Current Signal Transduction Therapy - Volume 7, Issue 1, 2012

Current Signal Transduction Therapy will start its 7th year in 2012 and in the past years this journal has had a very important contribution to our understanding the molecular pathomechanisms of various signaling related diseases including cancer, CNS diseases, various inflammatory and circulatory disease. It is generally accepted now that most of the molecular pathomechanisms result from intra- or intercellular communication disorders, while a series of genomic and proteomic changes can be the causes and/or consequences of these communication disorders. The major challenge of signal transduction therapy is to identify the pathologically causative signaling disorders. In a disease state in a pathological cell, a great number of genes can be differently expressed compared to normal cells. On the other hand genomic information alone may be insufficient for identifying specific changes in the molecular pathways that are predictive of a favourable treatment outcome. Although the cause of a disease is frequently an aberration at the genomic level, the functional consequences are mediated via protein networks, with various components of the network undergoing different degrees of activation, usually as a consequence of specific post-translational modifications such as phosphorylation. In the future issues of CSTT, we will put major emphasis on identifying the rate limiting key signaling pathways in the background of various diseases and to investigate the possible interference points with special emphasis on personalized therapy. Current research in the field combines data about genes, proteins, and metabolites to generate a comprehensive picture of the connections between the different parts. In the context of drug discovery, these data can be used to identify the pathways involved in a particular disease -leading to new therapeutic targets - or to determine whether a drug is hitting the intended pathway. On the other hand recently the role of tissue environment in generating and maintaining pathological signaling in a target organ has become a very hot topic. So the 1st issue of the 7th Vol of CSTT in 2012 is dedicated to the role of Astrocytic Signal Transduction in CNS Disease and Therapy. Astrocites contributes significantly to a complex signaling network through intracellular second messengers, and gliotransmitter release that mediates glial-glial and glial-neuron interactions and have very important functions in the maintenance of the neural environment. Dr. Liang Peng Shenyang as the guest editor of this “hot topic” has done a great job in selecting very important and exciting papers on this subject and we trust this will be very well received by the scientific community.

I am deeply grateful to professors Axel Ullrich and Gyorgy Keri that they trusted me to produce this ‘hot topic’ special issue about ‘Astrocytic Signal Transduction in CNS Disease and Therapy’. I am equally grateful to the nine contributors, not only for their excellent papers, but also for their effort and ability to meet the strict deadline, so that the issue will be timely published, as promised by the Publisher. Finally, a big thank you to the reviewers (Dr. L. Hertz in Canada, Dr. J. De Keyser in Belgium, Dr. Y. Chen in Washington, DC, and my own coworker, Dr. T. Du) for their prompt and thorough reviews, and no less to Dr. B. Li, who has helped me through a myriad of practical problems. 2011 is the one hundred year anniversary of Ramon y Cajal's “Histologie du Systeme Nerveux de l'Homme et des Vertebres”, in which he wisely wrote that the roles of glial cells were unknown and would remain so for a long time, because we did not have the equipment to investigate them. This has changed over the last half century, beginning with the Swedish Holger Hyden's microdissection and protein microanalysis, leading him to realize that astrocytic changes precede neuronal changes in Parkinson's disease, and from there spreading first to other neurochemical investigations, later to a huge burst of activity in studies of glial physiology, and much more slowly to pharmacology. I believe this issue is a ‘first’ in concentrating on signaling pathways involved in neurological, neurosurgical or psychiatric diseases and/or activated by drugs having therapeutic effects under these conditions. Classically, molecular biology has been of greatest importance in cancer therapy, and I am happy to begin the issue with a thoughtful and comprehensive paper by Dr. E.M. Halatsch on problems when targeting the epidermal growth factor receptor in the treatment of glioblastoma and how it may be possible to enhance the effect of such treatment in the future. Astrocytes are also important in multiple sclerosis, and Dr. J. De Keyser has pursued the roles of the loss of specifically β2-adrenergic receptors in white matter astrocytes all the way to the present comprehensive concept, how this loss may account for astrocytic, oligodendrocytic and neuronal deficiencies in MS, and how it might be possible to substitute for the missing noradrenergic receptor by fluoxetine-mediated activation of serotonergic signaling. Immunological disturbances are important not only in MS, but also greatly contribute to Alzheimer's disease and HIV encephalopathy. Drs. Iram and Frenkel elegantly and convincingly describe the enormous influence of astrocytes on β-amyloid deposition and clearance, once again bringing this toxic compound to the forefront of Alzheimer research interest. The huge increase in knowledge about astrocytic signaling in HIV-1 associated encephalopathy during the last few years, including the fascinating, and catastrophic, additive damage by illicit drugs is authoritatively discussed by Dr. V. Buch and her colleagues. Dr. M.D. Norenberg, a pioneer in hepatic encephalopathy and ammonia research, concentrates in his review on the newly established importance of nuclear factor-kappa B (NF-κB) as a major signaling molecule in the pathways eventually leading to brain swelling. My own paper also discusses brain swelling, but in this case induced by elevated K+ concentrations, known to occur during brain trauma, as well as pharmacological means to reduce swelling and provide neuroprotection. Astrocytic signaling in persistent, pathological, as compared to acute, pain has attracted intense interest during the last several years, and this topic is comprehensively reviewed by Dr. F. Wei, including the important involvement of supraspinal brain regions. Based on experiments in cultured astrocytes and astrocytes from fluoxetine-treated anmals, showing delayed depression- and antidepressant-relevant changes in gene expression, editing and function after chronic fluoxetine treatment, Dr. L. Hertz and his co-authors challenge the conventional view that the antidepressant ‘serotonin-specific reuptake inhibitors’ (SSRIs) owe their effects solely to inhibition of the serotonin transporter. Finally, Dr. O. Gonzalez-Perez and his team discusses differences between fibroblast growth factor (FGF), especially FGF2, actions on its receptors in the two major ‘niches’ for adult neurogenesis and oligodendrogenesis, the subventricular zone in the cerebral hemispheres, and the subgranular zone in hippocampus, differences that may become of great practical importance with the impending development of stem cell therapy. Personally, I am stunned by the magnitude of this combined source of information, which exceeds my wildest expectations, when we started this project. I feel this is an indication of the importance of astrocytic signaling in brain diseases, which already has lead to therapeutic advances, and in the future may contribute essentially to the treatment of some of the most devastating brain diseases. I wish the issue will have a wide-spread readership and also believe that each of us can learn from chapters by other authors, especially considering the many similarities in signaling under the various conditions

Glioblastoma multiforme (GBM) is the most common primary tumour of the central nervous system. The outcome after standard therapy, consisting of resection, radiation and chemotherapy, is poor: median survival is 40 to 60 weeks, with the tumour often recurring only a few millimetres away from the original location after gross total resection. The epidermal growth factor receptor (EGFR) is amplified and overexpressed in 40% to 50% of GBM, almost half of which co-expresses the mutated, constitutively activated EGFR variant III (EGFRvIII). As EGFR activation leads to cell proliferation, angiogenesis and reduced apoptosis, its increased activity may contribute to the aggressiveness of GBM. Therefore, to control these carcinogenic functions through EGFR inhibition is a logical therapeutic approach. Various trials of EGFR antagonists are ongoing, investigating tyrosine kinase inhibitors (TKIs), monoclonal antibodies (MAbs), RNA-based agents and vaccination against EGFRvIII. While TKIs, e.g. erlotinib and gefitinib, are currently the most advanced in clinical development, numerous trials indicate that a multiple target approach might be necessary to achieve therapeutically relevant effects.

Multiple sclerosis (MS) is characterized by demyelinating lesions disseminated throughout the central nervous system, and a progressive axonal degeneration. In this review we propose that an impaired cAMP signaling in white mater astrocytes, caused by a deficiency of β2-adrenergic receptors, may play a role in the pathogenesis of the disease. Reduced astrocytic cAMP signaling may, in a proinflammatory environment, facilitate astrocytes to become facultative antigen presenting cells, stimulating the development of inflammatory demyelinating lesions. It may reduce astrocytic glycogenolysis, which supplies energy and N-acetylaspartate (NAA) to axons and oligodendrocytes, reduce trophic and neuroprotective support to oligodendrocytes and neurons, and enhance astrogliosis.

Astrocytes are the most abundant cells in the brain and play an important role in the homeostasis and maintenance of the brain. Furthermore, astrocytes play a key role in brain protection and in functional recovery from injuries. Impairment in astrocytes activity may promote neurodegeneration and, eventually, retraction of neuronal synapses, which leads to cognitive deficits found in neurodegenrative diseases, such as Alzheimer's disease. Alzheimer's disease (AD) is the most common type of dementia affecting more than 18 million people worldwide. The main cause of AD is generally attributed to the increased production and accumulation of amyloid-β (Aβ), in association with neurofibrillary tangle (NFT) formation. In AD patient's brain, reactive astrocytes are integral components of neuritic plaques. Astrocytic activation seems to be particularly prominent around Aβ deposits both in the brain parenchyma and in the cerebrovasculature. Furthermore, recent evidence from AD patients suggests that pathological changes in the morphology of astrocyte occur prior to the appearance of Aβ plaques. The focus of this review is on astrocytic cells and their role in the progression of AD.

Astrocytes, the most abundant cells of the CNS are believed to play vital roles in brain development and functioning, providing trophic support to neurons and eliciting CNS responses to pathogens/injury. During HIV infection of the CNS, glial activation and infection play major roles in generating the immune activation, a process which, in turn, leads to release of neurotoxic mediators (viral and cellular). Accompanying the activation and proliferation of astroglia is also recruitment of mononuclear phagocytes across the endothelium. Regulated signal transduction pathways finely control all these processes. While earlier believed to support only abortive HIV infection, astrocytes are now recognized to be active participants of productive viral replication. Following infection and/or exposure to viral proteins released from neighboring infected cells, astrocytes become activated and elicit release of inflammatory mediators, such as cytokines, chemokines and growth factors, that are toxic not only for neurons but also for neighboring cells around astrocytes within the CNS. This cascade of inflammation triggers the ensuing neuropathogenesis associated with HIV-1. The normally neuroprotective role of astrocytes thus transforms into a functionally deleterious function, with the ultimate result of disrupted CNS homeostasis. The current review is an attempt to summarize the cellular signal transduction pathways critical for astrocyte activation and inflammation involved in HIV-1 associated dementia

Hepatic encephalopathy (HE) is a common clinical complication in patients with severe liver disease. While the pathogenesis of HE is incompletely understood, ammonia has been strongly implicated as an important etiological factor, and astrocytes appear to be the primary target of its neurotoxicity. In addition to ammonia, infection and inflammation have increasingly been implicated in the pathogenesis of HE. Nuclear factor-kappa B (NF-κB), a major signaling molecule involved in inflammation and immune responses, is activated in cultured astrocytes treated with ammonia, as well as in brains of experimental animals with HE. Such activation may be a consequence of systemic inflammatory events, or as a result of hyperammonemia-induced central nervous system inflammation. Once activated, NF-κB stimulates the transcription of genes involved in immune responses and inflammation, that produce factors which may contribute to cellular dysfunction such as astrocyte swelling and glutamate transport impairment as occurs in HE. This review summarizes the evidence for NF-κB activation in HE, the signaling pathways involved in its activation, and consequences of such activation.

The Lund project (1992) recommended treatment with clonidine (α2-adrenergic agonist) and metoprolol (β1-adrenergic antagonist) to improve recovery after brain trauma, and discouraged use of the V1 agonist vasopressin (ADH). Brain effects of these drugs and the ability of a post-traumatic elevation of extracellular K+ concentrations ([K+]o) to activate mechanism(s) leading to secondary cytotoxic (cellular) edema were then virtually unknown. Now, it is established that interactions occur between effects on astrocytes by high [K+]o and vasopressin or α2- and β1-adrenergic agonists and antagonists, and that the effects modify edema and thus intracranial pressure. In mouse astrocytes in primary cultures, reliably expressing characteristics of their in vivo counterparts, high [K+]o and each of the transmitters agonists activate a signal mechanism, transactivation, in which Ca2+ entry through depolarization-mediated channel opening or stimulation of Gq- or Gi/o protein-coupled receptors via PKC-, Ca2+- and metalloproteinase-mediated signaling leads to release of an epidermal growth factor (EGF) receptor agonist. Minor, but important, differences exist between individual pathways. The agonist released by dexmedetomidine decreases neuronal vulnerability to oxidative damage by a paracrine effect, and in all cases the released EGF receptor agonist has autocrine effects. These include mitogen-activated protein (MAP) kinase-mediated phosphorylation of astrocytic extracellular-regulated kinase (ERK), and with high [K+]o also the cotransporter NKCC1, accumulating Na+ and K+ together with 2 Cl- and water, causing edema. This effect, exerted specifically on astrocytes, is enhanced by β1-adrenergic or vasopressinergic V1 signaling, explaining the beneficial effect of β1-adrenergic antagonists and why vasopressin should be omitted in edema treatment after brain trauma.

Functional sensitization and structural plasticity in the nociceptive pathways and modulatory networks in the peripheral and central nervous system develop following tissue and nerve injury and result in persistent or chronic pain, a major challenge to clinical management. Development of novel analgesic drugs requires a better understanding of the molecular and cellular mechanisms underlying persistent pain. Research during the last three decades has focused on the involvement of neuronal mechanisms in persistent pain. Recently accumulating evidence indicates that reactive glial cells play a critical role in peripheral and central sensitization during the development of persistent pain in variety of animal pain models. The purpose of this review is to highlight important recent advances in astrocytic mechanisms in experimentally persistent pain and the potential to use this information to develop new drugs targeting astrocytic signaling in the treatment of pathological pain.

When fluoxetine, the first of the presently used serotonin-specific reuptake inhibitors (SSRIs), was approved in 1987, two effects of the drug had been established: inhibition of serotonin reuptake by the serotonin transporter (SERT), and partial displacement of serotonin binding to cultured astrocytes, which have no SERT expression. At that time astrocytes were generally assumed to be unimportant for brain function. Accordingly, inhibition of SERT has since been regarded as the mechanism responsible for SSRIs effects in spite of several problems: the delay in therapeutic activity, although the inhibition of serotonin uptake is immediate; lack of quantitative correlation between potency of inhibition by different SSRIs and their therapeutic plasma levels (even considering protein binding); and 80% SERT occupancy at minimum-effective doses. Moreover, little information has been obtained about the molecular mechanisms alleviating major depression and obsessive-compulsive disorder (OCD). In 1987 the 5-HT2B receptor was unknown, but it is now established to have the highest affinity between 5-HT receptors for SSRIs, with especially high affinity during chronic treatment. Here we summarize data from cultured mouse astrocytes and astrocytes obtained from the brains of fluoxetinetreated mice, supporting the role of the astrocytic binding: only small differences in affinity for the 5-HT2B receptor between different SSRIs; a week-long-delayed upregulation of the phospholipase, cPLA2a, and the kainate receptor GluK2, with simultaneous increased editing of the latter, reducing its possible stimulation of neuronal glutamatergic signaling. These effects are genetically and functionally correlated with major depression and OCD, including the therapeutic potential of drugs inhibiting glutamatergic activity.

There are two well-defined neurogenic regions in the adult brain, the subventricular zone (SVZ) lining the lateral wall of the lateral ventricles and, the subgranular zone (SGZ) in the dentate gyrus at the hippocampus. Within these neurogenic regions, there are neural stem cells with astrocytic characteristics, which actively respond to the basic fibroblast growth factor (bFGF, FGF2 or FGF-β) by increasing their proliferation, survival and differentiation, both in vivo and in vitro. FGF2 binds to fibroblast growth factor receptors 1 to 4 (FGFR1, FGFR2, FGFR3, FGFR4). Interestingly, these receptors are differentially expressed in neurogenic progenitors. During development, FGFR-1 and FGFR-2 drive oligodendrocytes and motor neuron specification. In particular, FGFR-1 determines oligodendroglial and neuronal cell fate, whereas FGFR-2 is related to oligodendrocyte specification. In the adult SVZ, FGF-2 promotes oligodendro-gliogenesis and myelination. FGF-2 deficient mice show a reduction in the number of new neurons in the SGZ, which suggests that FGFR-1 is important for neuronal cell fate in the adult hippocampus. In human brain, FGF-2 appears to be an important component in the anti-depressive effect of drugs. In summary, FGF2 is an important modulator of the cell fate of neural precursor and, promotes oligodendrogenesis. In this review, we describe the expression pattern of FGFR2 and its role in neural precursors derived from the SVZ and the SGZ.