title: Effects of the dimeric PSD-95 inhibitor UCCB01-144 in mouse models of pain, cognition and motor function.
abstract: NMDAR antagonism shows analgesic action in humans and animal pain models, but disrupts cognitive and motor functions. NMDAR-dependent NO production requires tethering of the NMDAR to neuronal NO synthase (nNOS) by the postsynaptic density protein-95 (PSD-95). Perturbing the NMDAR/PSD-95/nNOS interaction has therefore been proposed as an alternative analgesic mechanism. We recently reported that UCCB01-125, a dimeric PSD-95 inhibitor with limited blood-brain-barrier permeability, reduced mechanical hypersensitivity in the complete Freund's adjuvant (CFA) inflammatory pain model, without disrupting cognitive or motor functions. Here, we investigated the analgesic efficacy in the CFA model of UCCB01-144, a PSD-95 inhibitor with improved blood-brain-barrier permeability. To extend the comparison of UCCB01-125 and UCCB01-144, we also tested both compounds in the spared nerve injury (SNI) model of neuropathic pain. Potential cognitive effects of UCCB01-144 were examined using the social transmission of food preference (STFP) test and the V-maze test, and motor coordination was assessed with the rotarod test. UCCB01-144 (10mg/kg) reversed CFA-induced mechanical hypersensitivity after 1h, and completely normalised sensitivity after 24h. In the SNI model, UCCB01-144 (30mg/kg) partially reversed hypersensitivity after 1h, but no effect was observed after 24h. UCCB01-125 did not affect SNI-induced hypersensitivity. Rotarod performance was unaffected by UCCB01-144, but 30mg/kg UCCB01-144 impaired performance in the STFP test. Collectively, UCCB01-144 reversed both CFA and SNI-induced hypersensitivity, but the efficacy in the SNI model was only transient. This suggests that enhanced BBB permeability of PSD-95 inhibitors improves the analgesic action in neuropathic pain states.
authors.affiliation: Dept. of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Denmark. Electronic address: jta@sund.ku.dk.
authors.forename: Jesper T
authors.initials: JT
authors.lastname: Andreasen
authors.affiliation: Dept. of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Denmark.
authors.forename: Arafat
authors.initials: A
authors.lastname: Nasser
authors.affiliation: Dept. of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Denmark.
authors.forename: Maitane
authors.initials: M
authors.lastname: Caballero-Puntiverio
authors.affiliation: Dept. of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Denmark.
authors.forename: Maj
authors.initials: M
authors.lastname: Sahlholt
authors.affiliation: Dept. of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Bach
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Gynther
authors.affiliation: Dept. of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
authors.affiliation: Dept. of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Denmark.
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D019281:Dimerization; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005518:Food Preferences / Q000187:drug effects; D051528:Guanylate Kinases / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008568:Memory / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017288:Pain Threshold / Q000187:drug effects; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D045442:Rotarod Performance Test
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009842:Oligopeptides; C584048:UCCB01-125; D011092:Polyethylene Glycols; D051528:Guanylate Kinases
keywords: Behaviour; Cognition; Inflammatory pain; Mice; Neuropathic pain; PSD-95 inhibition