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OPEN ACCESS PLUS
Accepted articles are published online for free open access for all to view. Open access publishing provides the maximum dissemination of the article to the largest audience. Authors must pay for this service. All corresponding authors will be asked to indicate whether or not they wish to pay to have their paper made freely available on publication. If authors do not select the Open Access option, then their article will be published with standard subscription-based access at no charge.
Authors who opt for Open Access Plus may also self-archive publishers postprints. Bentham Science is compliant with the open access policy for the MRC, Cancer Research UK, NIH, and many other funders. For details, refer to http://www.benthamscience.com/permission.php or email to; openaccess@benthamscience.org.
Contents
Pp. 805 - 817
Jimmy Masjkur, Maria Adele Rueger, Stefan R. Bornstein, Ron McKay and Andreas Androutsellis-Theotokis
[Open Access Plus] |
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Stem cell – based therapies for central nervous system disorders are intensely pursued. Such approaches can be divided into two categories: Transplantation-based, and those that aim to pharmacologically target the endogenous stem cell population in the tissue. Endogenous stem cell – based strategies avoid the problem of immune incompatibility between the host and the grafted cells. They also avoid the placement of a large amount of cells in confined areas, a manipulation which alters the characteristics of the neurovascular microenvironment. We show here that massive pharmacological activation (increase in cell numbers) of the endogenous neural stem cell population in the adult rodent brain maintains the cytoarchitecture of the neurovascular niche. Distances between adjacent stem cells (identified by expression of Hes3) are maintained above a minimum. Hes3+ cells maintain their physical association with blood vessels. These results also suggest a mechanism by which the activation signal from the lateral ventricle can be propagated to areas a long distance away from the lateral ventricles, through autocrine/paracrine actions between adjacent Hes3+ cells, along blood vessels. Finally, powerful effects of angiopoietin 2 on Hes3+ cells help explain the prevalence of proliferating endogenous neural stem cells close to the subventricular zone (an area of high angiopoietin 2 concentration) and the quiescent state of stem cells away from the ventricles and their tight physical association with blood vessels (which express high levels of angiopoietin 1, a cytokine that opposes angiopoietin 2 functions).
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Pp. 670 - 684
M. A. Cenci, K. E. Ohlin and P. Odin
[Open Access Plus] |
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Dyskinesia and motor fluctuations affect up to 90% of patients with Parkinson's disease (PD) within ten years of L-DOPA pharmacotherapy, and represent a major challenge to a successful clinical management of this disorder. There are currently two main treatment options for these complications, namely, deep brain electrical stimulation or continuous infusion of dopaminergic agents. The latter is achieved using either subcutaneous apomorphine infusion or enteric L-DOPA delivery. Some patients also benefit from the antidyskinetic effect of amantadine as an adjunct to L-DOPA treatment. Ongoing research in animal models of PD aims at discovering additional, novel treatment options that can either prevent or reverse dyskinesia and motor fluctuations. Alternative methods of continuous L-DOPA delivery (including gene therapy), and pharmacological agents that target nondopaminergic receptor systems are currently under intense experimental scrutiny. Because clinical response profiles show large individual variation in PD, an increased number of treatment options for dyskinesia and motor fluctuations will eventually allow for antiparkinsonian and antidyskinetic therapies to be tailor-made to the needs of different patients and/or PD subtypes.
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Pp. 333 - 339
Adrian J. Harwood
[Open Access Plus] |
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Inhibition of prolyl oligopeptidase (PO) elevates inositol phosphate (IP) signalling and reduces cell sensitivity to lithium (Li+). This review discusses recent evidence that shows PO acts via the multiple inositol polyphosphate phosphatase (MIPP) to regulate gene expression. As a consequence, PO inhibition causes both a transient, rapid increase in I(1,4,5)P3 and a long-term elevation of IP signalling. This pathway is evolutionary conserved, being present in both the social amoeba Dictyostelium and human cell systems, and has potential implications for mental health.
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Pp. 693 - 700
R. M. Pruss
[Open Access Plus] |
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Target-directed drug design, although a conceptually rational approach, is only one strategy for drug discovery. In the case of neurodegenerative diseases where molecular targets and disease mechanisms are unknown, even when specific genes are known to trigger the disease, phenotypic screening offers another approach. This review describes the establishment of phenotypic screening assays using primary neurons subjected to a disease-relevant pathophysiological stress and measuring the most important functional outcome, survival. Although a challenge both to screening teams to reproducibly produce the cells and chemists to interpret structure-activity relationships, such systems have historically identified or produced effective drugs. The primary screening assay is only the start; once hits are validated, they must be characterized using traditional target-directed or mechanism-based secondary assays to establish their selectivity, lack of side-effect liability, and eventually be shown to produce the desired effects in a preclinical animal model of the disease. These compounds then provide valuable pharmacological tools to identify neurodegenerative disease targets and mechanisms, whether or not they have all the properties required of a drug candidate.
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Pp. 504 - 523
Frank Hirth
[Open Access Plus] |
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Human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people. The majority of the diseases are associated with pathogenic oligomers from misfolded proteins, eventually causing the formation of aggregates and the progressive loss of neurons in the brain and nervous system. Several of these proteinopathies are sporadic and the cause of pathogenesis remains elusive. Heritable forms are associated with genetic defects, suggesting that the affected protein is causally related to disease formation and/or progression. The limitations of human genetics, however, make it necessary to use model systems to analyse affected genes and pathways in more detail. During the last two decades, research using the genetically amenable fruitfly has established Drosophila melanogaster as a valuable model system in the study of human neurodegeneration. These studies offer reliable models for Alzheimers, Parkinsons, and motor neuron diseases, as well as models for trinucleotide repeat expansion diseases, including ataxias and Huntingtons disease. As a result of these studies, several signalling pathways including phosphatidylinositol 3-kinase (PI3K)/Akt and target of rapamycin (TOR), c-Jun N-terminal kinase (JNK) and bone morphogenetic protein (BMP) signalling, have been shown to be deregulated in models of proteinopathies, suggesting that two or more initiating events may trigger disease formation in an age-related manner. Moreover, these studies also demonstrate that the fruitfly can be used to screen chemical compounds for their potential to prevent or ameliorate the disease, which in turn can directly guide clinical research and the development of novel therapeutic strategies for the treatment of human neurodegenerative diseases.
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Pp. 536 - 557
J. Yan and J. M. Greer
[Open Access Plus] |
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Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) that afflicts over 2 million people worldwide. On the basis of the temporal course of disease, MS can be subdivided into three clinical groups: relapsing remitting MS (RR-MS), secondary progressive MS and primary progressive MS. There is a high degree of clinical diversity within these subgroups. The pathogenesis of MS in most patients is likely to result from autoreactive, activated CD4+ T cells moving from the periphery across the blood brain barrier into the CNS. Most therapeutic agents used in MS (e.g. immunosuppressive and immunomodulatory drugs and cell cycle interruption drugs) are only used for RR-MS. These treatments show some efficiency in lessening the relapse rate in RR-MS and time to progression, but cannot cure MS. Thus, there is a need for new efficient treatments for all types of MS. An increasing number of studies indicate that nuclear factor-κB plays an important role in controlling expression of genes relevant to the pathogenesis of autoimmunity. Genetic factors related to NF-κB may also be determinants of MS susceptibility, as polymorphisms in the molecules involved in regulation of the NF-κB signal transduction pathway differ between RRMS and progressive MS. Herein, the role of NF-κB in MS will be reviewed and its potential as a new therapeutic target in MS will be considered and compared with existing treatments.
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Pp. 211 - 224
Oliver Henschel, Keith E. Gipson and Angelique Bordey
[Open Access Plus] |
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GABA, acting via GABAA receptors, is well-accepted as the main inhibitory neurotransmitter of the mature brain, where it dampens neuronal excitability. The receptors properties have been studied extensively, yielding important information about its structure, pharmacology, and regulation that are summarized in this review. Several GABAergic drugs have been commonly used as anesthetics, sedatives, and anticonvulsants for decades. However, findings that GABA has critical functions in brain development, in particular during the late embryonic and neonatal period, raise worthwhile questions regarding the side effects of GABAergic drugs that may lead to long-term cognitive deficits. Here, we will review some of these drugs in parallel with the control of CNS development that GABA exerts via activation of GABAA receptors. This review aims to provide a basic science and clinical perspective on the function of GABA and related pharmaceuticals acting at GABAA receptors.
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