Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects.

Autor: Raffaele M; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic., Kovacovicova K; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.; Psychogenics Inc, Tarrytown, NY, USA., Biagini T; Laboratory of Bioinformatics, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy., Lo Re O; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.; Department of Translational Stem Cell Biology, Research Institute of the Medical University of Varna, Varna, Bulgaria., Frohlich J; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic., Giallongo S; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.; Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic., Nhan JD; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.; Department of Molecular and Computational Biology, Arts, and Sciences, Dornsife College of Letters, University of Southern California, Los Angeles, CA, USA., Giannone AG; Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Pathologic Anatomy Unit-University of Palermo, Palermo, Italy., Cabibi D; Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Pathologic Anatomy Unit-University of Palermo, Palermo, Italy., Ivanov M; Department of Anatomy and Cell Biology, Research Institute of the Medical University of Varna, Varna, Bulgaria., Tonchev AB; Department of Translational Stem Cell Biology, Research Institute of the Medical University of Varna, Varna, Bulgaria.; Department of Anatomy and Cell Biology, Research Institute of the Medical University of Varna, Varna, Bulgaria., Mistrik M; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic., Lacey M; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic., Dzubak P; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic., Gurska S; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic., Hajduch M; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic., Bartek J; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.; Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.; Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden., Mazza T; Laboratory of Bioinformatics, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy., Micale V; Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy., Curran SP; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.; Department of Molecular and Computational Biology, Arts, and Sciences, Dornsife College of Letters, University of Southern California, Los Angeles, CA, USA.; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Vinciguerra M; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic. manlio.vinciguerra@fnusa.cz.; Department of Translational Stem Cell Biology, Research Institute of the Medical University of Varna, Varna, Bulgaria. manlio.vinciguerra@fnusa.cz.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2022 Feb; Vol. 44 (1), pp. 463-483. Date of Electronic Publication: 2021 Nov 24.
DOI: 10.1007/s11357-021-00487-y
Abstrakt: Accumulation of senescent cells may drive age-associated alterations and pathologies. Senolytics are promising therapeutics that can preferentially eliminate senescent cells. Here, we performed a high-throughput automatized screening (HTS) of the commercial LOPAC®Pfizer library on aphidicolin-induced senescent human fibroblasts, to identify novel senolytics. We discovered the nociceptin receptor FQ opioid receptor (NOP) selective ligand 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB, a compound previously studied as potential anxiolytic) as the best scoring hit. The ability of MCOPPB to eliminate senescent cells in in vitro models was further tested in mice and in C. elegans. MCOPPB reduced the senescence cell burden in peripheral tissues but not in the central nervous system. Mice and worms exposed to MCOPPB also exhibited locomotion and lipid storage changes. Mechanistically, MCOPPB treatment activated transcriptional networks involved in the immune responses to external stressors, implicating Toll-like receptors (TLRs). Our study uncovers MCOPPB as a NOP ligand that, apart from anxiolytic effects, also shows tissue-specific senolytic effects.
(© 2021. The Author(s), under exclusive licence to American Aging Association.)
Databáze: MEDLINE
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