Current Pharmaceutical Design - Volume 12, Issue 20, 2006

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 In November 2004, the U.S. Olympic gold medal for the 1600 meter relay was revoked and given to France because US athlete Calvin Harrison tested positive for modafinil.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

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.

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.

The ascending dopamine system of the mammalian brain has been associated with motor, mnemonic and goaldirected 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.

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.

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.

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.

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. 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, Gonzalez A, Inestrosa NC. Role of Copper in Prion Diseases: Deleterious or Beneficial. Curr Pharm Design 2006; 12(20): 2587-2595.

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.

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.

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.

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.