1,721,237 research outputs found
Pharmacological and biotechnological in vitro approaches unveil the role of GPR17 signaling in regulating the timing of oligodendroglial differentiation
No full textBackground and Purpose - In the adult central nervous system there are many oligodendrocyte precursor cells (OPCs) that serve as the primary source of remyelinating cells in demyelinated lesions. Knowledge of the mechanisms regulating OPC maturation is needed to unveil novel pharmacological targets in demyelinating diseases. The G-protein-coupled membrane receptor GPR17, activated by both uracil nucleotides and cysteinyl-leucotrienes [1], has recently emerged as an important player in oligodendrogliogenesis [2,3]. It has been previously reported that GPR17 presence is restricted to NG2+-OPCs at early differentiation stages and is completely segregated from that of myelin proteins [4]. Here, we used purified primary OPCs from rat cortical parenchyma to assess the functional consequences of GPR17 modulation by either pharmacological or biotechnological approaches on the differentiation program of these cells.
Methods and Results - OPCs were exposed to the GPR17 agonists UDP-glucose, UDP and LTE4 for 48 hours. The degree of OPC differentiation was assessed on fixed cultures by immunostaining with an antibody against Myelin basic protein (MBP), a marker of mature oligodendrocytes. Data show that all these agonists increase the proportion of MBP+ cells compared to controls, suggesting acceleration of cell maturation by promoting receptor activation. Secondly, transfection experiments with fluorescent plasmids, enabling either silencing or over-expression of GPR17 were performed to univocally correlate the expression of this receptor with cell shape changes and phenotype acquisition during oligodendroglial maturation. Preliminary results show that suppression of GPR17 expression at early differentiation stages reduces the number of MBP+cells in culture, indicating that its silencing impairs the normal program of OPC differentiation.
Conclusions - Globally, these data point at GPR17 as a key regulator of oligodendrogliogenesis and at GPR17 ligands as extrinsic local regulators of OPCs under physiological conditions and during myelin repair.
References
[1] P. Ciana, M. Fumagalli, M.L. Trincavelli, C. Verderio, P. Rosa, D. Lecca, S. Ferrario, C. Parravicini, V. Capra, P. Gelosa, U. Guerrini, S. Belcredito, M. Cimino, L. Sironi, E. Tremoli, G.E. Rovati, C. Martini, M.P. Abbracchio, The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinil-leukotrienes receptor. EMBO J, 19, 4615-2627, 2006.
[2] D. Lecca, M.L. Trincavelli, P. Gelosa, L. Sironi, P. Ciana, M. Fumagalli, G. Villa, C. Verderio, C. Grumelli, U. Guerrini, E. Tremoli, P. Rosa, S. Cuboni, C. Martini, A. Buffo, M Cimino, M.P. Abbracchio, The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair. PloS One, 10, e3579, 2008.
[3] Y. Chen, H. Wu, S. Wang, H. Koito, J. Li, F. Ye, J. Hoang, S.S. Escobar, A. Gow, H.A. Arnett, B.D. Trapp, N.J. Karandikar, J. Hsieh, Q.R. Lu, The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination. Nature Neuroscience, 12, 1398-1406.
[4] M. Fumagalli, S. Daniele, D. Lecca, P.R. Lee, C. Parravicini, R.D. Fields,P. Rosa, F. Antonucci, C. Verderio, M.L Trincavelli, P. Bramanti, C. Martini, M.P. Abbracchio, Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation. The Journal of biology chemistry,12, 10593-10604
New regenerative medicine via P2Y and P2Y-like receptors : the case of GPR17, a new target for remyelination
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BEHAVIORAL TERATOLOGY - AN INAPPROPRIATE TERM FOR SOME UNINTERPRETABLE EFFECTS
No full textSince the thalidomide tragedy, the testing of new drugs on pregnant experimental animals has become a requirement in all countries. Many countries have recently introduced tests for subtle behavioral changes (in the absence of morphological damage). However Flaminio Cattabeni and Maria Pia Abbracchio argue that we do not yet know enough about the significance of these changes to make valid interpretations, or to extrapolate from animals to humans. They also propose that the term 'behavioral teratology' with its negative implications should be replaced by the more appropriate term 'chemical imprinting' to account also for chemicals inducing behavioral effects in animals which do not necessarily cause true neurological damage
Deorphanisation of G protein-coupled receptors : a tool to provide new insights in nervous system pathophysiology and new targets for psycho-active drugs
No full textG protein-coupled receptors represent the largest family of membrane receptors translating extracellular into intracellular signals. Endogenous ligands for these receptors range from physical stimuli (e.g., light and odorants) to ions and chemical transmitters, such as "classical" biogenic amines, nucleotides and peptides. Some of these receptors are pathologically altered in neurodegenerative and psychiatric diseases and indeed represent the target for a variety of already marketed psycho-active drugs. With the publication of the human genome, it has become evident that there still are many "orphan" G protein-coupled receptors, i.e., receptors responding to yet-unidentified endogenous ligands. A large amount of these receptors are expressed in nervous tissues, but, apart from their molecular structure, we have no information concerning their physiological roles and alterations in disease states. In this review, we summarise the advancements and pitfalls of the strategies that have been exploited in recent years to "deorphanise" some of these receptors. We also show how, in some cases, this deorphanisation process has resulted in the identification of new potential targets for drug development as well as in the discovery of previously unknown neurotransmitters, including bioactive peptides and substances that had been merely known as metabolic intermediates. We envisage that the deorphanisation of the remaining orphan G protein-coupled receptors will further advance our knowledge of nervous system pathophysiology and unveil additional targets for new therapeutic approaches to human diseases, including psychosis, depression, anxiety, pain and aging-associated neurodegenerative disorders
To be or not to be (inflamed) - is that the question in anti-inflammatory drug therapy of neurodegenerative disorders?
No full textA sustained inflammatory reaction is present in acute (e.g. stroke) and chronic (e.g. Alzheimer's disease, Parkinson's disease and multiple sclerosis) neurodegenerative disorders. Inflammation, which is fostered by both residential glial cells and blood-circulating cells that infiltrate the diseased brain, probably starts as a time- and site-specific defense mechanism that could later evolve into a destructive and uncontrolled reaction. In this article, we review the crucial dichotomy of brain inflammation, where failure to resolve an acute beneficial response could lead to a vicious and anarchic state of chronic activation. The possible use of non-steroidal anti-inflammatory drugs for the management of neurodegenerative diseases is discussed in light of recent data demonstrating a neuroprotective role of local innate and adaptive immune responses. Novel therapeutic approaches must rely on potentiation of endogenous anti-inflammatory pathways, identification of early markers of neuronal deterioration and a combination treatment involving immune modulation and antiinflammatory therapies
European Stroke Prevention Study-2 results: serendipitous demonstration of neuroprotection induced by endogenous adenosine accumulation?
No full textIn patients with prior stroke or transient ischaemic attack, anti- platelet treatment with dipyridamole substantially reduced stroke recurrence, with a beneficial effect comparable to and additive with that induced by aspirin (the European Stroke Prevention Study-2). Eugenio Picano and Maria Abbracchio present here a platelet-independent hypothesis, according to which cardiovascular and neuroprotective actions achieved by dipyridamole through chronic elevation of endogenous adenosine levels may have contributed to the therapeutic success of this study
SELECTIVE ACTIVITY OF BAMIFYLLINE ON ADENOSINE-A1-RECEPTORS IN RAT-BRAIN
No full textThe activity of the xanthine derivative bamifylline on central adenosine A1 and A2 receptors has been evaluated with radio-receptor binding in rat brain in comparison with other structure-related compounds. Bamifylline displaced3H-Cyclo-hexyl-adenosine and3H-Diethyl-8-phenyl-xanthine with a potency similar to that of 8-phenyl-theophylline, suggesting a high activity on A1-receptor subtype. In contrast, when3H-N-Ethyl-car{ballot box}amido adenosine was used to label A2 adenosine receptors in rat striatum, bamifylline displayed a lower activity comparable to that of enprofylline, an alkylxanthine considered a very weak antagonist of adenosine receptors. By calculating for each xanthine derivative its relative potency at A1 and A2 receptors (A2/A1 ratio), bamifylline turned out being the most selective A1 adenosine receptor antagonist so far tested
Adenosine signaling in glioma cells
No full textPurines and pyrimidines are fundamental signaling molecules in controlling the survival and proliferation of astrocytes, as well as in mediating cell-to-cell communication between glial cells and neurons in the healthy brain. The malignant transformation of astrocytes towards progressively more aggressive brain tumors (from astrocytoma to anaplastic glioblastoma) leads to modifications in both the survival and cell death pathways which overall confer a growth advantage to malignant cells and resistance to many cytotoxic stimuli. It has been demonstrated, however, that, in astrocytomas, several purinergic (in particular adenosinergic) pathways controlling cell survival and death are still effective and, in some cases, even enhanced, providing invaluable targets for purine-based chemotherapy, that still represents an appropriate pharmacological approach to brain tumors. In this chapter, the current knowledge on both receptor-mediated and receptor-independent adenosine pathways in astrocytomas will be reviewed, with a particular emphasis on the most promising targets which could be translated from in vitro studies to in vivo pharmacology
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