Current Pharmaceutical Design - Volume 11, Issue 8, 2005

Neuroinflammatory processes appear to play a fundamental role in the pathology associated with a number of neurodegenerative and psychiatric conditions. In this respect, the immunocompetent brain microglia and peripheral macrophages release a host of proinflammatory cytokines that not only modulate immunological processes but also influence neuronal functioning and even survival. For instance, alterations of the cytokines, tumor necrosis factor-α, as well as several of the interferons and interleukins have been associated with Parkinson;s disease (PD) and clinical depression. Importantly, anti-inflammatory treatments that block these cytokines may impart protection against behavioural pathology and neuronal damage in animal models of PD and depression involving exposure to environmental toxins and stressors, respectively. The present review highlights the involvement of inflammatory cells and cytokines in depression and PD and explores some of the potential cellular and molecular mechanisms through which the immunotransmitters affect neuronal functioning. Attention is also devoted to the possibility that cytokines may sensitize neuroinflammatory pathways that, in turn, favour long-term pathology.

Cytokines whose primary function is that of acting as signaling molecules of the immune system, have been implicated in the provocation or exacerbation of mood disorders such as depression. This position has been supported by several lines of evidence; (1) proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α) and bacterial endotoxins elicit sickness behaviors (e.g., fatigue, soporific effects) and symptoms of anxiety/depression that may be attenuated by chronic antidepressant treatment. Interleukin-2 (IL-2) induces less profound sickness, but elicits anhedonia, a key symptom of depression; (2) neuroendocrine and central neurotransmitter changes, reminiscent of those implicated in depression, may be elicited by some of these cytokines, and these effects are exacerbated by stressors; (3) severe depressive illness is accompanied by elevations of cytokine production or levels, although these effects are not necessarily attenuated with antidepressant medication; and (4) immunotherapy, using IL-2 or IFN-α, promote depressive symptoms that are attenuated by antidepressant treatment. It is proposed that chronic cytokine elevations engender neuroendocrine and brain neurotransmitter changes that are interpreted by the brain as being stressors, and contribute to the development of depression. Further, the effects of the cytokine treatments may act synergistically with stressors, and cytokines may provoke a sensitization effect so that the effects of later stressor experiences are exacerbated.

Cytokines circulating in the blood affect CNS function through a variety of pathways. One of these pathways is by being transported directly across the blood-brain barrier (BBB). Transport of blood-borne cytokines across the BBB is now known to be an operational pathway by which cytokines can directly affect CNS functions. Cytokine transport across the BBB, however, is a complex event. Not all cytokines are transported and, for those which are, transport rates differ among cytokines, among brain regions, with physiological circumstances, and with disease. Here we address some of the major principles and concepts relating to cytokine transport and BBB function which have emerged as important to neuroimmunology and neuropathology.

Since the first attempts to understand the mechanisms of learning, memory, development, and other instances of neuroplasticity, gene expression has been an attractive explanation for the persistence of such processes. It has been hypothesized that changes in the levels of expression of a gene, or a coordinated set of genes, would be necessary for dramatic structural changes like the growth of new neurites. And more subtle biochemical changes at existing synapses might also result from an alteration in the array of gene products being manufactured in the relevant cells. However, a great deal of what is classified as neuroplasticity is dependent on primary changes in electrophysiological activity or other conditions at synapses. Therefore, a seminal question to those interested in the molecular underpinnings of neuroplasticity is that of signal transduction: How do changes in synaptic activity get communicated to the nucleus? To many who learn about the regulation of the transcription factor NFκB with this question in mind, its utility seems clear. Furthermore, NFκB is an important signaling factor for cytokines that appear to participate in several pathological conditions (e.g., Parkinson;s disease, multiple sclerosis, and depression), so understanding its mechanisms of action and its relationship to other elements of cytokine signaling may be fundamental to determining the role of the inflammatory system in psychiatric and neurodegenerative conditions. For these reasons, NFκB has garnered considerable attention in various aspects of neuroplasticity, from long-term potentiation to the most dramatic forms of plasticity: cell birth and death. In a few cases, elegant experimental design has resulted in convincing evidence for the involvement of NFκB in specific phenomena. However, the complexity of this transcription factor-including confusion over what exactly is meant by “NFκB”-has led to some misleading conclusions, as well. This chapter highlights some of the potential red herrings to be encountered in the study of NFκB and will summarize the data and interpretations in which some degree of confidence can be placed. The final answers will depend on the application of models and tools only now in development.

Parkinson's disease (PD) is a movement disorder caused by degeneration of the nigrostriatal dopamine (DA) neurons in the substantia nigra pars compacta and the resultant deficiency in the neurotransmitter DA at the nerve terminals in the striatum. We and other investigators found increased levels of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6, and decreased levels of neurotrophins such as brain-derived neurotrophic factor (BDNF) in the nigrostriatal region of postmortem brains and/or in the ventricular or lumbar cerebrospinal fluid (CSF) from patients with sporadic PD, and in animal models, such as 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)- and 6-hydroxydopamine (6-OHDA)-induced PD. These changes in cytokine and neurotrophin levels may be initiated by activated microglia, which may then promote apoptotic cell death and subsequent phagocytosis of DA neurons. Cytokines as pleiotropic factors, promote signals that either lead to cell death or exert neuroprotective effects. The discovery of toxic changes in trophic microglia by M. Sawada and co-workers is important to this point. Ultimately, microglial cells may regulate cellular changes that cause either harm or benefit by producing cytokines or neurotrophins depending upon the primary cause and the circumstances during the inflammatory process of PD.

Naturally occurring sexual dimorphism has been implicated in the risk, progression and recovery from numerous neurological disorders. These include head injury, multiple sclerosis (MS), stroke, and neurodegenerative diseases (Parkinson's disease (PD), Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS). Accumulating evidence suggests that observed differences between men and women could result from estrogen's wide range of effects within the mammalian central nervous system (CNS), with it's neuroprotective effect being one of the most important. It seems possible that neuroprotective activity of estrogen could be partially a result of it's anti-inflammatory action. It has been well established that inflammation plays an important role in the etiopathogenesis and manifestation of brain pathological changes. In this regard, an important role has been suggested for pro-inflammatory cytokines produced by activated glial cells, neurons and immune cells that invade brain tissue. Within the CNS, cytokines stimulate inflammatory processes that may impair blood-brain barrier permeability as well as promote apoptosis of neurons, oligodendrocytes and induce myelin damage. Given that estrogen may modulate cytokine expression, coupled with the fact that gender differences of cytokine production are apparent in animal models of PD and MS, suggests an important connection between hormonal-cytokine link in neurodegeneration. Indeed, while MS patients and mice subjected to experimental autoimmune encephalomyelitis (EAE) display gender specific alterations of IFN-gamma and IL-12, variations of TNF and IL-6 were associated with PD. Also in case of more acute neurodegenerative conditions, such as stroke, the effect of IL-6 gene G-174C polymorphism was different in males and females. Given that our understanding of the role of estrogen on cytokine production and accompanying CNS pathological conditions is limited, the present reviews aims to present some of our recent findings in this area and further evaluate the evidence that may be relevant to the design of new hormonal anti-inflammatory treatment strategies for neurodegenerative diseases.

There has been a significant increase in the number of cytokines known to exist, over the past few years. This has led to a re-examination of the established roles of cytokines, as the functions of newly identified members are characterized. In this review, we describe how the recent discovery and characterization of interleukin (IL) -23 has led to a re-evaluation of the role of interferon (IFN) γ and IFNγ-inducing factors in experimental autoimmune encephalomyelitis (EAE). Recent studies suggest that IFNg-secreting T cells, considered the hallmark of EAE, may not be the major detrimental effector cell, and may even have a regulatory function. The impact of this on current understanding of cytokine networks underlying CNS inflammation in EAE is discussed.

Immune responses represent a source of sytemic stress which impacts the brain and modifies various neuroendocrine and behavioral functions. Therefore, the immune system has been conceived of as a potential contributor to stress-related behavioral abnormalities, such as depression. Much of this knowledge has been gained through research focused largely on the administration of cytokines and/or bacterial endotoxin (eg., LPS), which targets innate immune cells, such as macrophages. However, fewer studies have addressed the effects of T cell activation on central nervous sytem (CNS) function. The discovery and characterization of bacterial superantigens (SAgs) has introduced an important opportunity for studying how T cell activation influences CNS function. Superantigens target unique variable regions of the beta chain of the mouse and human T cell receptor. This is restricted by the class II molecule of the major histocompatibility complex (MHC), and results in the production of a cytokine cascade that includes interleukin-2 (IL-2), interferon-gamma (IFNγ), tumor necrosis factor (TNF) and many other cytokines, including IL-6. The best studied SAgs are the staphylococcal enterotoxins, of which staphylococcal enteroxins A and B (SEA and SEB), have been shown to produce significant changes in behavior and activation of the hypothalamic-pituitary-adrenal (HPA) axis. Importantly, a T cell requirement was necessary to produce these changes. Furthermore, the anorexic or hypophagic effects of SAg challenge in mice appears to be related to anxiety-like processes, since challenge with both SEA or SEB reduces consumption of mainly novel food or food presented in a novel context. In the present paper, these studies are reviewed and related to known alterations in both anxiogenic and anxiolytic neuropeptides. It is suggested that immunologicallyinduced changes in the brain activate both categories of neuropeptides, thereby sustaining an adaptive state of arousal that promotes appropriate behavioral adjustments during infectious illness.

Because intestinal microflora play a pivotal role in the development of inflammatory bowel disease (IBD), there is currently some interest in alternating the composition of the microflora toward a potentially more remedial community. This paper summarizes the clinical and experimental efficacy of the manipulation of microflora by the use of antibiotics, probiotics, and prebiotics in IBD. Germinated barley foodstuff (GBF) is a prebiotic whose unique characteristics make it highly suitable for applications in IBD. It also helps prolong remission in remissive ulcerative colitis (UC) patients and also attenuates clinical activity in non-remissive UC patients. GBF has shown to be converted into a preferential nutrient, butyrate, for colonocytes through the action of Eubacterium and Bifidobacterium, and this bacterial butyrate can provide anti-inflammatory effects. The probiotic approaches for IBD include VSL#3, Nissle1917, Clostridium butyricum, and Bifidobacterium-fermented milk. In this paper, we summarize the distinctive role of another probiotic, Eubacterium limosum (E. limosum), which is a commensal microorganism that is promoted by GBF administration. The metabolites of E. limosum included butyrate, which can accelerate intestinal epithelial growth and inhibit IL-6 production. This new probiotic approach may be useful as an adjunctive IBD treatment in the future. Although these strategies hold great promise and appear to be useful in some settings, more experimental and clinical studies are needed to firmly establish their relevance.

In vitro clonogenic assays have been developed and widely used since many years to investigate the proliferation and the differentiation both of pluripotent haemopoietic stem cells (PHSC) and of the different progenitors of blood cell lineages: megakaryocytes (Colony Forming Unit-Mk) granulocyte -macrophage (CFU-GM), erythrocytes (BFU-E/CFU-E). As these techniques have been introduced, they appeared to be very useful to investigate the pathogenic mechanisms of drug induced blood disorders and also for screening compound during preclinical safety study. Because the integrity of the hematopoiesis is also essential to guarantee the immunological function, the application to the toxicology of these clonogenic assays, provides an essential tool for better understanding the in vivo observation (experimental and clinical) by also helping in predicting the degree of a possible in vivo hematotoxic in drug treated patients. The review introduces to basic concepts on hematopoiesis and on classical evaluation of a drug hematotoxic phenomenon. It describes the application of each clonogenic test to assess the specific hematotoxicity action. Moreover it report the most recent studies on standardisation, prevalidation and validation of such assays and critically reviews a model for predicting myelotoxicity by discussing the main aspects referred to the evaluation of the in vivo acute neutropenia by using the in vitro CFU-GM assay.

The discovery of penicillin by Fleming in 1928 was an historical milestone in the fight against infectious disease. Over the following fifty years, pharmaceutical companies discovered and developed over 100 antibiotics effective against a wide range of human pathogens. More recently, the dramatic rise in antibiotic-resistant pathogens has stimulated renewed efforts to identify, develop or redesign antibiotics active against these multi-resistant bacteria. This review focuses on such efforts directed at one large and highly diverse family of toxins, the bacteriocins, which hold great promise as the next generation of antimicrobials. The majority of bacteriocins differ from traditional antibiotics in one critical way: they have a relatively narrow killing spectrum and are, therefore, toxic only to bacteria closely related to the producing strain. Accordingly, they can be considered drugs” that target specific bacterial pathogens. In this review we focus on recent attempts to generate custom designed bacteriocins using genetic engineering techniques. These efforts illustrate the potential of genetically-modified bacteriocins to solve some of the most challenging problems in disease control.