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Today, 12 Ιουλίου 2016, 4:20:09 μμ
Editorial (Thematic Issue: New Therapeutic Targets for Autism Spectrum Disorders)
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Repositioning of Drugs in Cardiometabolic Disorders: Importance and Current Scenario
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Cardiometabolic disorder (CMD) is a cluster of diseases, including cardiovascular diseases (CVDs), metabolic syndrome (MS) and diabetes mellitus (DM). Cardiometabolic disorders (CMDs) remain the principal cause of death in both developed and developing countries, accounting for nearly 32% of all deaths worldwide per year. In addition, dyslipidemia, angina, arrhythmia, cardiac failure, myocardial infarction (MI), and diabetes mellitus represent the leading killer with an estimated 19 million people died from CMDs in 2012. By 2030 more than 23 million people will die annually from CVDs. Existing drugs are not efficient enough to reduce the disease burden as well as mortality. Therefore, there is an urgent demand for new drugs in this area to reduce the mortality and control the associated disability. Nonetheless, new drug discovery (NDD) in CMDs has become more challenging for last couple of decades due to increased expenses and decreased success rate. In such a scenario, drug repositioning in the CMDs appears promising for introducing existing drugs for new therapeutic indication. Repositioning is quite an old strategy dating back to 1960s and mainly followed by serendipitous observations during clinical use of drugs. A major advantage of repositioning is that the safety profile of the drug is well established thus reducing the chances of failure due to adverse toxic effects. In addition, repositioning requires less time and investment than NDD. Considering these facts, pharmaceutical companies are now becoming increasingly interested in drug repositioning. In this follow-up, we have talked about the concept of repositioning with important examples of repositioned drugs in cardiometabolic disorder.
Population Studies of Association Between Lithium and Risk of Neurodegenerative Disorders
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Background: Lithium shows neuroprotective and neurotrophic effects in vitro and in vivo. Due to its involvement in hippocampal neurogenesis and the interaction with beta-amyloid and neurofibrillary tangle metabolism it has been hypothesized that lithium could have the potential to influence the development of dementia. Method: Using the PubMed database and cross-reference search strategies our aim was to specifically identify population (cohort or case-control) studies investigating the association between lithium and dementia. Results: Data from large cohort studies suggest an association between lithium treatment and dementia risk reduction or reduced dementia severity. Studies with smaller sample sizes yield more variable findings. Conclusions: Lithium may reduce the risk of dementia among middle-aged and older people. Beneficial lithium effects are possibly limited to specific types of neurodegenerative processes.
Recent Advances Using Phosphodiesterase 4 (PDE4) Inhibitors to Treat Inflammatory Disorders: Animal and Clinical Studies
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Phosphodiesterase 4 (PDE4) inhibitors can be effective drugs for treating inflammation in different tissues/organs caused by conditions such as asthma, chronic obstructive pulmonary disease (COPD), psoriasis, and Alzheimer’s disease. It has been demonstrated that PDE4 inhibitors used for drug therapy provide some advantages over conventional formulations, including sensitivity to selective inhibitors, unique tissue distribution, and ease of oral administration. To date, the U.S. Food and Drug Administration (USFDA) had approved two PDE4 inhibitors, roflumilast (Daxas®, Daliresp®) and apremilast (Otezla®), for treating respective COPD and plaque psoriasis. Several pharmaceutical companies and academic laboratories continuously develop novel PDE4 inhibitors for clinical application. A concern pertaining to the development of PDE4 inhibitors is the high occurrence rate of side effects such as emesis, nausea, and headache. This review describes recent developments using PDE4 inhibitors for inflammation management. Special attention is paid to the use of PDE4 inhibitors in treating pulmonary and cutaneous inflammation. This review article focuses on issues related to animal and human studies. The action mode of the inhibitors is also addressed.
The Emerging Role of Metabotropic Glutamate Receptors in the Pathophysiology of Chronic Stress-Related Disorders
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Chronic stress-related psychiatric conditions such as anxiety, depression, and alcohol abuse are an enormous public health concern. The etiology of these pathologies is complex, with psychosocial stressors being among the most frequently discussed risk factors. The brain glutamatergic neurotransmitter system has often been found involved in behaviors and pathophysiologies resulting from acute stress and fear. Despite this, relatively little is known about the role of glutamatergic system components in chronic psychosocial stress, neither in rodents nor in humans. Recently, drug discovery efforts at the metabotropic receptor subtypes of the glutamatergic system (mGlu1-8 receptors) led to the identification of pharmacological tools with emerging potential in psychiatric conditions. But again, the contribution of individual mGlu subtypes to the manifestation of physiological, molecular, and behavioral consequences of chronic psychosocial stress remains still largely unaddressed. The current review will describe animal models typically used to analyze acute and particularly chronic stress conditions, including models of psychosocial stress, and there we will discuss the emerging roles for mGlu receptor subtypes. Indeed, accumulating evidence indicates relevance and potential therapeutic usefulness of mGlu2/3 ligands and mGlu5 receptor antagonists in chronic stress-related disorders. In addition, a role for further mechanisms, e.g. mGlu7-selective compounds, is beginning to emerge. These mechanisms are important to be analyzed in chronic psychosocial stress paradigms, e.g. in the chronic subordinate colony housing (CSC) model. We summarize the early results and discuss necessary future investigations, especially for mGlu5 and mGlu7 receptor blockers, which might serve to suggest improved therapeutic strategies to treat stress-related disorders.
Personalized Treatment of Obsessive-Compulsive Disorder: Radiology, EEG, Pharmacogenetics and Biochemistry
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Background: Obsessive-compulsive disorder (OCD) is a common mental illness and a ubiquitous cause of disability. Approximately half of the patients with OCD only partially respond or do not respond at all to current ways of treatment. Even patients responding to treatment usually need high doses of medication and/or intense psychotherapy for a long time. It is obvious that therapeutic approaches to OCD need improving. In this article, we review the modalities of personalized medicine in OCD. </p><p> Methods: We conducted a search in PubMed (until June 2015) and Scopus (until June 2015) by using the following terms: “obsessive-compulsive disorder,” “personalized medicine,” “response prediction,” “pharmacogenetics,” “therapeutic drug monitoring,” “EEG,” “neuroimaging” and “serotonin.” The literature about neuroimaging including radiological techniques (positron emission tomography, single-photon emission tomography, functional and morphometric magnetic resonance imaging and magnetic resonance spectroscopy) and electroencephalography, therapeutic drug monitoring (measuring the plasma levels of drugs), pharmacogenetics (genes encoding cytochrome P450 enzymes, serotonin transporter, serotonin receptors, norepinephrine transporter, dopamine receptors, brain-derived neurotrophic factor [BDNF] and catechol-O-methyltransferase) and biochemistry (whole blood serotonin levels and neuroendocrine challenge tests) is investigated. </p><p> Results: Pre-treatment changes in glucose metabolism shown by radiological instruments might be related to response to medication. Increased alpha in EEG is predictive of good response whereas increased theta forecasts a poor response. BDNF, serotonin receptors and glutamatergic and serotonergic transmission have been found to be somewhat related to treatment response in OCD. Few studies on whole blood serotonin levels and hormone response to challenge with a serotonergic medication in patients seem to have a predictive value in OCD treatment. </p><p> Conclusion: Although the studies to elaborate a personalized treatment of OCD have produced some promising results, much more work is required to provide clinician with a reliable decision tree. </p><p>
A Systematic Review of Plant-Derived Natural Compounds for Anxiety Disorders
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Anxiety disorders are the most common mental illnesses affecting human beings. They range from panic to generalized anxiety disorders upsetting the well-being and psychosocial performance of patients. Several conventional anxiolytic drugs are being used which in turn results in several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being conducted by researchers. </p><p> The aim of the present study is to comprehensively review phytochemical compounds with well-established anxiolytic activities and their structure-activity relationships as well as neuropsychopharmacological aspects. </p><p> Results showed that phytochemicals like; alkaloids, flavonoids, phenolic acids, lignans, cinnamates, terpenes and saponins possess anxiolytic effects in a wide range of animal models of anxiety. The involved mechanisms include interaction with γ-aminobutyric acid (GABA)<sub>A</sub> receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5-hydrodytryptamine (5-HT)<sub>1A</sub> and 5-HT<sub>2A/C</sub> receptors, noradrenergic and dopaminergic systems, glycine and glutamate receptors, and κ-opioid receptor as well as cannabinoid (CB)1 and CB2 receptors. Phytochemicals also modulate the hypothalamo-pituitary-adrenal (HPA) axis, the levels of pro-inflammatory cytokines like interleukin (IL)-2, IL-6, IL-1β and tumor necrosis factor (TNF)-α, and improve brain derived neurotrophic factor (BDNF) levels. Transient receptor potential cation channel subfamily V (TRPV)3, nitric oxide cyclic guanosine monophosphate (NOcGMP) pathway and monoamine oxidase enzymes are other targets of phytochemicals with anxiolytic activity. </p><p> Taking together, these phytochemicals may be considered as supplements to conventional anxiolytic therapies in order to improve efficacy and reduce adverse effects. Further preclinical and clinical studies are still needed in order to recognize the structure-activity relationships, metabolism, absorption, and neuropsychopharmacological mechanisms of plantderived natural agents. </p><p>
Effects of Yokukansan, a Japanese Kampo Medicine for Symptoms Associated Autism Spectrum Disorder
Today, 12 Ιουλίου 2016, 4:20:10 μμ
A neuropsychiatric syndrome, Autism spectrum disorder (ASD) is qualified via impairments in qualitative communication, social interaction, and stereotyped or restricted, repetitive patterns of behavior, interests, or activities. While all ASDs are considered to have qualitative deficits in social relatedness to others, many people with ASDs have other symptoms, including irritability (which includes aggression, self-injurious behavior, and severe tantrums). In order to decrease these behaviors, it is often helpful to make use of behavioral therapy. In addition, due to the intensity and severity of irritability, adjunctive medications are sometimes needed. Although many of the adjunctive medications have been tested and demonstrated to be useful in treating ASD, no clear standardized treatment has emerged. While the adjunctive medications have shown efficacy, the associated side effects have proven to be a barrier to their accepted use. A traditional Japanese medicine, Yokukansan (YKS), is composed of seven kinds of dried herbs and is widely clinically prescribed for treating psychiatric disorders by acting mainly on the glutamatergic and serotonergic nervous systems. YKS may be safe and useful in treating dementia patients’ behavioral and psychological symptoms according to indications from recent studies. We introduce in this review, the ameliorative effects of YKS on Asperger's disorder in open-label studies and on ASDs including pervasive developmental disorder not otherwise specified (PDD-NOS). This review will suggest that YKS is well tolerated and effective for the treatment for subjects with ASD who have severe hyperactivity/noncompliance and irritability/agitation. Additionally, the serotonergic, glutamatergic, anti-inflammatory and neurogenesis effects are explored which are thought to be involved in the mechanisms underlying the efficacy of YKS.
Could Better Phenotyping Small Vessel Disease Provide New Insights into Alzheimer Disease and Improve Clinical Trial Outcomes?
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Alzheimer Disease (AD) is the most common primary cause of dementia with a burgeoning epidemic as life expectancy and general medical care improve worldwide. Recent data from pathologic studies has shown that the cooccurrence of other neurodegenerative and vascular pathologies is in fact the rule rather than the exception. In late onset AD, cerebral small vessel disease (SVD) is almost invariably co-existent to a greater or lesser extent and is known to promote cognitive deterioration. Previous observational studies and clinical trials have largely sought to divide dementia based on predominant neurodegenerative or vascular mechanisms. Given the high degree of overlap, findings from such studies may be difficult to interpret and apply to population cohorts. Additionally opportunities may be lost for uncovering novel interventions that target interactions between co-existent vascular and neurodegenerative pathologies. In the current review, we consider potential pathophysiologic mechanisms through which SVD may be associated with and promote AD pathology. In particular we explore shared environmental and genetic associations and how these may converge via neuroinflammatory pathways potentially providing novel therapeutic targets. SVD has heterogenous manifestations on cerebral imaging and at pathology. We discuss how studying SVD topography may enable us to better identify those at risk for more rapid cognitive decline and improve future clinical trial design.
Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Background: Preclinical studies have shown that lithium modifies pathological cascades implicated in certain neurodegenerative disorders, such as Alzheimer’s disease (AD), Huntigton`s disease (HD), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS). A critical question is whether these pharmacodynamic properties of lithium translate into neurodegenerative diseases modifying effects in human subjects. Methods: We reviewed all English controlled clinical trials published in PubMed, PsycINFO, Embase, SCOPUS, ISI-Web with the use of lithium for the treatment of neurodegenerative disorders between July 2004 and July 2014. Results: Lithium showed evidence for positive effects on cognitive functions and biomarkers in amnestic mild cognitive impairment (aMCI, 1 study) and AD (2 studies), even with doses lower than those used for mood stabilisation. Studies of Li in HD, MSA and CSI did not show benefits of lithium. However, due to methodological limitations and small sample size, these studies may be inconclusive. Studies in ALS showed consistently negative results and presented evidence against the use of lithium for the treatment of this disease. Conclusion: In absence of disease modifying treatments for any neurodegenerative disorders, the fact that at least 3 studies supported the effect of lithium in aMCI/AD is noteworthy. Future studies should focus on defining the dose range necessary for neuroprotective effects to occur.
Editorial (Thematic Issue: Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Diseases: Molecular Targets)
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Nutraceuticals as Lipid-Lowering Treatment in Pregnancy and Their Effects on the Metabolic Syndrome
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Maternal nutrition and lifestyle before and during pregnancy influence both mother and offspring’s health and can be correlated with the metabolic syndrome in later life. Findings from animal and human studies indicate that nutrition during pregnancy has an important role in microbiological, metabolic, physiologic and immunologic development and homeostasis. A low nutritional intake in early pregnancy may represent a risk for adverse effects during pregnancy as well as on birth outcome. It seems that dietary supplementation with probiotics in perinatal period may represent safe and practical approach in dealing with the most common adverse pregnancy outcomes such as obesity and gestational diabetes. The SPRING (Study of Probiotics in the prevention of Gestational diabetes) will give important answers about potential benefits of probiotics in pregnant women who are obese and overweight and otherwise at the high risk for complications during pregnancy. Fish oil supplementation during the last trimester of pregnancy showed no effects on plasma lipids and lipoproteins in offspring, as well as on their adiposity. The effect of hypercholesterolemia during pregnancy on both mothers and child needs to be further investigated as it could have a biological role. The guidelines for the eventual clinical approach currently do not exist. Potential benefits of nutraceuticals on several metabolic parameters have been suggested. Limited evidence does not allow to draw final conclusions on preventive health strategies and dietary patterns that should be promoted during pregnancy. Further prospective and intervention studies are needed to establish it. Healthy lifestyle and dietary advice with appropriate supplements usage should be considered.
Association of Oxidative Stress with Psychiatric Disorders
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Background: When concentrations of both reactive oxygen species and reactive nitrogen species exceed the antioxidative capability of an organism, the cells undergo oxidative impairment. Impairments in membrane integrity and lipid and protein oxidation, protein mutilation, DNA damage, and neuronal dysfunction are some of the fundamental consequences of oxidative stress. Methods: The purpose of this work was to review the associations between oxidative stress and psychological disorders. The search terms were the following: “oxidative stress and affective disorders,” “free radicals and neurodegenerative disorders,” “oxidative stress and psychological disorders,” “oxidative stress, free radicals, and psychiatric disorders,” and “association of oxidative stress.” These search terms were used in conjunction with each of the diagnostic categories of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders and World Health Organization’s International Statistical Classification of Diseases and Related Health Problems. Results: Genetic, pharmacological, biochemical, and preclinical therapeutic studies, case reports, and clinical trials were selected to explore the molecular aspects of psychological disorders that are associated with oxidative stress. We identified a broad spectrum of 83 degenerative syndromes and psychiatric disorders that were associated with oxidative stress. Conclusion: The multi-dimensional information identified herein supports the role of oxidative stress in various psychiatric disorders. We discuss the results from the perspective of developing novel therapeutic interventions.
Metabolic Basis of Polycystic Ovarian Syndrome; Indications for Biochemical Screening
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Background: Polycystic ovary syndrome (PCOS) is a heterogeneous condition with wide range of phenotype the cause of this disorder is unknown, however, increased ovarian androgen production including increased theca cell responsiveness to gonadotropin stimulation, increased pituitary secretion of luteinizing hormone, and hyperinsulinemia have been suggested. Some known risk factors are ethnicity and environmental factors including lifestyle and bodyweight. </p><p> Method: Relevant English language studies from January 1995 to September 2015 were identified, reviewed, synthesized and discussed extensively. </p><p> Result: various forms of PCOS, and the underlying mechanisms; and highlights biochemical, morphological and metabolic hallmarks of PCOS, including trends and emerging phenotypes; and presents a simplified synthesis that integrates current understanding of biochemical and metabolic endocrinology of PCOS are summarized. As no generally accepted criteria exist for its diagnosis, some existing diagnostic criteria that cut across different geographical regions are also highlighted. </p><p> Conclusion: Indeed, emerging evidence points that the severity of menstrual problems could serve as a predictor of the like-hood of insulin resistance in women of reproductive age, suggesting the need for routine metabolic screening and early intervention in PCOS. </p><p>
AMPK As A Target in Rare Diseases
Today, 12 Ιουλίου 2016, 4:20:10 μμ
The AMP-activated protein kinase (AMPK) has emerged as an important sensor of signals that control cellular energy balance in all eukaryotes. AMPK is also involved in fatty acid oxidation, glucose transport, antioxidant defense, mitochondrial biogenesis and the modulation of inflammatory processes. The numerous roles of AMPK in cell physiological and pathological states justified the notable increase in the number of publications in previous years, with almost 1500 scientific articles relative to this kinase in 2014. Due to its role in maintaining energy balance, a dysfunction in AMPK signalling pathway may result in perturbations at the systemic level that contribute to the development of many disease conditions. Among them, more than 7000 poorly-known rare diseases are particularly of social and scientific interest because they are usually chronically debilitating or even lifethreatening and lack effective and safe treatment. Several authors have demonstrated AMPK alterations and the beneficial effect of treatments with drugs regulating AMPK activity in some of these low prevalence pathologies. Among these rare diseases in which AMPK can play an important pathological role are mitochondrial disorders, muscular dystrophies, cardiovascular diseases, neurodegenerative pathologies, or even some types of cancer for the importance of AMPK as a suppressor of cell proliferation. This review focuses on current knowledge about the pathophysiological roles of AMPK and future approaches as therapeutic targeting in rare diseases.
Obstacles and Opportunities for Cholinergic Drug Development in the Treatment of Cognitive Disorders
Today, 12 Ιουλίου 2016, 4:20:10 μμ
The frequency of neuropsychiatric disorders is greater than that of cancer, cardiovascular disease, and diabetes combined, and is growing at a faster rate than any other ailments in the United States or Europe. Despite a considerable need for the development of treatments for central nervous system disorders, pharmaceutical companies continue to reduce investment in this area of research. Of particular concern is the treatment of diseases and disorders that affect cognitive function, which are often given a lower priority for research investment than life threatening conditions or those with overt physical symptoms. Several reasons exist for this reduced investment, including a poor understanding of the mechanisms underlying impaired cognitive function, costly and long periods of development for these medications, disproportionately lower success rates, and a stigma associated with the medical treatment of mental illness. This paper will discuss these issues, review some of the successes resulting from research investment and discuss opportunities that should encourage increased research investment in cognitive disorders and their treatment.
Smell and Taste Disorders Resulting from Cancer and Chemotherapy
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Malnutrition is common in both adult and pediatric patients undergoing treatment for cancer. Patients commonly attribute difficulties maintaining food intake to an altered taste developed during treatment. This review summarizes what is known about taste and smell dysfunction in patients with undergoing chemotherapy as their main treatment modality. Self-reported taste and smell alterations are prevalent in upwards of 86% of cancer patients. There is some evidence for decreased taste sensitivity in cancer patients when assessed using common gustatory tests. In some patients, taste and smell alterations may continue well after their cancer treatment has been completed. Such disorders can increase distress, reduce appetite and contribute towards poor nutritional status in cancer patients. There remain no effective interventions for improving the appetite or nutritional intake of patients with cancer experiencing taste and smell changes. There is a lack of consistency in assessment methodologies for measuring taste and smell changes in cancer patients and we therefore recommend that future work use well-established methods. Research should also take into account the role of food hedonics, food flavor and texture in assessing the association between taste dysfunction, poor oral intake and malnutrition in cancer patients. Both adult and child cancer patients should be counselled on the potential impact taste and smell dysfunction can have on their appetite and oral intake.
Evaluation of a Dramatic Writing Workshop in Youth With or Without Psychiatric Disorders
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Background: Metacognitive difficulties are frequent among youth with a psychiatric disorder. The present study evaluates the effectiveness of a dramatic writing workshop on the metacognition of youth aged from 14 to 25 years, the majority presenting a stabilized psychiatric disorder. </p><p> Methods: Twenty-four youth were recruited for the study, 12 youth who received the workshop and 12 who did not. Among each group of 12 eligible participants, 10 presented with a stabilized psychiatric disorder and two did not. Metacognition, social cognition, psychological and social functioning measures as well as questionnaires about objectives and appreciation regarding the workshop were used. </p><p> Results: Analyses revealed no differences between groups after the workshop in regard to youth’s metacognition, social cognition, nor psychological and social functioning. On the other hand, youth who participated in the workshop appreciated their experience, and their psychological and social functioning didn’t deteriorate. </p><p> Conclusions: Study results suggest that the duration of the workshop and the number of sessions should be extended. </p><p>
PDZ Binding Domains, Structural Disorder and Phosphorylation: A Menage-a-trois Tailing Dcp2 mRNA Decapping Enzymes
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Diverse cellular activities are mediated through the interaction of protein domains and their binding partners. One such protein domain widely distributed in the higher metazoan world is the PDZ domain, which facilitates abundant protein–protein interactions. The PDZ domain-PDZ binding domain interaction has been implicated in several pathologies including Alzheimer’s disease, Parkinson’s disease and Down syndrome. PDZ domains bind to C-terminal peptides/proteins which have either of the following combinations: S/T-X-hydrophobic-COOH for type I, hydrophobic-Xhydrophobic- COOH for type II, and D/E-X-hydrophobic-COOH for type III, although hydrophobicity in the termini form the key characteristic of the PDZ-binding domains. We identified and characterized a Dcp2 type mRNA decapping enzyme from Arabidopsis thaliana, a protein containing a putative PDZ-binding domain using mutagenesis and protein biochemistry. Now we are using bioinformatics to study the Cterminal end of mRNA decapping enzymes from complex metazoans with the aim of (1) identifying putative PDZ-binding domains (2) Correlating structural disorder with PDZ binding domains and (3) Demonstrating the presence of phosphorylation sites in C-terminal extremities of Dcp2 type mRNA decapping enzymes. It is proposed here that the trinity of PDZbinding domains, structural disorder and phosphorylation-susceptible sites are a feature of the Dcp2 family of decapping enzymes and perhaps is a wider trick in protein evolution where scaffolding/tethering is a requirement for localization and function. It is critical though laboratory-based supporting evidence is sought to back-up this bioinformatics exploration into tail regions of mRNA decapping enzymes.
The Role of mGlu Receptors in Hippocampal Plasticity Deficits in Neurological and Psychiatric Disorders: Implications for Allosteric Modulators as Novel Therapeutic Strategies
Today, 12 Ιουλίου 2016, 4:20:10 μμ
Long-term potentiation (LTP) and long-term depression (LTD) are two distinct forms of synaptic plasticity that have been extensively characterized at the Schaffer collateral-CA1 (SCCA1) synapse and the mossy fiber (MF)-CA3 synapse within the hippocampus, and are postulated to be the molecular underpinning for several cognitive functions. Deficits in LTP and LTD have been implicated in the pathophysiology of several neurological and psychiatric disorders. Therefore, there has been a large effort focused on developing an understanding of the mechanisms underlying these forms of plasticity and novel therapeutic strategies that improve or rescue these plasticity deficits. Among many other targets, the metabotropic glutamate (mGlu) receptors show promise as novel therapeutic candidates for the treatment of these disorders. Among the eight distinct mGlu receptor subtypes (mGlu<sub>1-8</sub>), the mGlu<sub>1,2,3,5,7</sub> subtypes are expressed throughout the hippocampus and have been shown to play important roles in the regulation of synaptic plasticity in this brain area. However, development of therapeutic agents that target these mGlu receptors has been hampered by a lack of subtype-selective compounds. Recently, discovery of allosteric modulators of mGlu receptors has provided novel ligands that are highly selective for individual mGlu receptor subtypes. The mGlu receptors modulate the multiple forms of synaptic plasticity at both SC-CA1 and MF synapses and allosteric modulators of mGlu receptors have emerged as potential therapeutic agents that may rescue plasticity deficits and improve cognitive function in patients suffering from multiple neurological and psychiatric disorders.
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