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.

• Authors: Jesper T Andreasen, Anders Bach, Mikko Gynther, Arafat Nasser, Jesper Mogensen, Kristian Strømgaard, Darryl S Pickering
• Journal: Neuropharmacology (Neuropharmacology) Vol. 67 Pg. 193-200 (Apr 2013) ISSN: 1873-7064 [Electronic] England
• PMID: 23178182 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Disks Large Homolog 4 Protein
• Dlg4 protein, mouse
• Enzyme Inhibitors
• Inflammation Mediators
• Membrane Proteins
• Oligopeptides
• Receptors, N-Methyl-D-Aspartate
• UCCB01-125
• Polyethylene Glycols
• Dizocilpine Maleate
• Guanylate Kinases

Topics

• Animals
• Cognition (drug effects, physiology)
• Dimerization
• Disks Large Homolog 4 Protein
• Dizocilpine Maleate (pharmacology, therapeutic use)
• Enzyme Inhibitors (chemistry, pharmacology, therapeutic use)
• Female
• Guanylate Kinases (antagonists & inhibitors, metabolism)
• Inflammation (drug therapy, metabolism)
• Inflammation Mediators (physiology)
• Membrane Proteins (antagonists & inhibitors, metabolism)
• Mice
• Motor Skills (drug effects, physiology)
• Oligopeptides (chemistry, pharmacology, therapeutic use)
• Pain (drug therapy, metabolism)
• Polyethylene Glycols (chemistry, pharmacology, therapeutic use)
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, metabolism)