UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801

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UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801. / Andreasen, Jesper T.; Bach, Anders; Gynther, Mikko; Nasser, Arafat; Mogensen, Jesper; Strømgaard, Kristian; Pickering, Darryl S.

In: Neuropharmacology, Vol. 67, 04.2013, p. 193-200.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Andreasen, JT, Bach, A, Gynther, M, Nasser, A, Mogensen, J, Strømgaard, K & Pickering, DS 2013, 'UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801', Neuropharmacology, vol. 67, pp. 193-200. https://doi.org/10.1016/j.neuropharm.2012.11.006

APA

Andreasen, J. T., Bach, A., Gynther, M., Nasser, A., Mogensen, J., Strømgaard, K., & Pickering, D. S. (2013). UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801. Neuropharmacology, 67, 193-200. https://doi.org/10.1016/j.neuropharm.2012.11.006

Vancouver

Andreasen JT, Bach A, Gynther M, Nasser A, Mogensen J, Strømgaard K et al. UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801. Neuropharmacology. 2013 Apr;67:193-200. https://doi.org/10.1016/j.neuropharm.2012.11.006

Author

Andreasen, Jesper T. ; Bach, Anders ; Gynther, Mikko ; Nasser, Arafat ; Mogensen, Jesper ; Strømgaard, Kristian ; Pickering, Darryl S. / UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801. In: Neuropharmacology. 2013 ; Vol. 67. pp. 193-200.

Bibtex

@article{6118cf9ff56c499392031e6bf3dd9e04,
title = "UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801",
abstract = "Excessive N-Methyl-d-aspartate receptor (NMDAR)-dependent production of nitric oxide (NO) is involved in the development and maintenance of chronic pain states, and is mediated by postsynaptic density protein-95 (PSD-95). By binding to both the NMDAR and neuronal NO synthase (nNOS), PSD-95 mediates a specific coupling between NMDAR activation and NO production. NMDAR antagonism shows anti-nociceptive action in humans and animal models of chronic pain but is associated with severe disturbances of cognitive and motor functions. An alternative approach to modulate the NMDAR-related activity is to perturb the NMDAR/PSD-95/nNOS complex by targeting PSD-95, thereby decreasing NO production without interfering with the NMDAR ion channel function. Here, we compared the effects of a dimeric PSD-95 inhibitor, UCCB01-125, and the NMDAR antagonist, MK-801, on mechanical hypersensitivity in the complete Freund's adjuvant (CFA) model of inflammatory pain. To examine side-effect profiles we also compared the effects of UCCB01-125 and MK-801 in tests of attention, long-term memory, and motor performance. When administered concurrently with CFA, both MK-801 and UCCB01-125 prevented the development of CFA-induced mechanical hypersensitivity 1 and 24 h after treatment. Moreover, UCCB01-125 was found to reverse CFA-induced hypersensitivity when administered 24 h after CFA treatment, an effect lasting for at least 3 days. At the dose reducing hypersensitivity, MK-801 disrupted attention, long-term memory, and motor performance. By contrast, even high doses of UCCB01-125 were devoid of side-effects in these tests. The data suggest that PSD-95 inhibition is a feasible strategy to prevent both development and maintenance of chronic inflammatory pain, while avoiding NMDAR antagonism-related side-effects.",
keywords = "Animals, Cognition, Dimerization, Dizocilpine Maleate, Enzyme Inhibitors, Female, Guanylate Kinase, Inflammation, Inflammation Mediators, Membrane Proteins, Mice, Motor Skills, Oligopeptides, Pain, Polyethylene Glycols, Receptors, N-Methyl-D-Aspartate",
author = "Andreasen, {Jesper T.} and Anders Bach and Mikko Gynther and Arafat Nasser and Jesper Mogensen and Kristian Str{\o}mgaard and Pickering, {Darryl S}",
note = "Copyright {\circledC} 2012 Elsevier Ltd. All rights reserved.",
year = "2013",
month = "4",
doi = "10.1016/j.neuropharm.2012.11.006",
language = "English",
volume = "67",
pages = "193--200",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Pergamon Press",

}

RIS

TY - JOUR

T1 - UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801

AU - Andreasen, Jesper T.

AU - Bach, Anders

AU - Gynther, Mikko

AU - Nasser, Arafat

AU - Mogensen, Jesper

AU - Strømgaard, Kristian

AU - Pickering, Darryl S

N1 - Copyright © 2012 Elsevier Ltd. All rights reserved.

PY - 2013/4

Y1 - 2013/4

N2 - Excessive N-Methyl-d-aspartate receptor (NMDAR)-dependent production of nitric oxide (NO) is involved in the development and maintenance of chronic pain states, and is mediated by postsynaptic density protein-95 (PSD-95). By binding to both the NMDAR and neuronal NO synthase (nNOS), PSD-95 mediates a specific coupling between NMDAR activation and NO production. NMDAR antagonism shows anti-nociceptive action in humans and animal models of chronic pain but is associated with severe disturbances of cognitive and motor functions. An alternative approach to modulate the NMDAR-related activity is to perturb the NMDAR/PSD-95/nNOS complex by targeting PSD-95, thereby decreasing NO production without interfering with the NMDAR ion channel function. Here, we compared the effects of a dimeric PSD-95 inhibitor, UCCB01-125, and the NMDAR antagonist, MK-801, on mechanical hypersensitivity in the complete Freund's adjuvant (CFA) model of inflammatory pain. To examine side-effect profiles we also compared the effects of UCCB01-125 and MK-801 in tests of attention, long-term memory, and motor performance. When administered concurrently with CFA, both MK-801 and UCCB01-125 prevented the development of CFA-induced mechanical hypersensitivity 1 and 24 h after treatment. Moreover, UCCB01-125 was found to reverse CFA-induced hypersensitivity when administered 24 h after CFA treatment, an effect lasting for at least 3 days. At the dose reducing hypersensitivity, MK-801 disrupted attention, long-term memory, and motor performance. By contrast, even high doses of UCCB01-125 were devoid of side-effects in these tests. The data suggest that PSD-95 inhibition is a feasible strategy to prevent both development and maintenance of chronic inflammatory pain, while avoiding NMDAR antagonism-related side-effects.

AB - Excessive N-Methyl-d-aspartate receptor (NMDAR)-dependent production of nitric oxide (NO) is involved in the development and maintenance of chronic pain states, and is mediated by postsynaptic density protein-95 (PSD-95). By binding to both the NMDAR and neuronal NO synthase (nNOS), PSD-95 mediates a specific coupling between NMDAR activation and NO production. NMDAR antagonism shows anti-nociceptive action in humans and animal models of chronic pain but is associated with severe disturbances of cognitive and motor functions. An alternative approach to modulate the NMDAR-related activity is to perturb the NMDAR/PSD-95/nNOS complex by targeting PSD-95, thereby decreasing NO production without interfering with the NMDAR ion channel function. Here, we compared the effects of a dimeric PSD-95 inhibitor, UCCB01-125, and the NMDAR antagonist, MK-801, on mechanical hypersensitivity in the complete Freund's adjuvant (CFA) model of inflammatory pain. To examine side-effect profiles we also compared the effects of UCCB01-125 and MK-801 in tests of attention, long-term memory, and motor performance. When administered concurrently with CFA, both MK-801 and UCCB01-125 prevented the development of CFA-induced mechanical hypersensitivity 1 and 24 h after treatment. Moreover, UCCB01-125 was found to reverse CFA-induced hypersensitivity when administered 24 h after CFA treatment, an effect lasting for at least 3 days. At the dose reducing hypersensitivity, MK-801 disrupted attention, long-term memory, and motor performance. By contrast, even high doses of UCCB01-125 were devoid of side-effects in these tests. The data suggest that PSD-95 inhibition is a feasible strategy to prevent both development and maintenance of chronic inflammatory pain, while avoiding NMDAR antagonism-related side-effects.

KW - Animals

KW - Cognition

KW - Dimerization

KW - Dizocilpine Maleate

KW - Enzyme Inhibitors

KW - Female

KW - Guanylate Kinase

KW - Inflammation

KW - Inflammation Mediators

KW - Membrane Proteins

KW - Mice

KW - Motor Skills

KW - Oligopeptides

KW - Pain

KW - Polyethylene Glycols

KW - Receptors, N-Methyl-D-Aspartate

U2 - 10.1016/j.neuropharm.2012.11.006

DO - 10.1016/j.neuropharm.2012.11.006

M3 - Journal article

C2 - 23178182

VL - 67

SP - 193

EP - 200

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -

ID: 74769448