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2. Resistance of α-Synuclein Null Mice to the Parkinsonian Neurotoxin MPTP

Author

Dauer, William, Kholodilov, Nikolai, Vila, Miquel, Trillat, Anne-Cecile, Goodchild, Rose, Larsen, Kristin E., Staal, Roland, Tieu, Kim, Schmitz, Yvonne, Yuan, Chao Annie, Rocha, Marcelo, Jackson-Lewis, Vernice, Hersch, Steven, Sulzer, David, Przedborski, Serge, Burke, Robert, and Hen, Rene

Published
2002

6. Inhibition of P2X7 receptors by Lu AF27139 diminishes colonic hypersensitivity and CNS prostanoid levels in a rat model of visceral pain

Author

Staal, Roland, primary, Gandhi, Adarsh, additional, Zhou, Hua, additional, Cajina, Manuel, additional, Jacobsen, Anne-Marie, additional, Hestehave, Sara, additional, Hopper, Allen, additional, Poda, Suresh, additional, Chandresana, Gamini, additional, Zorn, Stevin, additional, Campbell, Brian, additional, Segerdahl, Marta, additional, Moller, Thomas, additional, and Munro, Gordon, additional

Published
2022
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8. P2X7 receptor‐mediated release of microglial prostanoids and miRNAs correlates with reversal of neuropathic hypersensitivity in rats

Author

Staal, Roland, primary, Khayrullina, Tanzilya, additional, Christensen, Rie, additional, Hestehave, Sara, additional, Zhou, Hua, additional, Cajina, Manuel, additional, Nattini, Megan E., additional, Gandhi, Adarsh, additional, Fallon, Shaun M., additional, Schmidt, Megan, additional, Zorn, Stevin H., additional, Brodbeck, Robbin M., additional, Chandrasena, Gamini, additional, Segerdahl, Märta, additional, Breysse, Nathalie, additional, Hopper, Allen T., additional, Möller, Thomas, additional, and Munro, Gordon, additional

Published
2022
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10. Synthesis and Characterization of the Novel Rodent-Active and CNS-Penetrant P2X7 Receptor Antagonist Lu AF27139

Author

Hopper, Allen T., primary, Juhl, Martin, additional, Hornberg, Jorrit, additional, Badolo, Lassina, additional, Kilburn, John Paul, additional, Thougaard, Annemette, additional, Smagin, Gennady, additional, Song, Dekun, additional, Calice, Londye, additional, Menon, Veena, additional, Dale, Elena, additional, Zhang, Hong, additional, Cajina, Manuel, additional, Nattini, Megan E., additional, Gandhi, Adarsh, additional, Grenon, Michel, additional, Jones, Ken, additional, Khayrullina, Tanzilya, additional, Chandrasena, Gamini, additional, Thomsen, Christian, additional, Zorn, Stevin H., additional, Brodbeck, Robb, additional, Poda, Suresh Babu, additional, Staal, Roland, additional, and Möller, Thomas, additional

Published
2021
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12. Resistance of [alpha]-synuclein null mice to the parkinsonian neurotoxin MPTP

Author

Dauer, William, Kholodilov, Nikolai, Vila, Miquel, Trillat, Anne-Cecile, Goodchild, Rose, Larsen, Kristin E., Staal, Roland, Tieu, Kim, Schmitz, Yvonne, Yuan, Chao Annie, Rocha, Marcelo, Jackson-Lewis, Vernice, Hersch, Steven, Sulzer, David, Przedborski, Serge, Burke, Robert, and Hen, Rene

Subjects
Parkinson's disease -- Physiological aspects, MPTP (Neurotoxin) -- Physiological aspects, Science and technology
Abstract

Parkinson's disease (PD) is most commonly a sporadic illness, and is characterized by degeneration of substantia nigra dopamine (DA) neurons and abnormal cytoplasmic aggregates of [alpha]-synuclein. Rarely, PD may be caused by missense mutations in [alpha]-synuclein. MPTP, a neurotoxin that inhibits mitochondrial complex I, is a prototype for an environmental cause of PD because it produces a pattern of DA neurodegeneration that closely resembles the neuropathology of PD. Here we show that [alpha]-synuclein null mice display striking resistance to MPTP-induced degeneration of DA neurons and DA release, and this resistance appears to result from an inability of the toxin to inhibit complex I. Contrary to predictions from in vitro data, this resistance is not due to abnormalities of the DA transporter, which appears to function normally in [alpha]-synuclein null mice. Our results suggest that some genetic and environmental factors that increase susceptibility to PD may interact with a common molecular pathway, and represent the first demonstration that normal [alpha]-synuclein function may be important to DA neuron viability.

Published
2002

20. Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State

Author

Kurnik, Martin, primary, Sahin, Cagla, additional, Andersen, Camilla Bertel, additional, Lorenzen, Nikolai, additional, Giehm, Lise, additional, Mohammad-Beigi, Hossein, additional, Jessen, Christian Moestrup, additional, Pedersen, Jan Skov, additional, Christiansen, Gunna, additional, Petersen, Steen Vang, additional, Staal, Roland, additional, Krishnamurthy, Girija, additional, Pitts, Keith, additional, Reinhart, Peter H., additional, Mulder, Frans A.A., additional, Mente, Scot, additional, Hirst, Warren D., additional, and Otzen, Daniel E., additional

Published
2018
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22. Inhibition of the potassium channel K Ca 3.1 by senicapoc reverses tactile allodynia in rats with peripheral nerve injury

Author

Staal, Roland G.W., primary, Khayrullina, Tanzilya, additional, Zhang, Hong, additional, Davis, Scott, additional, Fallon, Shaun M., additional, Cajina, Manuel, additional, Nattini, Megan E., additional, Hu, Andrew, additional, Zhou, Hua, additional, Poda, Suresh Babu, additional, Zorn, Stevin, additional, Chandrasena, Gamini, additional, Dale, Elena, additional, Cambpell, Brian, additional, Biilmann Rønn, Lars Christian, additional, Munro, Gordon, additional, and Mӧller, Thomas, additional

Published
2017
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23. Critical data‐based re‐evaluation of minocycline as a putative specific microglia inhibitor

Author

Möller, Thomas, primary, Bard, Frédérique, additional, Bhattacharya, Anindya, additional, Biber, Knut, additional, Campbell, Brian, additional, Dale, Elena, additional, Eder, Claudia, additional, Gan, Li, additional, Garden, Gwenn A., additional, Hughes, Zoë A., additional, Pearse, Damien D., additional, Staal, Roland G. W., additional, Sayed, Faten A., additional, Wes, Paul D., additional, and Boddeke, Hendrikus W. G. M., additional

Published
2016
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27. P1-238: Soluble Aβ from PSAPP mice is different to that extracted from Alzheimer patients

Author

Hirst, Warren D., primary, Needle, Elie, additional, Staal, Roland G.W., additional, Crozier, Robert, additional, Breysse, Nathalie, additional, Nagy, Reka, additional, Sung, Amy, additional, Monaghan, Michael, additional, Riddell, David R., additional, Chin, Jeannie, additional, Walsh, Dominic M., additional, Pangalos, Menelas N., additional, Reinhart, Peter H., additional, and Jacobsen, J.S., additional

Published
2010
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28. Low Resolution Structure of a Membrane-Permeabilizing Oligomer of α-Synuclein: the Basis for a High-Throughput Screening of Compounds against α-Synuclein Aggregation

Author

Giehm, Lise, primary, Vestergaard, Bente, additional, Oliveira, Cristiano, additional, Pedersen, Jan S., additional, Svergun, Dmitri I., additional, Pitts, Keith, additional, Krishnamurthy, Girija, additional, Staal, Roland, additional, Reinhart, Peter, additional, and Otzen, Daniel E., additional

Published
2010
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29. Dopamine Release at Individual Presynaptic Terminals Visualized with FFNs

Author

Zhang, Hui, primary, Gubernator, Niko G., primary, Yue, Minerva, primary, Staal, Roland G. W., primary, Mosharov, Eugene V., primary, Pereira, Daniela, primary, Balsanek, Vojtech, primary, Vadola, Paul A., primary, Mukherjee, Bipasha, primary, Edwards, Robert H., primary, Sulzer, David, primary, and Sames, Dalibor, primary

Published
2009
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33. α-Synuclein Overexpression Increases Cytosolic Catecholamine Concentration.

Author

Mosharov, Eugene V., Staal, Roland G. W., Bove, Jordi, Prou, Delphine, Hananiya, Anthonia, Markov, Dmitriy, Poulsen, Nathan, Larsen, Kristin E., Moore, Candace M. H., Troyer, Matthew D., Edwards, Robert H., Przedborski, Serge, and Sulzer, David

Abstract

Dysregulation of dopamine homeostasis and elevation of the cytosolic level of the transmitter have been suggested to underlie the vulnerability of catecholaminergic neurons in Parkinson’s disease. Because several known mutations in α-synuclein or overexpression of the wild-type (WT) protein causes familial forms of Parkinson’s disease, we investigated possible links between α-synuclein pathogenesis and dopamine homeostasis. Chromaffin cells isolated from transgenic mice that overexpress A30P α-synuclein displayed significantly increased cytosolic catecholamine levels as measured by intracellular patch electrochemistry, whereas cells overexpressing the WT protein and those from knock-out animals were not different from controls. Likewise, catechol concentrations were higher in l-DOPA-treated PC12 cells overexpressing A30P or A53T compared with those expressing WT α-synuclein, although the ability of cells to maintain a low cytosolic dopamine level after l-DOPA challenge was markedly inhibited by either protein. We also found that incubation with low-micromolar concentrations of WT, A30P, or A53T α-synuclein inhibited ATP-dependent maintenance of pH gradients in isolated chromaffin vesicles and that the WT protein was significantly less potent in inducing the proton leakage. In summary, we demonstrate that overexpression of different types of α-synuclein disrupts vesicular pH and leads to a marked increase in the levels of cytosolic catechol species, an effect that may in turn trigger cellular oxyradical damage. Although multiple molecular mechanisms may be responsible for the perturbation of cytosolic catecholamine homeostasis, this study provides critical evidence about how α-synuclein might exert its cytotoxicity and selectively damage catecholaminergic cells. [ABSTRACT FROM AUTHOR]

Published
2006
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36. 8-(3-Chlorostyryl)caffeine May Attenuate MPTP Neurotoxicity through Dual Actions of Monoamine Oxidase Inhibition and A2AReceptor Antagonism*

Author

Chen, Jiang-Fan, Steyn, Salome, Staal, Roland, Petzer, Jacobus P., Xu, Kui, Van der Schyf, Cornelis J., Castagnoli, Kay, Sonsalla, Patricia K., Castagnoli, Neal, and Schwarzschild, Michael A.

Abstract

Caffeine and more specific antagonists of the adenosine A2Areceptor recently have been found to be neuroprotective in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. Here we show that 8-(3-chlorostyryl)caffeine (CSC), a specific A2Aantagonist closely related to caffeine, also attenuates MPTP-induced neurotoxicity. Because the neurotoxicity of MPTP relies on its oxidative metabolism to the mitochondrial toxin MPP+, we investigated the actions of CSC on striatal MPTP metabolism in vivo. CSC elevated striatal levels of MPTP but lowered levels of the oxidative intermediate MPDP+and of MPP+, suggesting that CSC blocks the conversion of MPTP to MPDP+in vivo. In assessing the direct effects of CSC and A2Areceptors on monoamine oxidase (MAO) activity, we found that CSC potently and specifically inhibited mouse brain mitochondrial MAO-B activity in vitrowith aKivalue of 100 nm, whereas caffeine and another relatively specific A2Aantagonist produced little or no inhibition. The A2Areceptor independence of MAO-B inhibition by CSC was further supported by the similarity of brain MAO activities derived from A2Areceptor knockout and wild-type mice and was confirmed by demonstrating potent inhibition of A2Areceptor knockout-derived MAO-B by CSC. Together, these data indicate that CSC possesses dual actions of MAO-B inhibition and A2Areceptor antagonism, a unique combination suggesting a new class of compounds with the potential for enhanced neuroprotective properties.

Published
2002
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37. Inhibition of Brain Vesicular Monoamine Transporter (VMAT2) Enhances 1-Methyl-4-phenylpyridinium Neurotoxicity In Vivo in Rat Striata11This work was supported by National Institutes of Health Grant AG08479.

Author

Staal, Roland G.W. and Sonsalla, Patricia K.

Abstract

Dopamine neurons from various animal species differ in sensitivity to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+). Compared with striatal vesicles isolated from mice, those from rats have a higher density of the brain vesicular monoamine transporter (VMAT2) and a greater ability to sequester MPP+, suggesting a larger storage capacity for MPP+in rat vesicles. In the present study, we examined whether striatal VMAT2-containing vesicles might provide protection against the neurotoxic effects of MPP+in vivo. Dose-response curves for striatally infused MPP+were determined in animals pretreated with or without a VMAT2 inhibitor. Ro 4-1284 administration (10 mg/kg i.p.; VMAT2 inhibitor) produced a 5-fold leftward shift in the MPP+dose-response curve and a significant lowering of the EC50concentration for MPP+-induced damage. These findings provide evidence for a substantial accumulation of MPP+in VMAT2-containing vesicles in vivo in the rat striatum and support the hypothesis that MPP+sequestration in vesicles can provide protection against its toxic actions. In mice, VMAT2 inhibition did not reliably enhance toxicity produced by a striatal infusion of MPP+or by systemic administration of MPTP. These data suggest that vesicular sequestration of MPP+may be of less importance in mice than in rats as relates to protection from the toxin. The present results also reveal that although VMAT2 inhibition enhanced striatal MPP+toxicity in the rat, the potency of MPP+in the rat striatum was less than that in mouse striatum. This implies that there are other factors that either exacerbate MPP+toxicity in the mouse or attenuate MPP+toxicity in rats.

Published
2000
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38. In Vitro Studies of Striatal Vesicles Containing the Vesicular Monoamine Transporter (VMAT2): Rat versus Mouse Differences in Sequestration of 1-Methyl-4-phenylpyridinium11This work was supported by National Institutes of Health Grant AG08479 and National Institute of Environmental Health Sciences Grant ES07148. The synthesis and characterization of [3H]DTBZ binding were supported by National Institutes of Health Grants AG08671 and MH47611 to Drs. Michael Kilbourn and Kirk Frey (University of Michigan).

Author

Staal, Roland G.W., Hogan, Kelly A., Liang, Chang-Lin, German, Dwight C., and Sonsalla, Patricia K.

Abstract

Significant differences exist in the sensitivity of mice and rats to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that cannot be explained by differences in exposure to or uptake of 1-methyl-4-phenylpyridinium (MPP+) into dopamine (DA) neurons. MPP+is also a substrate for the brain vesicular monoamine transporter (VMAT2), and sequestration into synaptic vesicles may be one mechanism of protection against MPP+toxicity. A greater sequestration of MPP+into vesicles of DA neurons in rats versus mice could explain the lower vulnerability of DA neurons in the rat to MPP+toxicity. To test this hypothesis, the kinetics of uptake for [3H]MPP+and [3H]DA as well as [3H]dihydrotetrabenazine binding to VMAT2 were compared in vesicles isolated from the striata of rats and mice. The Kmvalue of [3H]MPP+transport was similar in the two species. In contrast, the maximal transport rate (Vmax) was 2-fold greater in vesicles from rats than in those from mice. Likewise, theKmvalue for [3H]DA transport was similar in both preparations, but theVmaxvalue was 2-fold greater in rat than in mouse vesicles. The Bmaxvalue for [3H]dihydrotetrabenazine binding was also 2-fold greater in striatal vesicles from rats than in those from mice. Electron micrographs demonstrated that vesicles isolated from rats and mice were approximately the same size. Based on these observations, we propose that striatal vesicles from rats have more VMAT2 than vesicles from mice and that this species difference in VMAT2 density may help explain the reduced vulnerability of rat DA neurons to MPP+neurotoxicity.

Published
2000
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39. KCa 3.1-a microglial target ready for drug repurposing?

Author

Dale E, Staal RG, Eder C, and Möller T

Subjects
Acetamides chemistry, Acetamides pharmacology, Acetamides therapeutic use, Animals, Humans, Intermediate-Conductance Calcium-Activated Potassium Channels antagonists & inhibitors, Microglia drug effects, Pyrazoles chemistry, Pyrazoles pharmacology, Pyrazoles therapeutic use, Trityl Compounds chemistry, Trityl Compounds pharmacology, Trityl Compounds therapeutic use, Drug Repositioning, Intermediate-Conductance Calcium-Activated Potassium Channels metabolism, Microglia metabolism
Abstract

Over the past decade, glial cells have attracted attention for harboring unexploited targets for drug discovery. Several glial targets have attracted de novo drug discovery programs, as highlighted in this GLIA Special Issue. Drug repurposing, which has the objective of utilizing existing drugs as well as abandoned, failed, or not yet pursued clinical development candidates for new indications, might provide a faster opportunity to bring drugs for glial targets to patients with unmet needs. Here, we review the potential of the intermediate-conductance calcium-activated potassium channels KCa 3.1 as the target for such a repurposing effort. We discuss the data on KCa 3.1 expression on microglia in vitro and in vivo and review the relevant literature on the two KCa 3.1 inhibitors TRAM-34 and Senicapoc. Finally, we provide an outlook of what it might take to harness the potential of KCa 3.1 as a bona fide microglial drug target. GLIA 2016;64:1733-1741., (© 2016 Wiley Periodicals, Inc.)

Published
2016
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