Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor.

Autor: Bach A; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. Electronic address: anders.bach@sund.ku.dk., Clausen BH; Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; BRIDGE, Brain Research, Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark., Kristensen LK; Molecular Pathology Section, BRIC, Copenhagen Biocenter, University of Copenhagen, Copenhagen, Denmark., Andersen MG; Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Ellman DG; Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Hansen PBL; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Hasseldam H; Molecular Pathology Section, BRIC, Copenhagen Biocenter, University of Copenhagen, Copenhagen, Denmark., Heitz M; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Özcelik D; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Tuck EJ; Synome Ltd, Babraham Research Campus, Cambridge, United Kingdom., Kopanitsa MV; Synome Ltd, Babraham Research Campus, Cambridge, United Kingdom., Grant SGN; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom., Lykke-Hartmann K; Department of Biomedicine and Department of Clinical Medicine, University of Aarhus, Denmark and and the Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark., Johansen FF; Molecular Pathology Section, BRIC, Copenhagen Biocenter, University of Copenhagen, Copenhagen, Denmark., Lambertsen KL; Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; BRIDGE, Brain Research, Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Neurology, Odense University Hospital, Odense, Denmark. Electronic address: klambertsen@health.sdu.dk., Strømgaard K; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. Electronic address: kristian.stromgaard@sund.ku.dk.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2019 May 15; Vol. 150, pp. 100-111. Date of Electronic Publication: 2019 Mar 02.
DOI: 10.1016/j.neuropharm.2019.02.035
Abstrakt: Inhibition of postsynaptic density protein-95 (PSD-95) decouples N-methyl-d-aspartate (NMDA) receptor downstream signaling and results in neuroprotection after focal cerebral ischemia. We have previously developed UCCB01-144, a dimeric PSD-95 inhibitor, which binds PSD-95 with high affinity and is neuroprotective in experimental stroke. Here, we investigate the selectivity, efficacy and toxicity of UCCB01-144 and compare with the monomeric drug candidate Tat-NR2B9c. Fluorescence polarization using purified proteins and pull-downs of mouse brain lysates showed that UCCB01-144 potently binds all four PSD-95-like membrane-associated guanylate kinases (MAGUKs). In addition, UCCB01-144 affected NMDA receptor signaling pathways in ischemic brain tissue. UCCB01-144 reduced infarct size in young and aged male mice at various doses when administered 30 min after permanent middle cerebral artery occlusion, but UCCB01-144 was not effective in young male mice when administered 1 h post-ischemia or in female mice. Furthermore, UCCB01-144 was neuroprotective in a transient stroke model in rats, and in contrast to Tat-NR2B9c, high dose of UCCB01-144 did not lead to significant changes in mean arterial blood pressure or heart rate. Overall, UCCB01-144 is a potent MAGUK inhibitor that reduces neurotoxic PSD-95-mediated signaling and improves neuronal survival following focal brain ischemia in rodents under various conditions and without causing cardiovascular side effects, which encourages further studies towards clinical stroke trials.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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