Circumventricular Organs: Gateways to the Brain Role Of Circumventricular Organs In Pro-Inflammatory Cytokine-Induced Activation Of The Hypothalamic– Pituitary–Adrenal Axis

1. The past 15 years has seen the emergence of a new field of neuroscience research based primarily on how the immune system and the central nervous system can interact. A notable example of this interaction occurs when peripheral inflammation, infection or tissue injury activates the hypothalamic– pituitary–adrenal axis (HPA). 2. During such assaults, immune cells release the pro‐ inflammatory cytokines interleukin (IL)‐1, IL‐6 and tumour necrosis factor‐α into the general circulation. 3. These cytokines are believed to act as mediators for HPA axis activation. However, physical limitations of cytokines impede their movement across the blood–brain barrier and, consequently, it has been unclear as to precisely how and where IL‐1β signals cross into the brain to trigger HPA axis activation. 4. Evidence from recent anatomical and functional studies suggests two neuronal networks may be involved in triggering HPA axis activity in response to circulating cytokines. These are catecholamine cells of the medulla oblongata and the circumventricular organs (CVO). 5. The present paper examines the role of CVO in generating HPA axis responses to pro‐inflammatory cytokines and culminates with a proposed model based on cytokine signalling primarily involving the area postrema and catecholamine cells in the ventrolateral and dorsal medulla.     

Interactions of orphanin FQ/nociceptin (OFQ/N) system with immune system factors and hypothalamic–pituitary–adrenal (HPA) axis

BackgroundBrain–immune system interactions and neurohormonal changes which are induced by psychophysiological factors are growing areas of scientific interest. Central (CNS) and autonomic nervous-endocrine-immune system pathways are connected with a number of behavioral and physiological factors which may be linked to disease susceptibility and progression.MethodsIn this paper, influence of orphanin FQ/nociceptin receptor (OFQ/N) on the hypothalamic–pituitary–adrenal (HPA) axis and their influence on the immunological system was reviewed.ConclusionsThe neuroendocrine system, in particular the hypothalamic–pituitary–adrenal (HPA) axis, is closely connected with the cytokines. HPA axis activation by cytokines, via the release of glucocorticoids has, in turn, been found to play a critical role in restraining and shaping immune responses. Investigation of the OFQ/N system and G-proteins suggests a role for this receptor as a down-regulator of cytokine, chemokine and chemokine receptor expression.     

The role of corticotropin-releasing hormone in the pathophysiology of depression: therapeutic implications

Stress responses have been posited to be a key component of mental health and disease by playing essential roles both in normal adaptive processes and maladaptive physiological responses that in part underlie the pathogenesis of certain subtypes of mood and anxiety disorders. Early research focused on delineating the function of the hypothalamic-pituitary-adrenal (HPA) axis and subsequently examined its role in mediating the mammalian stress responses and its hyperactivity in depression. Much evidence now supports an important function of the biological mediators of this system in relation to not only depression, but also anxiety, substance abuse, and psychotic disorders, and implicates several components of this system as areas of intervention for novel pharmacotherapy. Perhaps the best studied central nervous system (CNS) component of this system is corticotropin-releasing factor (CRF), and considerable research has focused on its role in the HPA axis, as well in extrahypothalamic brain regions.     

Synthesis, 3H‐labelling and in vitro evaluation of a substituted dipiperidine alcohol as a potential ligand for chemokine receptor 2

The immune system is implicated in the pathology of neurodegenerative disorders. The C‐C chemokine receptor 2 (CCR2) is one of the key targets involved in the activation of the immune system. A suitable ligand for CCR2 could be a useful tool to study immune activation in central nervous system (CNS) disorders. Herein, we describe the synthesis, tritium radiolabelling, and preliminary in vitro evaluation in post‐mortem human brain tissue of a known potent small molecule antagonist for CCR2. The preparation of a tritium‐labelled analogue for the autoradiography (ARG) study gave rise to an intriguing and unexpected side reaction profile through a novel amination of ethanol and methanol in the presence of tritium. After successful preparation of the tritiated radioligand, in vitro ARG measurements on human brain sections revealed nonspecific binding properties of the selected antagonist in the CNS.     

Psychopharmacotherapy for addictive and comorbid disorders: Current studies

Summary

Proper diagnosis of comorbid disorders is crucial in treatment planning for the dually diagnosed. Since psychoactive substance use can obfuscate the diagnosis, special care must be taken to exclude organically based syndromes. Adequate periods of abstinence should first be achieved and subsequently the patient re‐examined for residual symptoms compatible with a nonaddictive, nonsubstance‐induced psychiatric disorder.

The integration of concurrent treatment of both the mental and the addictive disorders appears to be the best approach for treatment of comorbid psychiatric and addictive disorders. An abstinence‐based model that typically utilizes a 12‐step group therapy is often employed for the addictive illnesses. Other forms of psychosocial therapies such as case managers are being used as well.

Presently, physicians’ prescribing practices for comorbid addicted patients are based on traditional approaches to use of medications in psychiatric patients, and their attitudes towards addictive disorders may play a significant role in determining the overall success of treatment.     

Co-morbidity of drug addiction: An analysis of epidemiological data and possible etiological models

This review summarizes the literature on psychiatric co-morbidity of substance use. The author overviews general population epidemiological surveys as well as clinical studies, and discusses both DSM axis I and axis II disorders. After presenting epidemiological data the author analyzes the nature of relationship between psychoactive substance use and other mental disorders, and–through examples–four possible models of this relationship are examined. Despite the lack of precisely determined prevalence rates, some definite tendencies could be observed along the consistent results of the studies. Due to methodological problems, however, many questions remain unanswered. Although there are relatively comprehensive studies on psychiatric disorders associated with drug use and drug addiction, the question of causality is relatively unresolved. Theoretically possible relations regarding causality seem to overlap in practice, and in most cases linear type connection is unlikely. It can be concluded that general questions, such as which disorders have a great significance in connection to drug use, can be answered. Additional research is needed, however, to examine the effects of different drug types, race, and gender. Understanding causality also requires further research.     

肠道微生物群与精神疾病的关系

肠道微生物群种类繁多,对人类健康起至关重要作用.肠道微生物群可以影响人类的神经系统、内分泌系统、免疫系统.目前发现精神疾病中的抑郁症、焦虑症、孤独症均与肠道微生物群存在相关性,这将有望为治疗相关精神疾病提供新方法.此文就肠道微生物群与这3类精神疾病相关机制的研究作一综述.     

The psychoneuroimmunology of depression

Chronic stress, by initiating changes in the hypothalamic‐pituitary‐adrenal (HPA) axis and the immune system, acts as a trigger for anxiety and depression. There is experimental and clinical evidence that the rise in the concentration of pro‐inflammatory cytokines and glucocorticoids, which occurs in a chronically stressful situation and also in depression, contribute to the behavioural changes associated with depression. A defect in serotonergic function is associated with these hormonal and immune changes. Neurodegenerative changes in the hippocampus, prefrontal cortex and amygdalae are the frequent outcome of the changes in the HPA axis and the immune system. Such changes may provide evidence for the link between chronic depression and dementia in later life. Copyright © 2009 John Wiley & Sons, Ltd.     

Comorbidity of mental disorders and alcohol- and drug-use disorders: analysis of New South Wales inpatient data

Introduction and Aims. Alcohol‐ and other drug‐use disorders have been found to be associated with mental disorders, however, complete characteristics of these comorbid mental disorders are not completely clear in early population based studies. This study aimed to explore the extent and profiles of comorbid mental disorders with alcohol‐ and other drug‐use disorders using a large inpatient dataset. Methods. The data source was the New South Wales (NSW) Inpatient Statistic Data Collection which collects the clinical data of hospital admissions in NSW, Australia. The data were coded using the International Classification of Diseases—10th Revision (ICD‐10). The data were from 1 July 2005 to 30 June 2006 the Australian financial year and statistical analysis was performed using SAS. Results. Of 1 592 156 patients admitted, 91 510 (6%) had at least one mental disorder diagnosis and 18 283 (1.1%) had at least one alcohol‐ or other drug‐related diagnosis. Of these patients, an overall 9.6% had dual diagnoses. Comorbidity was nearly five times higher in alcohol‐ and other drug‐use disorders than in mental health disorders (52.4% vs. 10.5%). Comorbidity was higher in males than females (12% vs. 7.1%) and was the most common in patients aged from 20 to 49 regardless of sex. There was a significantly increased risk of developing a comorbid condition in all age groups above 10 years. The most common mental health disorders were major depressive disorders, followed by dementia, anxiety and severe stress. Alcohol‐use disorder was the most common diagnosis, followed by cannabis and opioids. Discussion and Conclusion. This study shows the characteristics of comorbid mental and alcohol‐ or other drug‐use disorders. The study extends our understanding of issues addressed in previous population studies.[Lai HMX, Huang QR. Comorbidity of mental disorders and alcohol‐ and drug‐use disorders: Analysis of New South Wales inpatient data. Drug Alcohol Rev 2009]     

以微生物群为靶标干预精神障碍的研究进展

人体微生物群通过多种方式参与维持宿主的健康已成为共识。近年来,随着对肠-脑轴的深入研究,微生物群被发现可以以多种方式在人体精神健康方面发挥重要作用。多种精神障碍的发生过程中也存在着微生物群的改变。现已有大量以微生物群为靶标干预精神障碍的相关研究。但是,目前尚未有商品化的以微生物群为靶标干预精神障碍的相关产品,且关于该领域的综述也较少。此文从微生物群与机体神经系统的相互作用,微生物群与精神障碍的关系以及以微生物群为靶标治疗精神障碍的相关研究进展等方面进行综述。     

PD‐1 Pathway Inhibitors: Immuno‐Oncology Agents for Restoring Antitumor Immune Responses

Immune checkpoint inhibitors are designed to restore a patient's own antitumor immune response that has been suppressed during tumor development. The first monoclonal antibodies against the immune checkpoint programmed death 1 (PD‐1) receptor, nivolumab and pembrolizumab, are now approved for clinical use. Both agents are indicated for the treatment of advanced melanoma, as well as for the treatment of metastatic non–small cell lung cancer (NSCLC). Nivolumab is also approved for the treatment of advanced renal cell carcinoma. In patients with melanoma, these agents result in objective response rates of ~25–40%, with durable responses lasting more than 2 years in some cases. Results from phase III trials have shown improved survival with nivolumab versus standard‐of‐care chemotherapy in both patients with advanced melanoma and those with advanced NSCLC. In patients with advanced melanoma, both PD‐1 inhibitors (nivolumab and pembrolizumab) have shown improved survival versus ipilimumab. PD‐1 inhibitors are associated with adverse events that have immune etiologies, with grade greater than 3 adverse events typically reported in 16% or less of patients. However, most immune‐mediated adverse events (including grade 3–4 adverse events) can be managed by using published management algorithms without permanent discontinuation of the agent. As nivolumab and pembrolizumab enter the clinic, and with more PD‐1 pathway agents in development for a range of tumor types, this review aims to provide pharmacists with a basic understanding of the role of PD‐1 in modulating the immune system and their use in the cancer treatment. The most recent clinical efficacy and safety data are discussed, highlighting the response characteristics distinctive to immune checkpoint inhibitors, along with pharmacokinetic and pharmacodynamic data and cost considerations.     

Intrarenal alterations of the angiotensin‐converting enzyme type 2/angiotensin 1–7 complex of the renin‐angiotensin system do not alter the course of malignant hypertension in Cyp1a1‐Ren‐2 transgenic rats

The role of the intrarenal renin‐angiotensin system (RAS) in the pathophysiology of malignant hypertension is not fully understood. Accumulating evidence indicates that the recently discovered vasodilator axis of the RAS, angiotensin‐converting enzyme (ACE) type 2 (ACE2)/angiotensin 1–7 (ANG 1–7), constitutes an endogenous system counterbalancing the hypertensiogenic axis, ACE/angiotensin II (ANG II)/AT1 receptor. This study aimed to evaluate the role of the intrarenal vasodilator RAS axis in the pathophysiology of ANG II‐dependent malignant hypertension in Cyp1a1‐Ren‐2 transgenic rats. ANG II‐dependent malignant hypertension was induced by 13 days′ dietary administration of indole‐3‐carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1‐Ren‐2 transgenic rats. It was hypothesized that pharmacologically‐induced inhibition of the ACE2/ANG 1–7 complex should aggravate, and activation of this axis should attenuate, the course of ANG II‐dependent malignant hypertension. Blood pressure (BP) was monitored by radiotelemetry. ACE2 inhibitor (DX 600, 0.2 μg/day) and ACE2 activator (DIZE, 1 mg/day) were administrated via osmotic minipumps. Even though ACE2 inhibitor significantly decreased and ACE2 activator increased intrarenal ANG 1–7 concentrations, the course of BP, as well as of albuminuria, cardiac hypertrophy and renal glomerular damage, were not altered. It was shown that intrarenal alterations in the ACE2/ANG 1–7 complex did not significantly modify the course of malignant hypertension in I3C‐induced Cyp1a1‐Ren‐2 transgenic rats. Thus, in our experimental setting alterations of this intrarenal vasodilator complex of the RAS do not significantly modify the form of malignant hypertension that clearly depends on the inappropriately increased activity of the ACE/ANG II/AT1 receptor axis.     

Carbohydrate-based drugs in the treatment of epilepsy, depression and other affective disorders

Mental illness affects a quarter of the US population. Recently, it has been shown that new, carbohydrate-based drugs hold promise in the treatment of central nervous system (CNS) disorders. A variety of ways in which drugs of this sort may reduce the symptoms of epilepsy, depression and other affective disorders have been proposed, including: targeting the immune system, disrupting glycolysis, acting at different sites in the hypothalamic-pituitary-adrenal (HPA) axis, and targeting specific biochemical pathways such as the inositol pathway. In the present review, the structure-activity relationships (SARs) of a wide variety of CNS-active carbohydrates are presented.     

A Review of Integrated Care for Concurrent Disorders: Cost Effectiveness and Clinical Outcomes

Objective: The recognition of concurrent disorders (combined mental health and substance use disorders) has increased substantially over the last three decades, leading to greater numbers of people with these diagnoses and a subsequent greater financial burden on the health care system, yet establishing effective modes of management remains a challenge. Further, there is little evidence on which to base recommendations for a particular mode of health service delivery. This paper will further summarize the existing treatment models for a comprehensive overview. The objectives of this study are to determine whether existing service models are effective in treating combined mental health and substance use disorders and to examine whether an integrated model of service delivery should be recommended to policy makers. The following two research questions are the focus of this paper: (1) Are the existing service models effective at treating mental health and substance use disorders? (2) How are existing service models effective at treating mental health and substance use disorders? Methods: We used various databases to systematically review the effectiveness of service delivery models to treat concurrent disorders. Models were considered effective if they are found to be cost-effective and significantly improve clinical and social outcomes. Results: This systematic review revealed that integrated models of care are more effective than conventional, nonintegrated models. Integrated models demonstrated superiority to standard care models through reductions in substance use disorders and improvement of mental health in patients who had diagnoses of concurrent disorders. Our meta-analysis revealed similar findings, indicating that the integrated model is more cost-effective than standard care. Conclusions: Given the limited number of studies in relation to service delivery for concurrent disorders, it is too early to make a strong evidence-based recommendation to policy makers and service providers as to the superiority of one approach over the others. However, the available evidence suggests that integrated care models for concurrent disorders are the most effective models for patient care. More research is needed, especially around the translation of research findings to policy development and, vice versa, around the translation from the policy level to the patients’ level.     

T‐helper cell‐mediated factors in drug‐induced liver injury

Drug‐induced liver injury (DILI) leads to a large burden on the healthcare system due to its potential morbidity and mortality. The key for predicting and preventing DILI is to understand the underlying mechanisms. Hepatic inflammation is one of the most common features of DILI. The inflammation can be attributed to the innate immune response. The adaptive immune system is also affected by the innate immune response resulting in liver damage. T‐helper cells are important regulators of acquired immunity. T‐helper cell‐mediated immune responses play pivotal roles in the pathogenesis of a variety of liver disorders. This review summarizes recent advances in the T‐helper cell‐mediated factors in DILI and potential mechanisms, which may lead to a better understanding of DILI. Copyright © 2015 John Wiley & Sons, Ltd.     

Evidence for a Dysregulated Immune System in the Etiology of Psychiatric Disorders

There is extensive bi-directional communication between the brain and the immune system in both health and disease. In recent years, the role of an altered immune system in the etiology of major psychiatric disorders has become more apparent. Studies have demonstrated that some patients with major psychiatric disorders exhibit characteristic signs of immune dysregulation and that this may be a common pathophysiological mechanism that underlies the development and progression of these disorders. Furthermore, many psychiatric disorders are also often accompanied by chronic medical conditions related to immune dysfunction such as autoimmune diseases, diabetes and atherosclerosis. One of the major psychiatric disorders that has been associated with an altered immune system is schizophrenia, with approximately one third of patients with this disorder showing immunological abnormalities such as an altered cytokine profile in serum and cerebrospinal fluid. An altered cytokine profile is also found in a proportion of patients with major depressive disorder and is thought to be potentially related to the pathophysiology of this disorder. Emerging evidence suggests that altered immune parameters may also be implicated in the neurobiological etiology of autism spectrum disorders. Further support for a role of immune dysregulation in the pathophysiology of these psychiatric disorders comes from studies showing the immunomodulating effects of antipsychotics and antidepressants, and the mood altering effects of anti-inflammatory therapies. This review will not attempt to discuss all of the psychiatric disorders that have been associated with an augmented immune system, but will instead focus on several key disorders where dysregulation of this system has been implicated in their pathophysiology including depression, schizophrenia and autism spectrum disorder.     

美沙酮维持治疗人员与精神障碍的共病分析

目的:调查美沙酮维持治疗人员共病其他精神障碍情况。方法:采用DSM-Ⅳ-TR轴Ⅰ障碍定式临床检查(SCID-P)及人格障碍用定式临床检查手册(SCID-Ⅱ)调查100名美沙酮维持治疗人员精神障碍情况。结果:美沙酮维持治疗人员共患轴Ⅰ障碍主要是心境障碍(终生患病率26.0%)、焦虑障碍(终生患病率为23.0%)、其他活性物质所致精神障碍(11.0%);共患轴Ⅱ障碍主要是反社会人格障碍的比例最高(20.0%),其次是边缘性人格障碍(18.0%)、强迫性人格障碍(17.0%)。结论:美沙酮维持治疗人员中较多合并其他精神障碍,应积极关注共患疾病的诊断和治疗。     

Neuroinflammation and synaptic plasticity: theoretical basis for a novel, immune-centred, therapeutic approach to neurological disorders

The fascinating capacity that the central nervous system (CNS) has for encoding and retaining memories is thought to be based on activity-dependent forms of synaptic plasticity. The CNS and the immune systems are known to be engaged in an intense bidirectional crosstalk, and glial cells are now viewed as a crucial third element of the synapse. In this opinion article, we review the principal mechanisms by which the immune system, and in particular immune diffusible mediators, influences synaptic transmission and the induction of brain plastic phenomena. Thereafter, we consider the potential implications of inflammation-related overexpression of diffusible mediators in the disruption of synaptic plastic processes and neuronal networks functioning during human neurological diseases. Finally, we propose that a more accurate characterization of the mechanisms underlying the immune-mediated control of synaptic plasticity could represent, in the future, the basis for the development of a novel immune-centred therapeutic approach to neurological disorders.     

Therapeutic peptidomimetic strategies for autoimmune diseases: costimulation blockade*

Abstract: Cognate interactions between immune effector cells and antigen‐presenting cells (APCs) govern immune responses. Specific signals occur between the T‐cell receptor peptide and APCs and nonspecific signals between pairs of costimulatory molecules. Costimulation signals are required for full T‐cell activation and are assumed to regulate T‐cell responses as well as other aspects of the immune system. As new discoveries are made, it is becoming clear how important these costimulation interactions are for immune responses. Costimulation requirements for T‐cell regulation have been extensively studied as a way to control many autoimmune diseases and downregulate inflammatory reactions. The CD28:B7 and the CD40:CD40L families of molecules are considered to be critical costimulatory molecules and have been studied extensively. Blocking the interaction between these molecules results in a state of immune unresponsiveness termed ‘anergy’. Several different strategies for blockade of these interactions are explored including monoclonal antibodies (mAbs), Fab fragments, chimeric, and/or fusion proteins. We developed novel, immune‐specific approaches that interfere with these interactions. Using experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis mediated by central nervous system (CNS)‐specific T‐cells, we developed a multi‐targeted approach that utilizes peptides for blockade of costimulatory molecules. We designed blocking peptide mimics that retain the functional binding area of the parent protein while reducing the overall size and are thus capable of blocking signal transduction. In this paper, we review the role of costimulatory molecules in autoimmune diseases, two of the most well‐studied costimulatory pathways (CD28/CTLA‐4:B7 and CD40:CD40L), and the advantages of peptidomimetic approaches. We present data showing the ability of peptide mimics of costimulatory molecules to suppress autoimmune disease and propose a mechanism for disease suppression.     

Potential for Early-Life Immune Insult Including Developmental Immunotoxicity in Autism and Autism Spectrum Disorders: Focus on Critical Windows of Immune Vulnerability

Early-life immune insults (ELII) including xenobiotic-induced developmental immunotoxicity (DIT) are important factors in childhood and adult chronic diseases. However, prenatal and perinatal environmentally induced immune alterations have yet to be considered in depth in the context of autism and autism spectrum disorders (ASDs). Numerous factors produce early-life-induced immune dysfunction in offspring, including exposure to xenobiotics, maternal infections, and other prenatal–neonatal stressors. Early life sensitivity to ELII, including DIT, results from the heightened vulnerability of the developing immune system to disruption and the serious nature of the adverse outcomes arising after disruption of one-time immune maturational events. The resulting health risks extend beyond infectious diseases, cancer, allergy, and autoimmunity to include pathologies of the neurological, reproductive, and endocrine systems. Because these changes may include misregulation of resident inflammatory myelomonocytic cells in tissues such as the brain, they are a potential concern in cases of prenatal–neonatal brain pathologies and neurobehavioral deficits. Autism and ASDs are chronic developmental neurobehavioral disorders that are on the rise in the United States with prenatal and perinatal environmental factors suspected as contributors to this increase. Evidence for an association between environmentally associated childhood immune dysfunction and ASDs suggests that ELII and DIT may contribute to these conditions. However, it is not known if this linkage is directly associated with the brain pathologies or represents a separate (or secondary) outcome. This review considers the known features of ELII and DIT and how they may provide important clues to prenatal brain inflammation and the risk of autism and ASDs.