Cognition as a therapeutic target in late-life depression: Potential for nicotinic therapeutics

Depression is associated with impairments to cognition and brain function at any age, but such impairments in the elderly are particularly problematic because of the additional burden of normal cognitive aging and in some cases, structural brain pathology. Individuals with late-life depression exhibit impairments in cognition and brain structural integrity, alongside mood dysfunction. Antidepressant treatment improves symptoms in some but not all patients, and those who benefit may not return to the cognitive and functional level of nondepressed elderly. Thus, for comprehensive treatment of late-life depression, it may be necessary to address both the affective and cognitive deficits. In this review, we propose a model for the treatment of late-life depression in which nicotinic stimulation is used to improve cognitive performance and improve the efficacy of an antidepressant treatment of the syndrome of late-life depression. The cholinergic system is well-established as important to cognition. Although muscarinic stimulation may exacerbate depressive symptoms, nicotinic stimulation may improve cognition and neural functioning without a detriment to mood. While some studies of nicotinic subtype specific receptor agonists have shown promise in improving cognitive performance, less is known regarding how nicotinic receptor stimulation affects cognition in depressed elderly patients. Late-life depression thus represents a new therapeutic target for the development of nicotinic agonist drugs. Parallel treatment of cognitive dysfunction along with medical and psychological approaches to treating mood dysfunction may be necessary to ensure full resolution of depressive illness in aging.     

新福菌素不同时间给药对大鼠免疫功能昼夜节律变化的研究

目的：探索不同时间注射新福菌素对正常大鼠免疫功能的影响是否存在昼夜节律，为临床制定新福菌素的时辰化疗方案提供必要的实验依据。方法：将60只大鼠按给药的6个时点随机分成6组，第一天用流式细胞仪记数用药前大鼠T淋巴细胞亚群，第二天按6个时点给药，第三天注射抗原。第十一天测抗体，第十二天测用药后大鼠淋巴细胞弧群及做足跖实验，24小时后观察足跖肿胀并计算足跖肿胀率。结果：不同时点用药组大鼠产生抗体的量、足跖肿胀率、淋巴细胞亚群的变化率差异均有统计学意义，且具有昼夜节律。结论：新福菌素在1天中不同时间给药对正常大鼠免疫功能的影响存在昼夜节律。     

A comparison of moclobemide, amitriptyline and placebo in depression: a Canadian multicentre study

In a 7-week prospective multicentre study, the efficacy, tolerability and safety of moclobemide were compared to those of amitriptyline and placebo in parallel groups of out-patients (n=173) fulfilling the DSM III-R criteria for a major depressive episode. Participants were required to have a minimum baseline total score of 18 on the 17-item Hamilton Depression Rating Scale (HAMD). After a 1-week placebo washout, patients were randomly allocated to the three treatment groups. Assessment of efficacy, as judged by the number of responders achieving a 50% reduction in HAMD score by the end of treatment, showed that both moclobemide and amitriptyline were significantly superior to placebo, but that they were not significantly different from each other. Both treatments differed significantly from placebo with respect to the Physician's Global Assessment of Efficacy (very good or good response: moclobemide 57%, amitriptyline 60% and placebo 35%). Assessment of tolerance as judged by the spontaneous reporting of adverse events showed a significant superiority of moclobemide over amitriptyline, but there was no significant difference between moclobemide and placebo. At termination of the study, amitriptyline patients showed a significant elevation of heart rate both supine (10.8 beats/min) and standing (15.5 beats/min), as well as significant weight gain (1.7 kg), but no changes were seen in the moclobemide or placebo groups. In conclusion, both moclobemide and amitriptyline were found to be more effective than placebo in the treatment of depression, while moclobemide had fewer side effects.     

VEGF as a potential target for therapeutic intervention in depression

Antidepressants are among the most widely prescribed drugs, however the mechanism underlying their therapeutic efficacy is not known. Neurotrophic factors represent a promising class of targets for antidepressant treatments. We recently characterized a role for vascular endothelial growth factor (VEGF) in cellular and behavioral antidepressant responses. VEGF is a potent mitogen and survival factor for endothelial cells (ECs) and neurons, and modulator of synaptic transmission. Because VEGF has been implicated in a variety of diseases, understanding the molecular and cellular specificity of antidepressant-induced VEGF will be crucial to determine its potential as a therapeutic target in depression.     

Importance of circadian rhythmicity in the cholinergic treatment of Alzheimer's disease: focus on galantamine

ABSTRACT

Objective and scope: This review article used data from an extensive literature search (including MEDLINE database searches) to explore the relationships between sleep, memory and Alzheimer's disease (AD). The importance of taking into account circadian rhythmicity and acetylcholine (ACh) levels when considering acetylcholinesterase inhibitors, galantamine in particular, in the treatment of patients with AD is discussed.

Review findings: Moderate changes of circadian rhythms may occur as part of the normal ageing process, but patients with AD exhibit circadian rhythm disturbances extending beyond those observed in non-demented elderly and this may lead to severe disruption of the sleep–wake cycle. Indeed, ACh plays an active role in maintaining a normal sleep pattern, which is important for memory consolidation. Low levels of ACh during slow-wave sleep compared with wakefulness have been shown to be critical for the consolidation of declarative memory. This suggests the existence of a circadian rhythm in central cholinergic transmission which modulates memory processes, with high ACh levels during wakefulness and reduced levels during slow-wave sleep. When using cholinesterase inhibitors to stimulate central cholinergic transmission in AD, respecting the natural circadian fluctuations of central cholinergic transmission may therefore be an important factor for patient improvement. Interfering with nocturnal cholinergic activity can add to memory problems and induce sleep disorders. Available data suggest that the type of cholinesterase inhibitor used and the time of administration may be critical with regard to the possible development of such disturbances. Plasma levels of galantamine, for example, are high during the waking day and lower at night, supporting a cholinergic stimulation that mirrors the physiological circadian rhythm of cholinergic activity. This may have beneficial implications with regard to sleep and memory.

Conclusions: The pharmacokinetic properties of cholinesterase inhibitors may need to be taken into account to avoid interference with sleep architecture and to achieve optimum benefits from treatment on cognitive processes.     

Glia mechanisms in mood regulation: a novel model of mood disorders

Introduction Recent evidence in clinical and preclinical studies has implicated glutamate neurotransmissions in pathophysiology of mood disorders. The regulation of amino acid neurotransmission, i.e., glutamate and gamma-aminobutyric acid (GABA) involves coordinated mechanisms of uptake and transport within a tripartite synaptic system that includes neurons and glia. Newly appreciated role of the glia, more specifically astrocytes on neuronal functions combined with reported postmortem abnormalities of glia in patients with mood disorders further supports the role of glia in mood disorders. Materials and methods This report presents some of our preliminary results utilizing glia-selective toxins and other pharmacological tools to suppress glial function within the limbic system to study the resulting behavioral abnormalities, and thus, elucidate glial involvement in the development of mood disorders. Results and discussion We demonstrate that chronic blockade of glutamate uptake by a glial/neuronal transporter antagonist l-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) within the amygdala, a key area implicated in mood regulation, results in dose-dependent reduction in social exploratory behavior and disrupts circadian activity patterns consistent with symptoms of mood disorders. Similarly, the selective astrocytic glutamate transporter type 1 (GLT-1) blocker dihydrokainic acid (DHK) injected into the amygdala also results in reduced social interaction that is blocked by selective glutamate N-methyl-d-aspartate (NMDA) type receptor antagonist AP5. The results are discussed in the context of glial and glutamate mechanisms in mood disorders and potential therapeutic avenues to address these mechanisms.     

CCR6 as a possible therapeutic target in psoriasis

Importance of the field: Psoriasis is a common, chronic autoimmune disease of the skin. Despite a number of effective treatments, new therapies are needed with enhanced efficacy, safety and convenience. Chemokine receptors are GPCRs that control leukocyte trafficking, and like other GPCRs, are good potential drug targets. The chemokine receptor CCR6 is expressed on the T_H17 subset of CD4⁺ T cells, which produces IL-17A/F, IL-22, TNF-α and other cytokines, and which has been implicated in the pathogenesis of psoriasis. CCR6 and its ligand, CCL20/MIP-3α, are highly expressed in psoriatic skin and CCR6 is necessary for the pathology induced in a mouse model of psoriasis-like inflammation.

Areas covered in this review: This review summarizes the evidence for the importance of the IL-23/T_H17 axis, and in particular CCR6 and CCL20 in psoriasis, dating from 2000 to the present, and discusses the possibility of inhibiting CCR6 as a treatment for the disease.

What the reader will gain: The review informs the reader of the current thinking on the mechanisms of inflammation in psoriasis and the possible roles for CCR6 (and CCL20) in disease pathogenesis.

Take home message: We conclude that CCR6 should be investigated as a potential therapeutic target in psoriasis.     

Coagulopathy as a therapeutic target for TRALI: rationale and possible sites of action

Transfusion-related acute lung injury (TRALI) is a subcategory of acute lung injury (ALI). As such, there are many similarities between the syndromes, both clinically and pathophysiologically. Pulmonary changes in fibrin turnover have emerged as a hallmark of ALI, thereby initiating studies investigating the potential of therapeutic interventions aimed at ameliorating this so-called pulmonary coagulopathy. Enhanced coagulation and impaired fibrinolysis are probably also important features of TRALI. In particular, platelets play an important role in mediating injury during a TRALI reaction. In this narrative review, the evidence of the role of coagulopathy and platelet activation in TRALI is discussed. Given that host risk factors for acquiring TRALI have been identified and that there is a time frame in which a preventive strategy in patients at risk for TRALI can be executed, preventive strategies are suggested. In this review, we discuss potential preventive anticoagulant interventions.     

Pharmacological modulation of circadian rhythms: a new drug target in psychotherapeutics

Daily variation in an organism's physiology and behaviour is regulated by the synchrony that is achieved between the internal timing mechanisms - the circadian rhythms of the biological clock - and the prevailing environmental cues. Proper synchrony constitutes an adaptive response; improper or lost synchrony may well yield maladaptation and, in the case of humans, a psychiatric disorder. On a basic level, the circadian system is comprised of three parts: a central oscillator, its various neuronal inputs and its outputs. For all three of these parts, the dissemination of new information is moving at an unprecedented pace, and the number of molecular targets for the opportunistic pharmacologist is growing in step. Monoamines, neuropeptides, kinases - sorting through all these, much less developing one into a drug discovery programme, may be the biggest challenge. However, the potential benefits in targeting a basic flaw in a fundamental biological system may be enormous.     

Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and clinical evidence

Research in the area of herbal psychopharmacology has increased markedly over the past decades. To date however, a comprehensive review of herbal antidepressant, anxiolytic and hypnotic psychopharmacology and applications in depression, anxiety and insomnia has been absent. A search of MEDLINE (PubMed), CINAHL, PsycINFO, and the Cochrane Library databases was conducted (up to February 21st 2011) on commonly used psychotropic herbal medicines. A review of the literature was conducted to ascertain mechanisms of action of these botanicals, in addition to a systematic review of controlled clinical trials for treatment of mood, anxiety and sleep disorders, which are common comorbid psychiatric disorders. Specific emphasis was given to emerging phytomedicines. Analysis of evidence levels was conducted, as were effect sizes (Cohen's d) where data were available. Results provided evidence of a range of neurochemical, endocrinological, and epigenetic effects for 21 individual phytomedicines, which are detailed in this paper. Sixty six controlled studies were located involving eleven phytomedicines. Several of these provide a high level of evidence, such as Hypericum perforatum for major depression, and Piper methysticum for anxiety disorders. Several human clinical trials provide preliminary positive evidence of antidepressant effects (Echium amoenum, Crocus sativus, and Rhodiola rosea) and anxiolytic activity (Matricaria recutita, Ginkgo biloba, Passiflora incanata, E. amoenum, and Scutellaria lateriflora). Caution should however be taken when interpreting the results as many studies have not been replicated. Several herbal medicines with in vitro and in vivo evidence are currently unexplored in human studies, and along with use of emerging genetic technologies “herbomics”, are areas of potential future research.     

Synaptic alterations associated with depression and schizophrenia: potential as a therapeutic target

Introduction: In recent years, the concept of ‘synaptopathy’ has been extended from neurodegenerative and neurological disorders to psychiatric diseases. According to this nascent line of research, disruption in synaptic structure and function acts as the main determinant of mental illness. Therefore, molecular systems and processes crucial for synaptic activity may represent promising therapeutic targets.

Areas covered: We review data on synaptic structural alterations in depression and schizophrenia and on specific molecular systems and/or mechanisms important for the maintenance of proper synaptic function. Specifically, we examine the involvement of the neuroligin system, the local protein translation, and the neurotrophin BDNF by reviewing clinical and preclinical studies, with particular attention to results provided by using animal models based on the role of stress in psychiatric diseases. Finally, we also discuss the impact of pharmacological treatment on these molecular systems/mechanisms.

Expert opinion: The relevance of synaptic dysfunctions in psychiatric diseases is undoubted and the potential to normalize, ameliorate, and shape such alterations by acting on molecular systems crucial to ensure synaptic function property is fascinating. However, future studies are required to elucidate several open issues.     

Nicotine and fluoxetine induce arousing effects on sleep-wake cycle in antidepressive doses: A possible mechanism of antidepressant-like effects of nicotine

A number of studies have reported an association between smoking and depression, and several reports suggest that nicotine (NIC) may act as an antidepressant. The present study was designed to determine whether the effects of NIC on sleep-wake patterns in rats are similar to those of the antidepressant fluoxetine (FLX), a selective serotonin reuptake inhibitor. Male rats were chronically implanted with a standard set of electrodes for sleep recording. We compared the effects of antidepressive doses of NIC, FLX and the combination of both drugs on sleep-wake pattern in rats subjected to one day, one week and two weeks of administration, as well as after the withdrawal of the two-week treatment. The changes observed in our study in an 8-h sleep recording period during one day, one week and two weeks of NIC administration are very similar to those observed in the rats that received FLX, which led to a decrease in both slow wave sleep II and rapid eye movement (REM) sleep as a consequence of an increase in wakefulness. In addition, all treatments also induced a significant lengthening of REM sleep latency onset. These data suggest that the antidepressant-like action of NIC could be caused by its arousing properties.     

The dexamethasone suppression test as a predictor of antidepressant response

There is some evidence to suggest that dexamethasone suppression test (DST) results obtained prior to treatment for depression might aid in selecting the proper type of antidepressant medication. Forty endogenously depressed outpatients were evaluated with the DST and 12 (30%) were identified as nonsuppressors. All patients were then treated with desipramine (150–350 mg/day). Plasma concentrations of desipramine were monitored to assure that therapeutic levels were achieved. At 5 weeks of treatment, patients were characterized as treatment responders or nonresponders on the basis of change in Hamilton Depression Scale scores.     

Histone deacetylases (HDACs) as therapeutic target for depressive disorders

Major depressive disorder (MDD) represents approximately 40% of the disability caused by mental illnesses globally. The poorly understood pathophysiology and limited efficiency of pharmacological treatment (based primarily on the principles of the monoaminergic hypothesis) make depression a serious medical, public and socio-economical problem. An increasing number of studies suggest that epigenetic modifications (alterations in gene expression that are not due to changes in DNA sequence) in certain brain regions and neural circuits represent a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of mental disorders. Accordingly, chromatin-based epigenetic regulation seems to be a promising direction for the development of new, more effective antidepressant drugs. Recently, several inhibitors of histone deacetylases (HDAC) have been extensively studied in the context of antidepressant action. So far, none of them has been used to treat depression in humans due to the low selectivity for specific HDAC isoforms, and consequently, a risk of serious adverse events. In this review, we focus on the HDAC inhibitors (HDACi) with the greatest antidepressant efficacy and their activity in the preclinical studies. Moreover, we discuss their potential therapeutic usefulness in depression and the main limitations.     

The drug treatment of depression in general practice: a comparison of nocte administration of trazodone with mianserin,dothiepin and amitriptyline

This 6-week, double-blind, randomised, multicentre study was performed to assess the efficacy and tolerability of evening administration of 150 mg trazodone as an initial and maintenance therapy and to compare this regimen with recommended dosages of mianserin, dothiepin and amitriptyline in the treatment of depressed, adult, general practice patients. A total of 227 eligible depressed patients were recruited into the study by a panel of general practitioners. One hundred and twelve patients were randomised to receive trazodone therapy, 36 received mianserin, 35 received dothiepin and 44 received amitriptyline. Trazodone was administered as a single daily dose of 150 mg. Mianserin was given at a dose of 30 mg for the first 7 days followed by 60 mg daily for the remaining 5 weeks. Dothiepin and amitriptyline were both given at a dosage of 75 mg daily for the 1st week; this was then increased to 150 mg and 100 mg, respectively, for the final 5 weeks of the study. Efficacy of the four treatments was assessed using the modified Hamilton depression rating scale scores and by the Investigator's judgment of both the global severity and improvement of the condition. No significant differences were shown, using any measure of efficacy, between trazodone and any of the three comparator drugs. All treatments resulted in significant improvement in both Ham-D scores and global measures over the period of the study. Using a total side-effect score to assess the incidence and severity of adverse events and adjusting for baseline differences, the four treatments were found to differ. Trazodone was associated with a lower incidence of dry mouth, visual disturbance and drowsiness than amitriptyline, and a lower incidence of dizziness/faintness than mianserin. All four treatments were associated with improvements in sleep quality and ease of getting to sleep. Trazodone and dothiepin were of greatest benefit and mianserin was of least benefit in this respect.     

Osteopontin as a therapeutic target for cancer

Introduction: Cancer is a complex pathological disorder, established as a result of accumulation of genetic and epigenetic changes, which lead to adverse alterations in the cellular phenotype. Tumor progression involves intricate signaling mediated through crosstalk between various growth factors, cytokines and chemokines. Osteopontin (OPN), a chemokine-like protein, is involved in promotion of neoplastic cancer into higher grade malignancies by regulating various facets of tumor progression such as cell proliferation, angiogenesis and metastasis.

Areas covered: Tumors as well as stroma-derived OPN play key roles in various signaling pathways involved in tumor growth, angiogenesis and metastasis. OPN derived from tumor-activated macrophages modulates the tumor microenvironment and thereby regulate melanoma growth and angiogenesis. OPN also regulates hypoxia-inducible factor-1α-dependent VEGF expression leading to breast tumor growth and angiogenesis in response to hypoxia. Thus, a clear understanding of the molecular mechanism underlying OPN-mediated regulation will shed light on exciting avenues for further investigation of targeted therapies. Silencing of OPN using RNAi technology, blocking OPN activity using specific antibodies and small-molecule inhibitors might provide novel strategies, which would aid in developing effective therapeutics for the treatment of various types of cancer.

Expert opinion: This review focuses on new possibilities to exploit OPN as a tumor and stroma-derived therapeutic target to combat cancer.