Treatment Of Many Neuropsychiatric Disorders Research Articles

A Conserved Intramolecular Ion-Pair Plays a Critical but Divergent Role in Regulation of Dimerization and Transport Function among the Monoamine Transporters.

The monoamine transporters, including the serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET), are the therapeutic targets for the treatment of many neuropsychiatric disorders. Despite significant progress in characterizing the structures and transport mechanisms of these transporters, the regulation of their transport functions through dimerization or oligomerization remains to be understood. In the present study, we identified a conserved intramolecular ion-pair at the third extracellular loop (EL3) connecting TM5 and TM6 that plays a critical but divergent role in the modulation of dimerization and transport functions among the monoamine transporters. The disruption of the ion-pair interactions by mutations induced a significant spontaneous cross-linking of a cysteine mutant of SERT and an increase in cell surface expression but with an impaired specific transport activity. On the other hand, similar mutations of the corresponding ion-pair residues in both DAT and NET resulted in an opposite effect on their oxidation-induced dimerization, cell surface expression, and transport function. Reversible biotinylation experiments indicated that the ion-pair mutations slowed down the internalization of SERT but stimulated the internalization of DAT. In addition, cysteine accessibility measurements for monitoring SERT conformational changes indicated that substitution of the ion-pair residues resulted in profound effects on the rate constants for cysteine modification in both the extracellular and cytoplasmatic substrate permeation pathways. Furthermore, molecular dynamics simulations showed that the ion-pair mutations increased the interfacial interactions in a SERT dimer but decreased it in a DAT dimer. Taken together, we propose that the transport function is modulated by the equilibrium between monomers and dimers on the cell surface, which is regulated by a potential compensatory mechanism but with different molecular solutions among the monoamine transporters. The present study provided new insights into the structural elements regulating the transport function of the monoamine transporters through their dimerization.

NMDA receptors: Biological properties and their roles in neuropsychiatric disorders

Proper signal transmission is the fundamental process of the brain activity. Changes and adaption of neuroplasticity based on the strength of synaptic transmission are essential for the information propagation in the central nervous system, which contribute to cognition, learning, and memory. Being the major excitatory neurotransmitter in the central nervous system, glutamate acts primarily through binding to the glutamate receptors, the glutamate-gated ion channels localized on post-synaptic membrane. The ionotropic glutamate receptors, pharmacologically grouped into α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, N-methyl-D-aspartic acid (NMDA) receptors, and kainate receptors, have been shown to play distinct roles in excitatory neurotransmission and synaptic plasticity. Due to their high permeability to Ca2+, the NMDA receptors have very unique function in neurotransmission and particular importance in the induction of long-term synaptic plasticity. Dysfunction of NMDA receptors causes impairment in synaptic plasticity and learning and memory. In recent years, with the development of genome-wide association studies and next-generation sequencing technology, mutations of NMDA receptor subunits have been in a variety of neuropsychiatric disorders, such as cognitive impairment, schizophrenia, autism or epilepsy. In clinical practice, NMDA receptors are known as the targets for the treatment of many neuropsychiatric disorders. In current review, we summarize current knowledge of NMDA receptors with different subunit compositions in the context of expression pattern, channel properties, protein trafficking, and synaptic plasticity as well as their roles in neuropsychiatric disorders.

The gut microbiota and mental health

INTRODUCTION AND PURPOSE
 Recent studies have shown that changes in the microbiome, probiotic and antibiotic supplementation, can significantly modulate various forms of neuropsychiatric disorders - such as depression, anxiety and stress-related disorders. There is growing body of evidence pointing to a bidirectional correlation along the brain-gut microbiota line. This axis is connected through endocrine, immune and neuronal pathways. The nerves that make up the enteric nervous system transmit modifications occurring in the gastrointestinal tract and through the vagus nerve to the central nervous system (1). The main purpose of this review is to update recent information on the correlation between the gut microbiota and mental health.
 STATE OF KNOWLEDGE
 Interactions between the gastrointestinal system and brain function have become an important field of psychiatric research in recent years. Probiotics are thought to be a potentially valuable player in the treatment of many neuropsychiatric disorders. However, the role of specific gut microbiota species in the development of these disorders remains unclear.
 CONCLUSIONS
 Increasing knowledge of the correlation between gut microbiota and mental health may improve the quality of treatment for patients with neuropsychiatric conditions. Further research on larger groups is needed to assess whether probiotics can modify altered psychological well-being and be integrated into current, conventional treatments.

Role of Transcranial Direct Current Stimulation in the Management of Post-Stroke Depression

Study Objectives: Stroke is a major neurological disease significantly threatening the human health and life with a high morbidity, disability, and mortality. Post-stroke depression (PSD) is one of the common complications of stroke. PSD has been a major factor hindering the recovery of neurological functions and daily activities in stroke patients and is closely related to the social avoidance and increased mortality of stroke patients. Although antidepressant drug treatment has improved during the last decades, symptoms in about 20% of the patients are not in remission two years after initiation of pharmacological intervention. Nowadays, non-invasive brain stimulation; techniques; transcranial direct current stimulation (tCDS) has gained an important interest in the treatment of many neuropsychiatric disorders which might be of some help in treatment of PSD. The goal of the current study is to evaluate the beneficial short term role of tDCS on post-stroke depression. Study Design: This was a randomized double blind placebo-controlled clinical trial included forty hemiparetic patients with post-stroke depression from outpatient clinic of Faculty of Physical Therapy, Cairo University, in the period between June 2018 to June 2019. All patients diagnosed as having a PSD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Depression was evaluated by Hamilton Depression Rating Scale (HAM-D) pre and post treatment and quality of life was evaluated by the Stroke Specific Quality Of Life scale (SS-QOL). Patients were assigned randomly into two groups: the study group A and the control group B. Both groups received antidepressant medication in addition to physical therapy program. Group A received tCDS for 30 minutes, three times per week for one month, while the group B received sham transcranial direct current stimulation. Results: Active tDCS was significantly superior to sham with significant improvement in depression and Stroke Specific Quality Of Life in treated group in comparison to group B, p = 0.000. Conclusion: tDCS was effective for post- stroke depression and might be a favorable option for treating post-stroke patients.

Amelioration of Behavioral Impairments and Neuropathology by Antiepileptic Drug Topiramate in a Transgenic Alzheimer’s Disease Model Mice, APP/PS1

Alzheimer’s disease (AD) is a neurodegenerative disease that is the main cause of dementia in the elderly. The aggregation of β-amyloid peptides is one of the characterizing pathological changes of AD. Topiramate is an antiepileptic drug, which in addition, is used in the treatment of many neuropsychiatric disorders. In this study, the therapeutic effects of topiramate were investigated in a transgenic mouse model of cerebral amyloidosis (APP/PS1 mice). Before, during, and after topiramate treatment, behavioral tests were performed. Following a treatment period of 21 days, topiramate significantly ameliorated deficits in nest-constructing capability as well as in social interaction. Thereafter, brain sections of mice were analyzed, and a significant attenuation of microglial activation as well as β-amyloid deposition was observed in sections from topiramate-treated APP/PS1 mice. Therefore, topiramate could be considered as a promising drug in the treatment of human AD.

Gut Permeability and Microbiota in Parkinson's Disease: Role of Depression, Tryptophan Catabolites, Oxidative and Nitrosative Stress and Melatonergic Pathways.

Increased gut permeability (leaky gut) and alterations in gut microbiota are now widely accepted as relevant to the etiology, course and treatment of many neuropsychiatric disorders, including Parkinson disease (PD). Although a wide array of data on the biological underpinnings of PD has not yet been linked to such gut-associated changes, increased gut permeability and dysregulated microbiota alter many pathways germane to PD. In this article we review and integrate these wider biological changes in PD, including increased oxidative and nitrosative stress, immune-inflammatory processes, tryptophan catabolites and alterations in serotoninergic and melatoninergic pathways. These wider biological changes in PD are compatible with alterations in gut permeability and changes in gut microbiota. By driving tryptophan down the kynurenine pathway, pro-inflammatory cytokines and chronic stress-driven activation of the hypothalamic-pituitary-adrenal axis decrease the availability of serotonin as a precursor for activation of the melatonergic pathways. Decreased local melatonin synthesis in glia, gut, neuronal and immune cells is likely to be important to the etiology, course and management of PD.

High‐throughput screening for identification of novel allosteric modulators of the D 3 dopamine receptor

Dopamine receptors (DARs) are involved in the treatment of many neuropsychiatric disorders including schizophrenia and Parkinson's disease. Many currently available dopaminergic drugs modulate multiple receptor subtypes due to high homology in their orthosteric binding sites, leading to potential side effects. As an approach to discover highly selective allosteric modulators for the D3 DAR, our lab employed high throughput screening technologies. The NIH Molecular Libraries Program 400,000+ small molecule library was initially screened using a D3 DAR-mediated β-arrestin recruitment assay. Confirmation and counter-screens were performed to obtain an initial assessment of selectivity and mechanisms of action and identified 57 potential negative allosteric modulators (NAMs), 63 potential positive allosteric modulators (PAMs), and 62 potential allosteric agonists. Further triage and characterization identified several D3 DAR-selective putative NAMs, PAMs, and allosteric agonists that are currently being characterized using additional assays to confirm their selectivity, activity, and mechanism of action. As D3-preferring D2/D3 DAR orthosteric agonists show promise as neuroprotective/neurorestorative agents, we conducted preliminary studies using one of the lead allosteric agonists, and found that it displays neuroprotective properties using a cell culture model system. We ultimately hope that these probes will prove useful as in vitro and in vivo pharmacological tools or leads for therapeutic drugs.

Influence of sex and stress exposure across the lifespan on endophenotypes of depression: focus on behavior, glucocorticoids, and hippocampus.

Sex differences exist in vulnerability, symptoms, and treatment of many neuropsychiatric disorders. In this review, we discuss both preclinical and clinical research that investigates how sex influences depression endophenotypes at the behavioral, neuroendocrine, and neural levels across the lifespan. Chronic exposure to stress is a risk factor for depression and we discuss how stress during the prenatal, postnatal, and adolescent periods differentially affects males and females depending on the method of stress and metric examined. Given that the integrity of the hippocampus is compromised in depression, we specifically focus on sex differences in how hippocampal plasticity is affected by stress and depression across the lifespan. In addition, we examine how female physiology predisposes depression in adulthood, specifically in postpartum and perimenopausal periods. Finally, we discuss the underrepresentation of women in both preclinical and clinical research and how this limits our understanding of sex differences in vulnerability, presentation, and treatment of depression.

Identification of a novel, highly potent D3 dopamine receptor‐selective agonist (662.8)

Dopamine receptors (DARs) are involved in the development and/or treatment of many neuropsychiatric disorders including schizophrenia and Parkinson’s disease. Many currently available dopaminergic drugs modulate both D2 and D3 DARs due to high homology in their orthosteric binding sites, leading not only to potential unwanted side effects, but also uncertainty as to the roles each DAR subtype plays in normal and pathological processes. In order to discover compounds that target unique, less conserved allosteric sites of these DARs, our lab employed a high throughput screening approach. Through the NIH Molecular Libraries Program, compound 3843 was originally identified as a D2 antagonist in a screen of a 380,000+ small molecule library. Counter‐screening assays of beta‐arrestin recruitment revealed that this compound selectively activates the D3 DAR, yet also acts as an antagonist at the D2 DAR. Over 270 analogs were synthesized and tested to explore the structure‐activity relationship of 3843 for the D2 and D3 DARs, and several compounds with a 1,000‐fold or greater increase in D3 DAR agonist potency were found. Initial competition binding assays suggest these compounds act in an allosteric manner at the D3 DAR, and initial ADME studies performed on 3843 were favorable. We ultimately hope these probes will be useful in vitro and in vivo pharmacological tools to elucidate D3 DAR specific physiology and pathology.Grant Funding Source: Supported by NIH IRP

High‐throughput screening for novel allosteric modulators of the D1 dopamine receptor (662.4)

Dopamine is a critically important neurotransmitter in the CNS and peripheral nervous system, with five receptor subtypes mediating its effects. Importantly, D1 receptor (D1R)‐selective agents may prove beneficial in the treatment of many neuropsychiatric disorders. In an effort to identify novel selective allosteric modulators of the D1R we used a high throughput screening approach. 380,000 small molecules in the NIH Molecular Libraries Screening Center Network library were screened using a cell line expressing the D1R coupled to G15 resulting in a robust Ca2+ signal upon receptor stimulation. Hit compounds were triaged through secondary functional and radioligand displacement binding assays to determine subtype selectivity and their allosteric versus orthosteric nature. We initially identified 96 putative positive allosteric modulator (PAM) hits that enhanced the EC20 activity of dopamine in the Ca2+ response ‐ 6 of these were subsequently confirmed during triage and were chosen for further characterization. In addition we found approximately 115 agonist and 125 antagonist hits that failed to completely inhibit radioligand binding and have been classified as potential allosteric agonists and antagonists or negative allosteric modulators (NAMs). These compounds are currently being characterized using additional assays to confirm their selectivity, activity, and classification.Grant Funding Source: NINDS Intramural Program

New horizon for the therapeutic modality of exercise on neuropsychiatric disorders

Since discovery of the possibility that neuronal precursors cells can differentiate into neurons (Reynolds and Weiss, 1992), neurogenesis in the olfactory bulb (Tarozzo et al., 1995) and hippocampus (Eriksson et al., 1998) of the adult mammals has been confirmed. The hippocampus plays a major role in spatial learning and memory in animals as well as humans. Neurogenesis in the hippocampus occurs throughout postnatal life, and is influenced by environment and behavior factors. Many studies have focused on the modulating factors of the neurogenesis. Enriched environment, learning, electroconvulsive therapy, anti-depressive agents, acupuncture, and exercise have been suggested as the increasing factor for neurogenesis. Adult hippocampal neurogenesis is considered to be composed of several development stages: proliferation, differentiation, migration, targeting and synaptic integration, and various characteristic neuronal markers are expressed during the specific stages. Adult hippocampal neurogenesis is closely implicated with hippocampal functions and decreased hippocampal neurogenesis is associated with neurodegenerative disorders. Exercise is known to have many beneficial effects on health, such as increasing of cardiovascular function, prevention of chronic diseases, and decreasing of body fat. Exercise improves learning ability and memory function, protects against neurodegenerative diseases, delays age-related cognitive decline, and alleviates symptoms of the developmental and neuropsychiatric disorders. Many studies have suggested the possibility that exercise can be a therapeutic modality for brain diseases. Neurogenesis induced by exercise is reported to be necessary in the hippocampal-dependent learning process. Suppression of hippocampal neurogenesis may contribute to cognitive dysfunction in aging, dementia, epilepsy, and other brain inflammatory conditions. The fact that exercise increases neurogenesis has enabled new research on the role of exercise. Most widely studied effect of exercise is on the depression. In our studies, treadmill exercise enhanced neurogenesis with increment of serotonin expression, which resulted in improvement of depressive symptoms (Baek et al., 2012). Treadmill exercise alleviated aging-induced memory impairment by enhancing neurogenesis (Kim et al., 2010). Kim et al. (2013) reported that exercise also accelerated maturation of neurons under the brain inflammatory conditions. These therapeutic efficacies of treadmill exercise can be ascribed to the enhancing effect of exercise on neurogenesis. Thus, the enhancing effect of exercise on neurogenesis may open new horizon for the treatment of many neuropsychiatric disorders.

Identification of a novel dopaminergic agonist that selectively activates the D3 dopamine receptor

Dopamine receptors (DARs) are involved in the development and/or treatment of many neuropsychiatric disorders, with specific receptor subtypes playing distinct roles. D2 DAR antagonism is thought to be responsible for the efficacy of antipsychotics, while D3 DAR agonists may be useful as neuroprotective and neurorestorative antiparkinsonian medications. Many antipsychotic drugs belong to the class of 1,4‐disubstituted aromatic piperazines and piperidines (1,4‐DAPS), although many produce limiting side effects due to the high conservation of the orthosteric binding site among DAR subtypes and other related GPCRs. In order to identify novel small‐molecule ligands of DARs with the potential to be highly selective and therefore better drug candidates, our lab has employed a high throughput screening (HTS) approach. Through the NIH Molecular Libraries Program, a novel 1,4 DAP, Compound 3843, was originally identified as a D2 antagonist in a D2‐Gqi5 calcium HTS of a 370,000+ small molecule library. Counter‐screening assays of beta‐arrestin recruitment revealed that this compound selectively activates the D3 DAR and acts as an antagonist at the D2 DAR. Compound 3843 also functions as a D3 DAR agonist in a Go BRET activation assay. We ultimately hope Compound 3843, or its analogs, will be a useful in vitro or in vivo pharmacological tool.

Repetitive transcranial magnetic stimulation for tinnitus

Tinnitus is the perception of sound, in the ear or in the head, in the absence of any external acoustic stimulation. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive means of inducing electrical currents in the brain, and has received increasing attention in recent years for the treatment of many neuropsychiatric disorders, including tinnitus. To assess the effectiveness and safety of rTMS versus placebo in patients with tinnitus. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 24 May 2011. Randomised controlled trials of rTMS versus sham rTMS. Two review authors reviewed the titles, abstracts and keywords of all records retrieved. Three review authors independently collected and extracted data, and assessed the risk of bias of the trials. Five trials comprising of 233 participants met our inclusion criteria. Each study described the use of a different rTMS device that delivered different waveforms at different frequencies. All five trials were relatively small studies but generally they demonstrated a low risk of bias.When considering the impact of tinnitus on patients' quality of life, the results of only one study demonstrated a statistically significant improvement in Tinnitus Handicap Inventory (THI) scores at four months follow-up (defined as a 'partial improvement' by the study authors (THI reduction of 21% to 80%)) when low-frequency rTMS was compared with a sham control treatment. However, no statistically significant improvement was demonstrated by another two studies that considered rTMS at the same frequency. Furthermore, this single positive finding should be taken in the context of the many different variables which were recorded at many different points in time by the study authors.In accordance with our pre-specified subgroup analysis we extracted the data from one study to consider the differential effectiveness between 'lower' low-frequency rTMS (1 Hz) and 'higher' low-frequency rTMS (10 Hz, 25 Hz). In doing this we were able to demonstrate a statistically significant difference between rTMS employing a frequency of 1 Hz and the sham group when considering tinnitus severity and disability after four months follow-up ('partial' improvement). However, no statistically significant difference was demonstrated between 10 Hz and 25 Hz rTMS, and the sham control group, when considering the severity and disability of tinnitus at four months follow-up.When considering tinnitus loudness in patients undergoing rTMS we were able to demonstrate a statistically significant reduction in tinnitus loudness when the results of two studies were pooled (risk ratio 4.17, 95% confidence interval 1.30 to 13.40). However, this finding was based on two small trials and consequently the confidence interval was particularly wide.No serious adverse effects were reported in any of the trials. There is very limited support for the use of low-frequency rTMS for the treatment of patients with tinnitus. When considering the impact of tinnitus on patients' quality of life, support is from a single study with a low risk of bias based on a single outcome measure at a single point in time. When considering the impact on tinnitus loudness, this is based on the analysis of pooled data with a large confidence interval.Studies suggest that rTMS is a safe treatment for tinnitus in the short-term, however there were insufficient data to provide any support for the safety of this treatment in the long-term.More prospective, randomised, placebo-controlled, double-blind studies with large sample sizes are needed to confirm the effectiveness of rTMS for tinnitus patients. Uniform, validated, tinnitus-specific questionnaires and measurement scales should be used in future studies.

Modulation of central cholinergic activity by GABA and serotonin: PET studies with 11C-benztropine in primates.

The pharmacologic treatment of many neuropsychiatric disorders (Alzheimer's disease, schizophrenia, depressive illness) has been targeted at the central hypothesis that defects in a single neurotransmitter system underlie the pathophysiology of the disease state. With the recognition that such treatments have not been efficacious consistently, recent drug development has been directed at altering other functionally linked neurotransmitters involved in these diseases. Using positron emission tomography, we have noninvasively investigated the effects of two noncholinergic drugs on the release of acetylcholine. By examining the effects of gamma-vinyl gamma-aminobutyric acid (GABA) (a GABA transaminase inhibitor) or altanserin (a serotonergic antagonist) on the regional binding of 11C-benztropine in the primate brain (Papio anubis), we demonstrated that drugs acting upon either GABAergic or serotonergic neurons produce profound regional changes in acetylcholine release. These findings indicate that the mechanisms of action and the subsequent therapeutic efficacy of these centrally acting drugs may be linked to their multitransmitter effects. This application of positron emission tomography represents an extremely promising experimental approach that can be directed towards elucidating abnormalities in neurotransmitter modulation relevant to disease progression and pharmacologic treatment.