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  • 1
    Online Resource
    Online Resource
    Effects of Rho Kinase Inhibitors on Grafts of Dopaminergic Cell Precursors in a Rat Model of Parkinson's Disease
    Oxford University Press (OUP) ; 2016
    In:  Stem Cells Translational Medicine Vol. 5, No. 6 ( 2016-06-01), p. 804-815
    Details
    In: Stem Cells Translational Medicine, Oxford University Press (OUP), Vol. 5, No. 6 ( 2016-06-01), p. 804-815
    Abstract: In models of Parkinson's disease (PD), Rho kinase (ROCK) inhibitors have antiapoptotic and axon-stabilizing effects on damaged neurons, decrease the neuroinflammatory response, and protect against dopaminergic neuron death and axonal retraction. ROCK inhibitors have also shown protective effects against apoptosis induced by handling and dissociation of several types of stem cells. However, the effect of ROCK inhibitors on dopaminergic cell grafts has not been investigated. In the present study, treatment of dopaminergic cell suspension with ROCK inhibitors yielded significant decreases in the number of surviving dopaminergic neurons, in the density of graft-derived dopaminergic fibers, and in graft vascularization. Dopaminergic neuron death also markedly increased in primary mesencephalic cultures when the cell suspension was treated with ROCK inhibitors before plating, which suggests that decreased angiogenesis is not the only factor leading to cell death in grafts. Interestingly, treatment of the host 6-hydroxydopamine-lesioned rats with ROCK inhibitors induced a slight, nonsignificant increase in the number of surviving neurons, as well as marked increases in the density of graft-derived dopaminergic fibers and the size of the striatal reinnervated area. The study findings discourage treatment of cell suspensions before grafting. However, treatment of the host induces a marked increase in graft-derived striatal reinnervation. Because ROCK inhibitors have also exerted neuroprotective effects in several models of PD, treatment of the host with ROCK inhibitors, currently used against vascular diseases in clinical practice, before and after grafting may be a useful adjuvant to cell therapy in PD. Significance Cell-replacement therapy is one promising therapy for Parkinson's disease (PD). However, many questions must be addressed before widespread application. Rho kinase (ROCK) inhibitors have been used in a variety of applications associated with stem cell research and may be an excellent strategy for improving survival of grafted neurons and graft-derived dopaminergic innervation. The present results discourage the treatment of suspensions of dopaminergic precursors with ROCK inhibitors in the pregrafting period. However, treatment of the host (patients with PD) with ROCK inhibitors, currently used against vascular diseases, may be a useful adjuvant to cell therapy in PD.
    Type of Medium: Online Resource
    ISSN: 2157-6564 , 2157-6580
    URL: Article
    DOI: 10.5966/sctm.2015-0182
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2016
    detail.hit.zdb_id: 2642270-0
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  • 2
    Online Resource
    Online Resource
    A single zinc finger motif in the silencing factor REST represses the neural-specific type II sodium channel promoter
    Proceedings of the National Academy of Sciences ; 1997
    In:  Proceedings of the National Academy of Sciences Vol. 94, No. 4 ( 1997-02-18), p. 1177-1182
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 94, No. 4 ( 1997-02-18), p. 1177-1182
    Abstract: The type II voltage-dependent sodium channel is present in neuronal cells, where it mediates the propagation of nerve impulses. Restricted expression of the type II sodium channel gene to neurons is due, at least in part, to binding of the repressor protein REST (also termed NRSF or XBR) to the RE1 (also called NRSE) sequence in the type II sodium channel gene. Previous studies have shown that a domain in REST containing eight GL1-Krüppel zinc finger motifs mediates DNA binding. Deletional and GAL4-fusion gene analyses now reveal repressor domains that lie outside of the DNA-binding domain in both the amino and carboxyl termini of REST. Mutational analysis further identifies a single zinc finger motif in the carboxyl-terminal domain as being essential for repressing type II sodium channel reporter genes. These studies reveal two domains in REST that may mediate interactions with other proteins involved in restricting expression of a large set of genes to the vertebrate nervous system.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.94.4.1177
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1997
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons
    Proceedings of the National Academy of Sciences ; 1997
    In:  Proceedings of the National Academy of Sciences Vol. 94, No. 4 ( 1997-02-18), p. 1527-1532
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 94, No. 4 ( 1997-02-18), p. 1527-1532
    Abstract: Membrane excitability in different tissues is due, in large part, to the selective expression of distinct genes encoding the voltage-dependent sodium channel. Although the predominant sodium channels in brain, skeletal muscle, and cardiac muscle have been identified, the major sodium channel types responsible for excitability within the peripheral nervous system have remained elusive. We now describe the deduced primary structure of a sodium channel, peripheral nerve type 1 (PN1), which is expressed at high levels throughout the peripheral nervous system and is targeted to nerve terminals of cultured dorsal root ganglion neurons. Studies using cultured PC12 cells indicate that both expression and targeting of PN1 is induced by treatment of the cells with nerve growth factor. The preferential localization suggests that the PN1 sodium channel plays a specific role in nerve excitability.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.94.4.1527
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1997
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 4
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    Chaperoned amyloid proteins for immune manipulation: α‐Synuclein/Hsp70 shifts immunity toward a modulatory phenotype
    Wiley ; 2014
    In:  Immunity, Inflammation and Disease Vol. 2, No. 4 ( 2014-12), p. 226-238
    Details
    In: Immunity, Inflammation and Disease, Wiley, Vol. 2, No. 4 ( 2014-12), p. 226-238
    Abstract: α‐Synuclein (αSyn) is a 140‐residue amyloid‐forming protein whose aggregation is linked to Parkinson's disease (PD). It has also been found to play a critical role in the immune imbalance that accompanies disease progression, a characteristic that has prompted the search for an effective αSyn‐based immunotherapy. In this study, we have simultaneously exploited two important features of certain heat‐shock proteins (HSPs): their classical “chaperone” activities and their recently discovered and diverse “immunoactive” properties. In particular, we have explored the immune response elicited by immunization of C57BL/6 mice with an αSyn/Hsp70 protein combination in the absence of added adjuvant. Our results show differential effects for mice immunized with the αSyn/Hsp70 complex, including a restrained αSyn‐specific (IgM and IgG) humoral response as well as minimized alterations in the Treg (CD4 + CD25 + Foxp3 + ) and Teff (CD4 + Foxp3 − ) cell populations, as opposed to significant changes in mice immunized with αSyn and Hsp70 alone. Furthermore, in vitro‐stimulated splenocytes from immunized mice showed the lowest relative response against αSyn challenge for the “αSyn/Hsp70” experimental group as measured by IFN‐γ and IL‐17 secretion, and higher IL‐10 levels when stimulated with LPS. Finally, serum levels of Th1‐cytokine IFN‐γ and immunomodulatory IL‐10 indicated a unique shift toward an immunomodulatory/immunoprotective phenotype in mice immunized with the αSyn/Hsp70 complex. Overall, we propose the use of functional “HSP‐chaperoned amyloid/aggregating proteins” generated with appropriate HSP‐substrate protein combinations, such as the αSyn/Hsp70 complex, as a novel strategy for immune‐based intervention against synucleinopathies and other amyloid or “misfolding” neurodegenerative disorders.
    Type of Medium: Online Resource
    ISSN: 2050-4527 , 2050-4527
    URL: Issue
    URL: Article
    DOI: 10.1002/iid3.2014.2.issue-4
    DOI: 10.1002/iid3.39
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 2740382-8
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  • 5
    Online Resource
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    Chaperome screening leads to identification of Grp94/Gp96 and FKBP4/52 as modulators of the α‐synuclein‐elicited immune response
    Wiley ; 2016
    In:  The FASEB Journal Vol. 30, No. 2 ( 2016-02), p. 564-577
    Details
    In: The FASEB Journal, Wiley, Vol. 30, No. 2 ( 2016-02), p. 564-577
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v30.2
    DOI: 10.1096/fj.15-275131
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 1468876-1
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  • 6
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    Immunization with α‐synuclein/Grp94 reshapes peripheral immunity and suppresses microgliosis in a chronic Parkinsonism model
    Wiley ; 2018
    In:  Glia Vol. 66, No. 1 ( 2018-01), p. 191-205
    Details
    In: Glia, Wiley, Vol. 66, No. 1 ( 2018-01), p. 191-205
    Abstract: Neuroinflammation mediated by chronically activated microglia, largely caused by abnormal accumulation of misfolded α‐synuclein (αSyn) protein, is known to contribute to the pathophysiology of Parkinson's disease (PD). In this work, based on the immunomodulatory activities displayed by particular heat‐shock proteins (HSPs), we tested a novel vaccination strategy that used a combination of αSyn and Grp94 (HSPC4 or Gp96) chaperone and a murine PD model. We used two different procedures, first, the adoptive transfer of splenocytes from αSyn/Grp94‐immunized mice to recipient animals, and second, direct immunization with αSyn/Grp94, to study the effects in a chronic mouse MPTP‐model of parkinsonism. We found that both approaches promoted a distinct profile in the peripheral system—supported by humoral and cellular immunity—consisting of a Th1‐shifted αSyn‐specific response accompanied by an immune‐regulatory/Th2‐skewed general phenotype. Remarkably, this mixed profile sustained by αSyn/Grp94 immunization led to strong suppression of microglial activation in the substantia nigra and striatum , pointing to a newly described positive effect of anti‐αSyn Th1‐responses in the context of PD. This strategy is the first to target αSyn and report the suppression of PD‐associated microgliosis. Overall, we show that the αSyn/Grp94 combination supports a distinct and long‐lasting immune profile in the peripheral system, which has an impact at the CNS level by suppressing chronic microglial activation in an MPTP model of PD. Furthermore, our study demonstrates that reshaping peripheral immunity by vaccination with appropriate misfolding protein/HSP combinations could be highly beneficial as a treatment for neurodegenerative misfolding diseases.
    Type of Medium: Online Resource
    ISSN: 0894-1491 , 1098-1136
    URL: Issue
    URL: Article
    DOI: 10.1002/glia.v66.1
    DOI: 10.1002/glia.23237
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1474828-9
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  • 7
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    Neuroprotection by Transgenic Expression of Glucose-6-Phosphate Dehydrogenase in Dopaminergic Nigrostriatal Neurons of Mice
    Society for Neuroscience ; 2006
    In:  The Journal of Neuroscience Vol. 26, No. 17 ( 2006-04-26), p. 4500-4508
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 26, No. 17 ( 2006-04-26), p. 4500-4508
    Abstract: Oxidative damage to dopaminergic nigrostriatal (DNS) neurons plays a central role in the pathogenesis of Parkinson's disease (PD). Glucose-6-phosphate dehydrogenase (G6PD) is a key cytoprotective enzyme that provides NADPH, the major source of the reducing equivalents of a cell. Mutations of this enzyme are the most common enzymopathies worldwide. We have studied in vivo the role of G6PD overexpressed specifically in the DNS pathway and show that the increase of G6PD activity in the soma and axon terminals of DNS neurons, separately from other neurons or glial cells, protects them from parkinsonism. Analysis of DNS neurons by histological, neurochemical, and functional methods showed that even a moderate increase of G6PD activity rendered transgenic mice more resistant than control littermates to the toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The neuroprotective action of G6PD was also observed in aged animals despite that they had a greater susceptibility to MPTP. Therefore, overexpression of G6PD in dopaminergic neurons or pharmacological activation of the native enzyme should be considered as potential therapeutic strategies to PD.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0122-06.2006
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2006
    detail.hit.zdb_id: 1475274-8
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  • 8
    Online Resource
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    Chronic and progressive Parkinson's disease MPTP model in adult and aged mice
    Wiley ; 2016
    In:  Journal of Neurochemistry Vol. 136, No. 2 ( 2016-01), p. 373-387
    Details
    In: Journal of Neurochemistry, Wiley, Vol. 136, No. 2 ( 2016-01), p. 373-387
    Abstract: Despite the different animal models of Parkinson's disease developed during the last years, they still present limitations modelling the slow and progressive process of neurodegeneration. Here, we undertook a histological, neurochemical and behavioural analysis of a new chronic parkinsonian mouse model generated by the subcutaneous administration of low doses of MPTP (20 mg/kg, 3 times per week) for 3 months, using both young adult and aged mice. The MPTP ‐induced nigrostriatal neurodegeneration was progressive and was accompanied by a decrease in striatal dopamine levels and motor impairment. We also demonstrated the characteristic neuroinflammatory changes (microglial activation and astrogliosis) associated with the neurodegenerative process. Aged animals showed both a faster time course of neurodegeneration and an altered neuroinflammatory response. The long‐term systemic application of low MPTP doses did not induce any increase in mortality in either young adult or aged mice and better resembles the slow evolution of the neurodegenerative process. This treatment could be useful to model different stages of Parkinson's disease, providing a better understanding of the pathophysiology of the disease and facilitating the testing of both protective and restorative treatments. image Here, we show a new chronic and progressive parkinsonian mouse model, in young and aged mice. This model produces a stable degeneration of the dopaminergic nigrostriatal pathway, continuous neuroinflammatory reaction and motor deficits. Aged animals showed a faster neurodegeneration and an altered neuroinflammatory response. This treatment could be useful to model different stages of PD and to test both protective and restorative therapeutic approaches.
    Type of Medium: Online Resource
    ISSN: 0022-3042 , 1471-4159
    URL: Issue
    URL: Article
    DOI: 10.1111/jnc.2016.136.issue-2
    DOI: 10.1111/jnc.13409
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2020528-4
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  • 9
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    Rat Adrenal Chromaffin Cells Are Neonatal CO 2 Sensors
    Society for Neuroscience ; 2005
    In:  The Journal of Neuroscience Vol. 25, No. 28 ( 2005-07-13), p. 6631-6640
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 25, No. 28 ( 2005-07-13), p. 6631-6640
    Abstract: We studied the participation of adrenal medulla (AM) chromaffin cells in hypercapnic chemotransduction. Using amperometric recordings, we measured catecholamine (CAT) secretion from cells in AM slices of neonatal and adult rats perfused with solutions bubbled with different concentrations of CO 2 . The secretory activity augmented from 1.74 ± 0.19 pC/min at 5% CO 2 to 6.36 ± 0.77 pC/min at 10% CO 2 . This response to CO 2 was dose dependent and appeared without changes in extracellular pH, although it was paralleled by a drop in intracellular pH. Responsiveness to hypercapnia was higher in neonatal than in adult slices. The secretory response to hypercapnia required extracellular Ca 2+ influx. Both the CO 2 -induced internal pH drop and increase in CAT secretion were markedly diminished by methazolamide (2 μ m ), a membrane-permeant carbonic anhydrase (CA) inhibitor. We detected the presence of two CA isoforms (CAI and CAII) in neonatal AM slices by in situ hybridization and real-time PCR. The expression of these enzymes decreased in adult AM together with the disappearance of responsiveness to CO 2 . In patch-clamped chromaffin cells, hypercapnia elicited a depolarizing receptor potential, which led to action potential firing, extracellular Ca 2+ influx, and CAT secretion. This receptor potential (inhibited by methazolamide) was primarily attributable to activation of a resting cationic conductance. In addition, voltage-gated K + current amplitude was also decreased by high CO 2 . The CO 2 -sensing properties of chromaffin cells may be of physiologic relevance, particularly for the adaptation of neonates to extrauterine life, before complete maturation of peripheral and central chemoreceptors.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1139-05.2005
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2005
    detail.hit.zdb_id: 1475274-8
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  • 10
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    Neuroprotective and reparative effects of carotid body grafts in a chronic MPTP model of Parkinson's disease
    Elsevier BV ; 2013
    In:  Neurobiology of Aging Vol. 34, No. 3 ( 2013-03), p. 902-915
    Details
    In: Neurobiology of Aging, Elsevier BV, Vol. 34, No. 3 ( 2013-03), p. 902-915
    Type of Medium: Online Resource
    ISSN: 0197-4580
    URL: Article
    DOI: 10.1016/j.neurobiolaging.2012.06.001
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
    detail.hit.zdb_id: 1498414-3
    SSG: 12
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