical level.
[Back to top]
Improving Memory: A Role for Phosphodiesterases
A. Blokland, R. Schreiber and J. Prickaerts
During the last decennia, our understanding of the
neurobiological processes underlying learning and memory has
continuously improved, leading to the identification of targets
for the development of memory-enhancing drugs. Here we review
a class of drugs which has more recently been identified:
the phosphodiesterase (PDE) inhibitors. An overview is given
of the different PDEs that are known and we focus on three
PDEs which have been identified as possible relevant targets
for memory improvement: PDE2, PDE4 and PDE5. PDEs differ in
the substrate, i.e. cyclic adenosine monophosphate (cAMP)
and/or cyclic guanosine monophosphate (cGMP), being hydrolyzed.
Since these cyclic nucleotides have been suggested to play
distinct roles in processes of memory, selective PDE inhibitors
preventing the breakdown of cAMP and/or cGMP could improve
memory. The present data suggest that PDE4 (cAMP) is involved
in acquisition processes, although a possible role in late
consolidation processes cannot be excluded. PDE5 (cGMP) is
involved in early consolidation processes. Since PDE2 inhibition
affects both cAMP and cGMP, PDE2 inhibitors may improve both
memory processes. The field of PDEs is highly dynamic and
new isoforms of PDEs are still being described. This may lead
to the discovery and development of new memory enhancing drugs
that selectively inhibit such isoforms. Such drugs may exert
their effects only in specific brain areas and hence possess
an improved side effect profile.
[Back to top]
Human Cognition Assessment in Drug Research
W.J. Riedel, M.A. Mehta and P.J. Unema
In this article cognition assessments as outcome measures
in CNS drug development research are described. An outline
is given of the various choices that can be made and the reasons
for them, depending on the approach followed. First, a brief
historical context is provided of the psychological sciences
that have contributed to today’s psychopharmacology
of cognition assessment. Subsequently, the focus is on identifying
cognitive domains and criteria for selecting appropriate tests.
In applied cognitive performance assessment in human psychopharmacology,
a number of approaches can be recognised, each associated
with models that connect cognitive functions with physiological
functions and neural structures. The product-oriented approach
of cognition assessment is usually characterised by the use
of a battery of several cognitive tasks as an assessment instrument
and aims to demonstrate an effect of a pharmaceutical substance
without much attempt to determine which cognitive process
is primarily influenced by a drug. The process-oriented approach
precisely defines the cognitive process in terms of at least
a single factor linear model of a process (e.g. by manipulating
levels of difficulty) and then compares how diseases and drugs
modify the parameters of that process. The associated factor
analytical-, resource-strategy- and staged information processing
models respectively are described. Finally a brief review
is presented on possible physiological markers or biomarkers
of human cognitive functions.
Therapeutics for Protein Misfolding Diseases
Executive Editor: Claudio Soto
[Back to top]
Editorial
Therapeutics for Protein Misfolding Diseases
The appropriate functioning of living organisms depends upon
the correct performance and inter-relationship of different
organs and tissues. Cells are the basic units of tissues and
their proper function depends upon a network of thousand of
proteins, each of which plays an important and specific role.
The biological function of a protein depends on its threedimensional
structure, which is determined by its amino acid sequence
during the process of protein folding. In spite that protein
folding is a process carefully regulated to avoid and correct
mistakes; in the last few years, it has become clear that
diverse diseases are the result of protein misfolding. These
diseases are now grouped together under the name of protein
misfolding disorders (PMDs). This group includes Alzheimer’s
disease, transmissible spongiform encephalopathies, serpin-deficiency
disorders, hemolytic anemia, Huntington disease, cystic fibrosis,
diabetes type II, Amyotrophic Lateral Sclerosis, Parkinson
disease, spinocerebellar ataxias, dialysis-related amyloidosis
and more than 15 other less well-known diseases. The hallmark
event in these diseases is the misfolding of an otherwise
normal protein, which usually aggregates and accumulates in
diverse tissues (Fig. 1), inducing cell death,
tissue damage and organ dysfunction.
Fig. (1).. The misfolding of a protein into
fibrillar aggregates is a hallmark feature of several human
diseases, known as Protein Misfolding Disorders. The misfolded
protein aggregates typically accumulate in the affected tissue
as amyloid-like plaques. Interfering with protein misfolding
and aggregation has become one of the most promising targets
for therapeutic intervention.
This issue of Current Pharmaceutical Design contains 4 articles
reviewing different approaches for therapy of these diseases.
Some of the articles are focused in a particular disease,
but the approaches described can be extrapolated to other
members of the group.
The first article by Herbst and Wanker [1] describes the identification
and evaluation of small chemical molecules to inhibit misfolding
and aggregation of poly-glutamine rich proteins, implicated
in the pathogenesis of Huntington disease, spinocerebellar
ataxias and other rare diseases. The authors also describe
the possibility of inducing a heat-shock response to upregulate
the concentration of molecular chaperon proteins that may
interfere or correct the misfolding event.
The second article by Estrada and Soto [2] reviews the use
of short synthetic peptides rationally designed to interact
specifically with the protein undergoing misfolding and prevents
the conformational changes leading to the accumulation of
misfolded aggregates. The peptide approach has been extensively
used in several PMDs and some of the more developed compounds
have reached clinical trials.
The article by Sigurdsson [3] describes the immunotherapeutic
approach for preventing misfolding and aggregation. This strategy
is based on using the immune system, either by active or passive
immunization to remove specifically the protein implicated
in the different diseases. Much progress has been done in
analyzing the effectiveness of the immunotherapy, mainly in
Alzheimer’s disease and prion-related disorders.
Finally, the article by Varela-Nallar, Gonzalez and Inestrosa
[4] discusses the role of metal ions in protein misfolding,
focusing specifically on prion diseases. Metal ions, and particularly
copper, zinc and aluminum, have been extensively implicated
in the process of protein misfolding and aggregation in several
PMDs. Despite various therapeutic strategies have been designed
to interfere with the binding of the metal ions to the misfolded
protein, it is still not clear whether this interaction is
beneficial or detrimental.
The overall aim of these 4 articles is to discuss the strengths
and limitations of different strategies used and the under
development which interferes with protein misfolding and aggregation
and possibility to use them as a novel treatment for a variety
of diseases.
References
[1] Herbst M, Wanker EE. Therapeutic Approaches to Polyglutamine
Diseases: Combating Protein Misfolding and Aggregation. Curr
Pharm Design 2006; 12(20): 2543-2555.
[2] Estrada LD, Soto C. Inhibition of Protein Misfolding and
Aggregation by Small Rationally-Designed Peptides. Curr Pharm
Design 2006; 12(20): 2557-2567.
[3] Sigurdsson EM. Immunotherapy for Conformational Diseases.
Curr Pharm Design 2006; 12(20): 2569-2585.
[4] Varela-Nallar L, González A, Inestrosa NC. Role
of Copper in Prion Diseases: Deleterious or Beneficial. Curr
Pharm Design 2006; 12(20): 2587-2595.
Claudio Soto, PhD
Green Distinguished University Chair in Neuroscience and Professor
Dept. of Neurology, Biochemistry and Neuroscience & Cell
Biology
Director George and Cynthia Mitchell Center for Alzheimer’s
Disease Research
University of Texas Medical Branch
Galveston, TX 77555
USA
E-mail: clsoto@utmb.edu
[Back to top]
Therapeutic Approaches to Polyglutamine Diseases:
Combating Protein Misfolding and Aggregation
M. Herbst and E.E. Wanker
Polyglutamine diseases are autosomal dominant, late-onset
neurodegenerative disorders. Expansion of a polyglutamine
(polyQ) tract above a threshold size leads to misfolding and
aggregation and eventual intracellular accumulation of the
disease-specific protein. To date, only symptomatic treatments
of limited effectiveness are available. Various research strategies
aim to interfere with known steps in the pathomechanism. Protein
misfolding and aggregation probably occur very early in the
cascade of pathogenic events and are therefore attractive
targets for potential drug treatment. Misfolding of polyQ
proteins may either be prevented by drugs that stabilize the
native conformation or via induction of cellular
chaperones. Several amyloid-binding dyes as well as small
molecules that inhibit polyQ protein aggregation have been
identified in compound screens and may be entered into drug
development. Small molecule inhibitors of further pathogenic
phenomena like transcriptional repression, excitotoxicity,
mitochondrial dysfunction, and neuronal cell death have been
tested in vitro and in vivo. The first drugs
have now reached clinical trial stage. More general studies
of how putative steps in the pathomechanism can be modulated
will yield further insights into the pathogenesis of polyQ
disorders.
[Back to top]
Inhibition of Protein Misfolding and Aggregation by
Small Rationally-Designed Peptides
L.D. Estrada and C. Soto
Several human diseases are associated with the presence
of toxic fibrillar protein deposits. These diseases called
protein misfolding disorders, are characterized by the accumulation
of misfolded protein aggregates in diverse tissues. Strong
evidence indicates that the conversion of a normal soluble
protein into a β-sheet-rich
oligomeric structure and further fibrillar aggregation are
the key events in the disease pathogenesis. Therefore, a promising
therapeutic target consists of the prevention and dissolution
of misfolded protein aggregates. Peptides designed to specifically
bind to the pathogenic protein and block and/or reverse its
abnormal conformational change constitute a new class of drugs.
This article reviews this approach, describing diverse compounds
reported to have this activity.
[Back to top]
Immunotherapy for Conformational Diseases
E.M. Sigurdsson
The seminal finding that immunization with amyloid-β
1-42 in Alzheimer’s disease (AD) mouse model prevented
formation of and/or cleared amyloid plaques has led to numerous
studies exploring related approaches for AD and other conformational
degenerative disorders. While clinical trials in AD patients
were discouraging because of serious side effects, this approach
remains promising in light of recent findings in animal models,
in which refinements aimed at reducing potential adverse reactions
continue to lead to cognitive improvements. In addition to
AD and its models, this type of therapy has primarily been
assessed in prion disease with positive results, further supporting
the potential of immunotherapy for a variety of protein-related
diseases in which clearance of the pathogenic agent is likely
to alleviate symptoms.
[Back to top]
Role of Copper in Prion Diseases: Deleterious
or Beneficial
L. Varela-Nallar, A. González and N.C. Inestrosa
Prion diseases are fatal neurodegenerative disorders
associated with conformational conversion of the cellular
prion protein (PrPC) into an isoform designated
PrPSc. The pathogenic mechanism that links this
conformational distortion with the development of prion diseases
is unknown. PrPC is a GPI-anchored cell surface
protein that associates with lipid rafts, undergoes endocytosis
and recycles. Although the physiological function of PrPC
remains unknown it has been related with a number of processes,
including cellular copper transport and metabolism. PrPC
has two copper binding domains and copper induces changes
in PrPC conformation and endocytic behavior. However,
the role of copper in prion diseases is unclear. PrPC
expression and interaction with PrPSc are required
for prion progression. Therefore, factors that modify PrPC
expression levels, conformation, intracellular trafficking
and segregation into membranous microdomains could change
the opportunities for and the quality of PrPC interactions
with PrPSc and thus influence prion pathogenesis.
Here we discuss the potential of copper as modifier of these
processes, attempting to integrate apparently contradictory
observations which so far left uncertain whether copper exerts
beneficial or detrimental effects upon prion diseases. The
outcome of copper effects might be the resultant of two opposite
conditions: one promoting misfolding of PrPC leading
to prion conversion and the other promoting PrPC
trafficking through pathways that prevent PrPSc-PrPC
interaction. Which of these predominates might vary under
distinct conditions that need to be defined before deciding
on the feasibility of either incorporating or avoiding metal
influences in prion disease therapies.
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