Cell atrophy and loss in depression: reversal by antidepressant treatment

Depression is associated with structural alterations in limbic brain regions that control emotion and mood. Studies of chronic stress in animal models and postmortem tissue from depressed subjects demonstrate that these structural alterations result from atrophy and loss of neurons and glial cells. These findings indicate that depression and stress-related mood disorders can be considered mild neurodegenerative disorders. Importantly, there is evidence that these structural alterations can be blocked or even reversed by elimination of stress and by antidepressant treatments. A major focus of current investigations is to characterize the molecular signaling pathways and factors that underlie these effects of stress, depression, and antidepressant treatment. Recent advances in this research area are discussed and potential novel targets for antidepressant development are highlighted.     

Cognitive disruptions in stress-related psychiatric disorders: A role for corticotropin releasing factor (CRF)

This article is part of a Special Issue “SBN 2014”.Stress is a potential etiology contributor to both post-traumatic stress disorders (PTSD) and major depression. One stress-related neuropeptide that is hypersecreted in these disorders is corticotropin releasing factor (CRF). Dysregulation of CRF has long been linked to the emotion and mood symptoms that characterize PTSD and depression. However, the idea that CRF also mediates the cognitive disruptions observed in patients with these disorders has received less attention. Here we review literature indicating that CRF can alter cognitive functions. Detailed are anatomical studies revealing that CRF is poised to modulate regions required for learning and memory. We also describe preclinical behavioral studies that demonstrate CRF’s ability to alter fear conditioning, impair memory consolidation, and alter a number of executive functions, including attention and cognitive flexibility. The implications of these findings for the etiology and treatment of the cognitive impairments observed in stress-related psychiatric disorders are described.     

Review: When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C

Vitamin C (or ascorbic acid) is regarded as the most important water-soluble antioxidant in human plasma and mammalian cells which have mechanisms to recycle and accumulate it against a concentration gradient, suggesting that the vitamin might also have important intracellular functions. In this review we summarize evidence from human trials that have attempted an association between vitamin C supplementation and an effect on biomarkers of oxidative DNA damage. Most studies reviewed herein showed either a vitamin C-mediated reduction in oxidative DNA damage or a null effect, whereas only a few studies showed an increase in specific base lesions. We also address the possible beneficial effects of vitamin C supplementation for the prevention of cancer and cardiovascular disease. Finally, we discuss the contribution of cell culture studies to our understanding of the mode of action of vitamin C and we review recent evidence that vitamin C is able to modulate gene expression and cellular function, with a particular interest in cell differentiation.     

ReviewPart of the Series: From Dietary Antioxidants to Regulators in Cellular Signalling and Gene ExpressionReview: When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C

Vitamin C (or ascorbic acid) is regarded as the most important water-soluble antioxidant in human plasma and mammalian cells which have mechanisms to recycle and accumulate it against a concentration gradient, suggesting that the vitamin might also have important intracellular functions. In this review we summarize evidence from human trials that have attempted an association between vitamin C supplementation and an effect on biomarkers of oxidative DNA damage. Most studies reviewed herein showed either a vitamin C-mediated reduction in oxidative DNA damage or a null effect, whereas only a few studies showed an increase in specific base lesions. We also address the possible beneficial effects of vitamin C supplementation for the prevention of cancer and cardiovascular disease. Finally, we discuss the contribution of cell culture studies to our understanding of the mode of action of vitamin C and we review recent evidence that vitamin C is able to modulate gene expression and cellular function, with a particular interest in cell differentiation.     

The HPA Axis under Stress and Aging: Individual Vulnerability is Associated with Behavioral Patterns and Exposure Time

With aging, incidence of severe stress-related diseases increases. However, mechanisms, underlying individual vulnerability to stress and age-related diseases are not clear. The goal of this review is to analyze finding from the recent literature on age-related characteristics of the hypothalamic-pituitary-adrenal (HPA) axis associated with stress reactivity in animals that show behavioral signs of anxiety and depression under mild stress, and in human patients with anxiety disorders and depression with emphasis on the impact of the circadian rhythm and the negative feedback mechanisms involved in the stress response. One can conclude that HPA axis reaction to psycho-emotional stress, at least acute stress, increases in the aged individuals with anxiety and depression behavior. Elevated stress reactivity is associated with disruption of the circadian rhythm and the mineralocorticoid receptor-mediated glucocorticoid negative feedback. The disordered function of the HPA axis in individuals with anxiety and depression behavior can contribute to aging-related pathology.     

A-to-I editing of the 5HT2C receptor and behaviour.

Site-specific deamination of five adenosine residues in the pre-mRNA of the serotonin 2C receptor, 5HT2CR, alters the amino acid sequence of the encoded protein. Such RNA editing can produce 32 mRNA variants, encoding 24 protein isoforms that vary in biochemical and pharmacological properties. Because serotonin functions in the regulation of mood and behaviour, modulation of serotonin signalling by RNA editing may be relevant to such psychiatric disorders as anxiety and depression. Several recent human studies have reported changes in 5HT2CR editing in schizophrenia, major depression or suicide, but results are variable and not conclusive. Rodent studies have begun to examine effects of drug treatments and stress. Understanding the importance of 5HT2CR editing in mood and behaviour will be assisted by experiments designed to analyse multiple strains of mice, in different behavioural tests, with optimal evaluation of the time course of molecular changes.     

The neurobiology of depression—revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms

The serotonin (5-HT) hypothesis of depression dates from the 1960s. It originally postulated that a deficit in brain serotonin, corrected by antidepressant drugs, was the origin of the illness. Nowadays, it is generally accepted that recurring mood disorders are brain diseases resulting from the combination, to various degrees, of genetic and other biological as well as environmental factors, evolving through the lifespan. All areas of neuroscience, from genes to behaviour, molecules to mind, and experimental to clinical, are actively engaged in attempts at elucidating the pathophysiology of depression and the mechanisms underlying the efficacy of antidepressant treatments. This first of two special issues of Philosophical Transactions B seeks to provide an overview of current developments in the field, with an emphasis on cellular and molecular mechanisms, and how their unravelling opens new perspectives for future research.     

The neurobiology of depression--revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms

The serotonin (5-HT) hypothesis of depression dates from the 1960s. It originally postulated that a deficit in brain serotonin, corrected by antidepressant drugs, was the origin of the illness. Nowadays, it is generally accepted that recurring mood disorders are brain diseases resulting from the combination, to various degrees, of genetic and other biological as well as environmental factors, evolving through the lifespan. All areas of neuroscience, from genes to behaviour, molecules to mind, and experimental to clinical, are actively engaged in attempts at elucidating the pathophysiology of depression and the mechanisms underlying the efficacy of antidepressant treatments. This first of two special issues of Philosophical Transactions B seeks to provide an overview of current developments in the field, with an emphasis on cellular and molecular mechanisms, and how their unravelling opens new perspectives for future research.     

Regulation of the glucocorticoid response to stress-related disorders by the Hsp90-binding immunophilin FKBP51

Immunophilin is the collective name given to a family of proteins that bind immunosuppressive drugs: Some immunophilins are Hsp90-binding cochaperones that affect steroid receptor function. Mood and anxiety disorders are stress-related diseases characterized by an impaired function of the mineralocorticoid and glucocorticoid receptors, two of the major regulatory elements of the hypothalamus-pituitary-adrenocortical axis. Genetic variations of the FK506-binding protein of 51-kDa, FKBP51, one of the immunophilins bound to those steroid receptor complexes, were associated with the effectiveness of treatments against depression and with a major risk-factor for the development of post-traumatic stress disorders. Interestingly, immunophilins show polymorphisms and some polymorphic isoforms of FKBP51 correlate with a greater impairment of steroid receptor functions. In this review, we discuss different aspects of the role of FKBP51 in such steroid receptor function and the impact of genetic variants of the immunophilin on the dysregulation of the stress response.     

Mood and anxiety disorders in women with PCOS

Women with polycystic ovary syndrome have gynecologic, reproductive and metabolic co-morbidities that span their entire lifespan. More recently a higher risk of mood and anxiety disorders has been reported in women with PCOS. Women with PCOS have higher depression scores and a higher risk of depression independent of BMI. Although clinical features of hyperandrogenism affect health related quality of life, the association between hirsutism, acne, body image and depression is currently unclear. Similarly there is limited data on the association between variables such as biochemical hyperandrogenism or infertility and depression. Women with PCOS are also at risk for symptoms of generalized anxiety disorder. There is insufficient data examining the risk of other anxiety disorders such as social phobia, obsessive compulsive disorders and panic disorder. In a number of patients some of these disorders coexist increasing the health burden. These data underscore the need to screen all women with PCOS for mood and anxiety disorders and adequately treat women who are diagnosed with these conditions.     

Enhancement of the 5-HT neurotransmission by antidepressant treatments

The hypothesis of an etiopathogenic role of 5-HT and that of a mediation by the 5-HT system in the effect of antidepressant treatments have often been confused. Little unequivocal evidence exists for a 5-HT deficit in depression. However, several recent animal and clinical data suggest that the 5-HT system might contribute to the therapeutic effect of various antidepressant treatments. Long-term administration of tricyclic antidepressant (TCA) drugs induces a sensitization of rat forebrain neurons to iontophoretically-applied 5-HT. Repeated electroconvulsive shocks result also in an increased sensitivity of forebrain 5-HT receptors. However, chronic administration of a new antidepressant drug, zimelidine, a potent and long-lasting 5-HT uptake blocker, fails to modify 5-HT receptor sensitivity. These results suggest that enhancement of 5-HT neurotransmission obtained via either pre- or postsynaptic mechanisms might determine the antidepressant effect of these treatments. In a recent clinical study, we observed that lithium administration to TCA-resistant depressive patients induced a rapid relief of depression. It is possible that the presynaptic enhancing effect of lithium on the 5-HT system might unveil the TCA-induced sensitization of the postsynaptic 5-HT receptors. Most depressed patients exhibit marked diurnal variations of mood. Preliminary experiments in rats revealed that the responsiveness of hippocampal neurons to iontophoretically-applied 5-HT is enhanced in the evening. Similar diurnal variations of 5-HT receptor sensitivity might occur in human brain and be related to diurnal variation of mood in depression. Since normal individuals do not show these fluctuations of mood, it is proposed that the "mood regulating system" might become 5-HT dependent in depressed patients.     

Activity of selected aromatic amino acids in biological systems

Besides the structural function in proteins, aromatic amino acids are precursors of many important biological compounds essential for normal functioning of the human organism. Many of these compounds may be used as markers for identification of specific pathological states. Comprehensive knowledge about the metabolism of aromatic amino acids and mechanisms of action of their metabolites made it possible to develop effective treatments for many disorders. However, it should not be forgotten that in some pathological conditions, these compounds could not only be involved in the pathogenesis of many disease entities but could also be used as an important tool in prediction of many diseases. This paper contains a review of published literature on aromatic amino acids in the context of physiological processes of the human body and chosen social disorders, such as cancers; psychiatric disorders: depression, anxiety states, schizophrenia, bipolar affective disorders; neurodegenerative, and cardiovascular diseases; chronic kidney insufficiency or diabetes.     

Leading compounds for the validation of animal models of psychopathology

Modelling of complex psychiatric disorders, e.g., depression and schizophrenia, in animals is a major challenge, since they are characterized by certain disturbances in functions that are absolutely unique to humans. Furthermore, we still have not identified the genetic and neurobiological mechanisms, nor do we know precisely the circuits in the brain that function abnormally in mood and psychotic disorders. Consequently, the pharmacological treatments used are mostly variations on a theme that was started more than 50 years ago. Thus, progress in novel drug development with improved therapeutic efficacy would benefit greatly from improved animal models. Here, we review the available animal models of depression and schizophrenia and focus on the way that they respond to various types of potential candidate molecules, such as novel antidepressant or antipsychotic drugs, as an index of predictive validity. We conclude that the generation of convincing and useful animal models of mental illnesses could be a bridge to success in drug discovery.     

Psychopathological symptoms in patients with primary hyperaldosteronism--possible pathways

A close comorbidity between endocrine diseases and psychopathological symptoms has been described in the literature. Until now only a few studies have reported about an increased anxiety and depressive symptoms in patients with primary hyperaldosteronism (PHA). The exact pathways of psychiatric comorbidities have not been totally clarified yet, although the renin-angiotensin-aldosterone-system has gained more attention in research on anxiety and depression. There are several structures and factors, which could mediate anxiety or a depressive symptomatology. Additionally a possible influence of the standardised treatment with a mineralocorticoidreceptor (MR) antagonist or adrenalectomy should be investigated as they have been shown to affect mood. Psychiatric comorbidities are not only an additional burden in these patients, but as depression and anxiety are additional risk factors in patients with cardiovascular diseases. Possible pathomechanisms in the relation between PHA and psychiatric symptoms should be more closely investigated. For the clinical practice a regular screening for psychiatric comorbidities and an adequate treatment are required.     

A neurocognitive model for understanding treatment action in depression

The way in which emotion is represented and processed in the human brain is an expanding area of research and has key implications for how we understand and potentially treat affective disorders such as depression. Characterizing the effects of pharmacological manipulations of key neurotransmitter systems can also help reveal the neurochemical underpinnings of emotional processing and how common antidepressant drugs may work in the treatment of depression and anxiety. This approach has revealed that depression is associated with both neural and behavioural biases towards negative over positive stimuli. Evidence from pharmacological challenge studies suggests that antidepressant treatment acts to normalize these biases early on in treatment, resulting in patients experiencing the world in a more positive way, improving their mood over time. This model is supported by evidence from both pharmacological and non-pharmacological interventions. The unique perspective on antidepressant treatment offered by this approach provides some insights into individual response to treatment, as well as novel approaches to drug development.     

Effect of high‐dose vitamin C supplementation on growth,tissue ascorbic acid concentrations and physiological response to transportation stress in juvenile silver pomfret,Pampus argenteus

This study investigated the effect of high‐dose vitamin C supplementation on growth, tissue ascorbic acid concentrations and physiological response to transportation stress in juvenile silver pomfret, Pampus argenteus (initial average weight 6.2 ± 0.2 g). Three practical diets were formulated to contain 100 (control), 450 and 800 mg ascorbic acid/kg diet, respectively, supplied as l‐ascorbyl‐2‐polyphosphate. Each diet was fed to triplicate groups of fish in circular tanks (3 m ø, 1.5 m depth) (60 fish/tank) for 9 weeks. Growth did not change significantly with dietary vitamin C levels, although an improvement tendency with an increase in vitamin C supplementation was observed. Ascorbic acid concentrations in the liver and muscle of fish fed diets containing graded levels of vitamin C were positively correlated with dietary levels of this vitamin. Tissue ascorbic acid concentrations significantly increased with increasing vitamin C supplementation. After 9 weeks, the fish were subjected to transportation stress for 4 h to determine the influence of high vitamin C supplementation on the physiological response to this stressor. Serum cortisol, glucose and lactate levels significantly increased in stressed fish. Serum cortisol and glucose concentrations after stress were significantly higher in fish fed the control diet (7.91 μg L^?1 and 0.80 mm , respectively) than in the other groups. However, there were no significant differences in serum cortisol and glucose levels after stress between the 450 and 800 mg kg^?1 diets. No significant change could be found in serum lactate levels after stress among the different treatments. In conclusion, the dietary administration of high doses of vitamin C could reduce stress in silver pomfret and increase the survival of fish under stress conditions.     

Sex differences in molecular and cellular substrates of stress

Women are twice as likely as men to suffer from stress-related psychiatric disorders, like unipolar depression and post-traumatic stress disorder. Although the underlying neural mechanisms are not well characterized, the pivotal role of stress in the onset and severity of these diseases has led to the idea that sex differences in stress responses account for this sex bias. Corticotropin-releasing factor (CRF) orchestrates stress responses by acting both as a neurohormone to initiate the hypothalamic-pituitary-adrenal (HPA) axis and as a neuromodulator in the brain. One target of CRF modulation is the locus coeruleus (LC)-norepinephrine system, which coordinates arousal components of the stress response. Hypersecretion of CRF and dysregulation of targets downstream from CRF, such as the HPA axis and LC-norepinephrine system, are characteristic features of many stress-related psychiatric diseases, suggesting a causal role for CRF and its targets in the development of these disorders. This review will describe sex differences in CRF and the LC-norepinephrine system that can increase stress sensitivity in females, making them vulnerable to stress-related disorders. Evidence for gonadal hormone regulation of hypothalamic CRF is discussed as an effect that can lead to increased HPA axis activity in females. Sex differences in the structure of LC neurons that create the potential for hyperarousal in response to emotional stimuli are described. Finally, sex differences at the molecular level of the CRF(1) receptor that make the LC-norepinephrine system more reactive in females are reviewed. The implications of these sex differences for the treatment of stress-related psychiatric disorders also will be discussed.     

Evidence for the influence of vitamin C on age- and heat exposure-dependent deterioration of biochemical function in rat's liver and kidney

Molecular mechanisms responsible for age-dependent deterioration of biochemical functions have not been completely revealed as yet. We studied the role of ascorbic acid food supplementation in young and aged acute heat-exposed rats. The duration of heat exposure (40±0.5 °C) for heat-exposed Wistar rats, at the age of 35 days and 22–24 months, was approximately 2 h. In the aged heat-unexposed animals cholesterol and triglycerides were considerably high, whereas tissues ascorbic acid, glutathione and methylglyoxal were significantly low. Administration of vitamin C reverted these age-associated differences to the status comparable to young rats. The role of vitamin C supplementation was almost the same in young heat-exposed animals. In this direction in young rats suppression of LTC₄ synthesis is evident during acute heat exposure as a result of vitamin C treatment. The importance of vitamin C treatment for young heat-exposed rats is in the protection of apoptosis, if it is determined across the LTC₄ changes. In contrary, in old heat-exposed rats, vitamin C does not suppress the apoptotic processes. The results suggest that oxidative and apoptotic processes in the liver and the kidney as a result of the acute heat exposure is presumably subject of ascorbic acid deficiency.     

Mammalian cystatin and protagonists in brain diseases

Abstract

Cystatins are the thiol Proteinase inhibitors, present ubiquitously in mammalian body. They prevent unwanted proteolysis and play important role in several diseases. Regulation of cysteine Proteinase and their inhibitors is of utmost importance in neurodegenerative diseases like Alzheimer, amyloid angiopathy and in many other diseases. The action of these cysteine proteases is biologically controlled by proteinase inhibitors namely cystatins(cys) they constitute a superfamily of homologous proteins. The major role of cystatins is to protect the organism against endogenous proteases released from lysosomes, invading microorganisms and parasites that use cysteine proteases to enter the body. An enormous progress has been made in understanding of protein degradation process under normal and pathological conditions; in fact proteases are now clearly viewed as important drug targets. Some studies have suggested that cystatin C is a target for intervention in neurological disorders because its expression increases in response to human neurological disorders and in animal models of neurodegenerative states. Although, these studies did not clarify whether CysC up-regulation is a pathogenic factor in neurodegenerative disorders or whether it represents a neuroprotective compensatory response of the organisms aimed to prevent progression of the disease. However, for other diseases in some cases cystatins other than cys C are up regulated and in some it is down regulated.

Cystatins have been implicated in the processes of neuronal degeneration and repair of the nervous system. Both CysC and CysB are potent, reversible inhibitors of most of the currently known cathepsins. The extent of proteolytic activity at any given time and location is the result of a balance between active proteases and physiological inhibitors. Uncontrolled proteolysis as a result of imbalance between active proteases and their endogenous inhibitors has been associated with neuronal cell death in different neuronal diseases, including brain tumors, stroke, some forms of epilepsy, Alzheimer’s disease, and neurological autoimmune diseases.

An antidepressant is a psychiatric medication used to alleviate mood disorders, major depression and other brain diseases. Drugs including the monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) are most commonly used antidepressant. They are also used to treat other conditions, such as anxiety disorders, obsessive compulsive disorder, eating disorders, and chronic pain. Although the mechanisms of the action of these antidepressants are not precisely understood, their principal target of action is at the monoamine transporter proteins located at nerve endings. Monoamine neurotransmitter transporters act to terminate synaptic neurotransmission. Selective serotonin reuptake inhibitors or SSRIs are also most widely used class of antidepressants. They work by increasing the level of serotonin in the brain. SSRIs have fewer and milder side effects, fewer drug interactions, and are much less likely to be associated with suicide than TCAs.

These antidepressants shows binding when incubated with cystatin, presenting the involvement of these antidepressant in cascade of disease, as leaving no cystatin to inhibit the cathepsin showing the myriad side effect after the administration of antidepressant. This might be one of the reason in the mechanism of action of antidepressant.

So this review expound about the role of cystatins in neurological diseases which is considered to be highly significant as it pave the way for commanding tool in the drug design.

Communicated by Ramaswamy H. Sarma     

维生素C对凡纳滨对虾生长及抗病力的影响

以不同水平维生素C 2 磷酸酯 (添加量分别为 0、75、15 0、30 0和 6 0 0mg/kg)的饲料喂养凡纳滨对虾 10周 ,研究维生素C 2 磷酸酯对凡纳滨对虾生长及抗病力的影响。结果显示 :在养殖前 4周 ,饲料中添加维生素C 2 磷酸酯显著促进凡纳滨对虾的生长 ,然而对对虾的成活以及饲料利用不产生影响 (P >0 0 5 ) ;而到实验后期添加维生素C 2 磷酸酯不能促进凡纳滨对虾的生长 ,却显著提高凡纳滨对虾的成活率 (P <0 0 5 )。维生素C 2 磷酸酯对对虾体水分、脂肪、蛋白质和维生素C在肝胰脏中的积累量的影响显著 (P <0 0 5 ) ,对对虾体灰分影响不显著 (P >0 0 5 )。维生素C 2 磷酸酯对对虾血清中超氧化物歧化酶活力无显著影响 ,饲料中未添加维生素C或过量添加 (超过 30 0mg/kg饲料 )均导致血清中酚氧化酶活力、血细胞总数和溶菌酶活力的显著下降。以生长、成活和酚氧化酶活力为指标 ,饲料中维生素C 2 磷酸酯的适宜添加量为 15 0mg/kg。