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

Abstract

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.

• Authors: Anders Bach, Bettina H Clausen, Lotte K Kristensen, Maria G Andersen, Ditte Gry Ellman, Pernille B L Hansen, Henrik Hasseldam, Marc Heitz, Dennis Özcelik, Ellie J Tuck, Maksym V Kopanitsa, Seth G N Grant, Karin Lykke-Hartmann, Flemming F Johansen, Kate L Lambertsen, Kristian Strømgaard
• Journal: Neuropharmacology (Neuropharmacology) Vol. 150 Pg. 100-111 (05 15 2019) ISSN: 1873-7064 [Electronic] England
• PMID: 30836092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Disks Large Homolog 4 Protein
• Ethers
• Neuroprotective Agents
• UCCB01-144

Topics

• Animals
• Brain (drug effects, pathology)
• Brain Ischemia (drug therapy, pathology)
• Disease Models, Animal
• Disks Large Homolog 4 Protein (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Ethers (adverse effects, pharmacology, therapeutic use)
• Female
• Male
• Mice
• Neuroprotection (drug effects)
• Neuroprotective Agents (adverse effects, pharmacology, therapeutic use)
• Rats
• Signal Transduction (drug effects)
• Time Factors