Open Access Articles – Glutamatergic Deficits in Schizophrenia – Biomarkers and Pharmacological Interventions within the Ketamine Model

Journal Name: Current Pharmaceutical Biotechnology

Author(s): Moritz Haaf, Gregor Leicht, Stjepan Curic, Christoph Mulert*.




Graphical Abstract:




Background: The observation that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists such as ketamine transiently induce schizophrenia-like positive, negative and cognitive symptoms has led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. NMDAR hypofunction can explain many schizophrenia symptoms directly due to excitatory-to-inhibitory (E/I) imbalance, but also dopaminergic dysfunction itself. However, so far no new drug targeting the NMDAR has been successfully approved. In the search for possible biomarkers it is interesting that ketamine-induced psychopathological changes in healthy participants were accompanied by altered electro-(EEG), magnetoencephalographic (MEG) and functional magnetic resonance imaging (fMRI) signals.

Methods: We systematically searched PubMed/Medline and Web of Knowledge databases (January 2006 to July 2017) to identify EEG/MEG and fMRI studies of the ketamine model of schizophrenia with human subjects. The search strategy identified 209 citations of which 46 articles met specified eligibility criteria.

Results: In EEG/MEG studies, ketamine induced changes of event-related potentials, such as the P300 potential and the mismatch negativity, similar to alterations observed in schizophrenia patients. In fMRI studies, alterations of activation were observed in different brain regions, most prominently within the anterior cingulate cortex and limbic structures as well as task-relevant brain regions. These alterations were accompanied by changes in functional connectivity, indicating a balance shift of the underlying brain networks. Pharmacological treatments did alter ketamine-induced changes in EEG/MEG and fMRI studies to different extents.

Conclusion: This review highlights the potential applicability of the ketamine model for schizophrenia drug development by offering the possibility to assess the effect of pharmacological agents on schizophrenia- like symptoms and to find relevant neurophysiological and neuroimaging biomarkers.



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EDITOR’S CHOICE – N-3 (Omega-3) Fatty Acids: Effects on Brain Dopamine Systems and Potential Role in the Etiology and Treatment of Neuropsychiatric Disorders

Journal: CNS & Neurological Disorders – Drug Targets

Author(s): Michelle Healy-Stoffel, Beth Levant

Graphical Abstract:



Background & Objective: A number of neuropsychiatric disorders, including Parkinson’s disease, schizophrenia, attention deficit hyperactivity disorder, and, to some extent, depression, involve dysregulation of the brain dopamine systems. The etiology of these diseases is multifactorial, involving genetic and environmental factors. Evidence suggests that inadequate levels of n-3 (omega- 3) polyunsaturated fatty acids (PUFA) in the brain may represent a risk factor for these disorders. These fatty acids, which are derived from the diet, are a major component of neuronal membranes and are of particular importance in brain development and function. Low levels of n-3 PUFAs in the brain affect the brain dopamine systems and, when combined with appropriate genetic and other factors, increase the risk of developing these disorders and/or the severity of the disease. This article reviews the neurobiology of n-3 PUFAs and their effects on dopaminergic function.

Conclusion: Clinical studies supporting their role in the etiologies of diseases involving the brain dopamine systems and the potential of n-3 PUFAs in the treatment of these disorders are discussed.

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Article by Disease – “Brain Aging and Disorders of the Central Nervous System: Kynurenines and Drug Metabolism”

Article by Disease on “Metabolic Disorders”


Introduction: The kynurenine pathway includes several neuroactive compounds, including kynurenic acid, picolinic acid, 3-hydroxykynurenine and quinolinic acid. The enzymatic cascade of the kynurenine pathway is tightly connected with the immune system, and may provide a link between the immune system and neurotransmission.

Main Areas Covered: Alterations in this cascade are associated with neurodegenerative, neurocognitive, autoimmune and psychiatric disorders, such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine or schizophrenia.

Highlights: This review highlights the alterations in this metabolic pathway in the physiological aging process and in different disorders. A survey is also presented of therapeutic possibilities of influencing this metabolic route, which can be achieved through the use of synthetic kynurenic acid analogues, enzyme inhibitors or even nanotechnology.

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Articles by disease – Genetics of Schizophrenia and other Psychotic Disorders

Article by disease on “Genetic Diseases

Abstract: Research into the genetic basis of schizophrenia is advancing rapidly. This review gives a broad overview of results from successive phases of studies in this field, linking these with recent findings and likely future research directions. Among recent findings, large-scale epidemiological studies based on Scandinavian population registers, have provided further evidence of substantial heritability and evidence that a wide range of psychotic and non-psychotic disorders partly share genetic risk factors with schizophrenia. In molecular genetics, large collaborative genomewide association studies (GWAS) are providing evidence of common risk variants, each of small effect, and many more variants are likely to be found as samples sizes increase further. A range of rarer chromosomal copy number variants (CNVs) have been associated with schizophrenia, and both GWAS and CNV studies have provided molecular evidence of genetic overlap between schizophrenia and other disorders.

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Autism and Schizophrenia Known To Have Close Ties!

Mental disorders, like autism and schizophrenia, are very complex for laypeople to comprehend. Thus, we feel intrigued to dig in further to learn their origin, symptoms, causes and such. Autism is a neurodevelopmental disorder which is now considered as a group rather than a single problem. It is now called ‘Autism Spectrum Disorders’ and this group covers various neurotic problems. These are basically thinking and communication issues where the autistic people cannot socialize and have problems with verbal and non-verbal communications. They may also have hampered cognitive functioning too.

causes-of-schizophrenia (1)

Schizophrenia, on the other hand, is also a neurodevelopmental problem where the sufferer cannot make out the difference in real and imaginary situations. They are socially disconnected and tend to show poor emotional and social intelligence. At times they can be violent in nature but that is a rarity, for the information of most. Schizophrenia patients prefer to stay in their own thoughts far away from reality.

In the journal, Adolescent Psychiatry, the research paper, Blurred Edges: Evolving Concepts of Autism Spectrum Disorders and Schizophrenia, presents the idea that both Autism and Schizophrenia have similar origin. Both start at very early ages and cement in the sufferers as they grow up. The diagnosis for neurotic disorders is still not very helpful in finding their solutions. Ironically, this group of mental disorders keeps growing and search for cure is testing the patience.

Article by Disease – Genetics of Schizophrenia and other Psychotic Disorders

Journal: Current Psychiatry Reviews

Abstract: Research into the genetic basis of schizophrenia is advancing rapidly. This review gives a broad overview of results from successive phases of studies in this field, linking these with recent findings and likely future research directions. Among recent findings, large-scale epidemiological studies based on Scandinavian population registers, have provided further evidence of substantial heritability and evidence that a wide range of psychotic and non-psychotic disorders partly share genetic risk factors with schizophrenia.

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Is it true?

Chinese Authors have made substantial contributions to Bentham Science Journal Current Drug Targets:

Journal Name: Current Drug Targets

7-18-2014 9-12-03 AM

Article Title:

Molecular Mechanisms and Treatment of Radiation-Induced Lung Fibrosis

Author(s): Nian-Hua Ding, Jian Jian Li and Lun-Quan Sun


Radiation-induced lung fibrosis (RILF) is a severe side effect of radiotherapy in lung cancer patients that presents as a progressive pulmonary injury combined with chronic inflammation and exaggerated organ repair. RILF is a major barrier to improving the cure rate and well-being of lung cancer patients because it limits the radiation dose that is required to effectively kill tumor cells and diminishes normal lung function. Although the exact mechanism is unclear, accumulating evidence suggests that various cells, cytokines and regulatory molecules are involved in the tissue reorganization and immune response modulation that occur in RILF. In this review, we will summarize the general symptoms, diagnostics, and current understanding of the cells and molecular factors that are linked to the signaling networks implicated in RILF. Potential approaches for the treatment of RILF will also be discussed. Elucidating the key molecular mediators that initiate and control the extent of RILF in response to therapeutic radiation may reveal additional targets for RILF treatment to significantly improve the efficacy of radiotherapy for lung cancer patients.

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Article Title: Novel Targeted Therapies to Overcome Trastuzumab Resistance in HER2- Overexpressing Metastatic Breast Cancer

Author(s): Yuan Huang, Peifen Fu and Weimin Fan


Overexpression of the human epidermal growth factor receptor 2 (HER2) is identified in approximately 25- 30% of breast cancers and indicates a poor prognosis. Trastuzumab, the anti-HER2 monoclonal antibody (mAb), has shown significant clinical effects selectively in HER2-overexpressing metastatic breast cancer (MBC) with improved overall survival and reduced recurrent risk. However, there is an urgent need to develop new strategies to overcome innate and acquired trastuzumab resistance, which has increasingly occurred. Recently, an increased understanding of mechanisms of trastuzumab resistance significantly promotes the development of novel targeted therapies for trastuzumabrefractory disease. It is believed that aberrant activations of several signaling pathways involving the human epidermal growth factor receptor (EGFR/HER) family, phosphoinositide 3 kinase/Akt (PI3K/Akt) pathway, and vascular endothelial growth factor (VEGF) family, contribute to the development of trastuzumab resistance. Novel agents that target these relevant signal pathways provide some potential solutions, such as tyrosine kinase inhibitors (TKIs) and mAbs. HER2 is also recognized as an immunotherapeutic target. The failure to induce immune-mediated antitumor response is another important reason for trastuzumab resistance. Strategies to boost T cell-mediated immune responses specific to HER2 including HER2 vaccines and bispecific antibodies (bsAbs) could be developed as a promising way to prevent relapse or combat trastuzumab resistance. In this review, the emerging data from preclinical and clinical studies related to these novel therapies will be discussed.

Article Title: Improving the Embryo Implantation Via Novel Molecular Targets

Author(s): Jingjie Li, Xiaoyan Liang and Zijiang Chen


With the development of modern assisted reproductive technology(ART), the treatment of infertility and the pregnant outcome by ART have been significantly improved. However, implantation failure, particularly the unexplained repeated implantation failure (RIF), is still the unsolved and principal problem to affect the outcome of ART. The completed embryo, the receptive uterus and a series of precisely controlled molecular events between the blastocyst and endometrium are all indispensable for the success of implantation. Thus, deep insight into the molecular mechanisms that impact the endometrial receptivity and embryo implantation is an effective way to improve the implantation rate. Here the novel molecular targets and biomarkers have been reviewed that are reported and proved during more recent years in the aspects of ion channels, aquaporins, long noncoding RNAs and microRNAs, kruppel like factors, metabolism related molecules and the endogenous retroviruses. Evaluation of implantation markers may help clinicians to predict pregnancy outcome and detect occult implantation deficiency. Moreover, these novel molecular targets are expected to apply to the clinical practice from bench to bedside and improve the implantation efficiency in ART and natural conception.

Article Title:

Recent Developments in the Discovery of Novel Antipsychotic Agents Modualating Dopamine and Serotonin Receptors

Author(s): Xin Li and Shutao Ma


Currently, schizophrenia, as a serious psychiatric disorder, continues affecting the quality of life in the psychotics. This disease is often debilitating and chronic, showing broad symptoms at one end by hallucinations, delusions, thought disorder and the other end by affective flattening, catatonia, social isolation. In order to combat this disease, many antipsychotic drugs have been developed and introduced into clinical practice in the past half century. However, only a small minority of them can treat effectively schizophrenia without side effects. In view of this situation, high attention has been given to the exploration of desired antipsychotic agents influential especially through the modulation of dopamine and serotonin receptors with substantial strides made in recent years, leading to the discovery of many novel chemical entities with intriguing profiles. In this review, we summarize novel structural antipsychotics in development and discuss the future direction of ideal antipsychotic drug candiates. In particular, the promising atypical antipsychotic profiles of new molecules and the inspirations for their design are highlighted.

Scholarly Publications by Japanese Authors in BSP Journal: CNS & Neurological Disorders – Drug Targets

CNS & Neurological Disorders – Drug TargetsImage

Biosynthetic Pathways of Bioactive N-Acylethanolamines in Brain

Author(s): Kazuhito Tsuboi, Natsuki Ikematsu, Toru Uyama, Dale G. Deutsch, Akira Tokumura and Natsuo Ueda

Affiliation: Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan.


Ethanolamides of long-chain fatty acids are a class of endogenous lipid mediators generally referred to as Nacylethanolamines (NAEs). NAEs include anti-inflammatory and analgesic palmitoylethanolamide, anorexic oleoylethanolamide, and the endocannabinoid anandamide. Since the endogenous levels of NAEs are principally regulated by enzymes responsible for their biosynthesis and degradation, these enzymes are expected as targets for the development of therapeutic agents. Thus, a better understanding of these enzymes is indispensable. The classic “N-acylationphosphodiesterase pathway” for NAE biosynthesis is composed of two steps; the formation of Nacylphosphatidylethanolamine (NAPE) by N-acyltransferase and the release of NAE from NAPE by NAPE-hydrolyzing phospholipase D (NAPE-PLD). However, recent studies, including the analysis of NAPE-PLD-deficient (NAPE-PLD-/-) mice, revealed the presence of NAPE-PLD-independent multi-step pathways to form NAEs from NAPE in animal tissues. Our recent studies using NAPE-PLD-/- mice also suggest that NAE is formed not only from NAPE, but also from Nacylated plasmalogen-type ethanolamine phospholipid (N-acyl-plasmenylethanolamine) through both NAPE-PLDdependent and -independent pathways. Here, we present recent findings on NAE biosynthetic pathways mainly occurring in the brain.

Author(s): Saki Shimizu, Yuto Mizuguchi and Yukihiro Ohno

Affiliation: Laboratory of Pharmacology, OsakaUniversity of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.


Patients with schizophrenia exhibit various clinical symptoms including positive and negative symptoms, neurocognitive impairments and mood disturbances. Although a series of second generation antipsychotics (SGAs) (e.g., risperidone, olanzapine and quetiapine) have been developed in the past two decades, clinical reports do not necessarily show advantages over first generation antipsychotics (FGAs) in the treatment of schizophrenia, especially in their efficacy against cognitive impairment and ability to cause extrapyramidal side effects (EPS). Recently, several lines of studies have revealed therapeutic roles of 5-HT receptors in modulating cognitive impairments and extrapyramidal motor disorders. Specifically, inhibition of 5-HT1A, 5-HT3 and 5-HT6 receptors or activation of 5-HT4 receptors alleviates cognitive impairments (e.g., deficits in learning and memory). In addition, stimulation of 5-HT1A receptors or inhibition of 5-HT3and 5-HT6 receptors as well as 5-HT2A/2C receptors can ameliorate extrapyramidal motor disorders. Thus, controlling the activity of 5-HT1A, 5-HT3 or 5-HT6receptors seems to provide benefits by both alleviating cognitive impairments and reducing antipsychotic-induced EPS. This article reviews the functional roles and mechanisms of 5-HT receptors in the treatment of schizophrenia, focusing on the serotonergic modulation of cognitive and extrapyramidal motor functions, and illustrates future therapeutic strategies.


Beyond Rodent Models of Pain: Non-Human Primate Models for Evaluating Novel Analgesic Therapeutics and Elaborating Pain Mechanisms

Author(s): Aldric T. Hama, Katsuo Toide and Hiroyuki Takamatsu

Affiliation: Hamamatsu Pharma Research, Kita-ku, 1-3-7 Shinmiyakoda, Hamamatsu 431-2103, Japan.


Evaluation of potential analgesic therapeutics and the elaboration of the neurobiology of pain have heavily relied on pain models developed in rodents. However, a limitation of rodents is their phylogenetic distance from humans, which could in part account for the failure of some preclinical findings to translate to clinical utility. By contrast, given their genetic closeness and phenotypic similarities to humans, it is suggested that there be greater utilization of non-human primates (NHP) in preclinical pain studies. Methods to induce chronic pain-like states and quantify changes in nociception that have been developed in rodents could be adapted to the NHP. Similarly, human experimental injury-induced sensitization, which attempts to temporarily mimic the neuropathology and symptoms observed in the chronic pain state, could be adapted to the NHP. The NHP could then serve as a platform to validate human experimental models as well as proof-of-concept studies. Beyond experimentally modeled pain states, a number of naturally occurring disease states, such as osteoarthritis, are expressed by NHP, which could be utilized for both hypothesis testing and proof-of-concept studies. While NHP studies are logistically cumbersome, it is envisioned that NHP pain models will add value to current preclinical data and greatly facilitate the discovery of novel analgesic treatments.

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