(+)-trans-Cannabidiol-2-hydroxy pentyl is a dual CB 1 R antagonist/CB 2 R agonist that prevents diabetic nephropathy in mice.

Autor: González-Mariscal I; Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, 29009 Málaga, Spain. Electronic address: isabel.gonzalez@ibima.eu., Carmona-Hidalgo B; Emerald Health Biotechnology, Córdoba, Spain., Winkler M; Symrise AG, Holzminden, Germany., Unciti-Broceta JD; Emerald Health Biotechnology, Córdoba, Spain., Escamilla A; Microscopy platform, IBIMA, Malaga, Spain., Gómez-Cañas M; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, CIBERNED and IRYCIS, Madrid, Spain., Fernández-Ruiz J; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, CIBERNED and IRYCIS, Madrid, Spain., Fiebich BL; VivaCell Biotechnology GmbH, Dezlingen, Germany., Romero-Zerbo SY; Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, 29009 Málaga, Spain., Bermúdez-Silva FJ; Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, 29009 Málaga, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain., Collado JA; Instituto Maimónides de Investigación Biomédica de Córdoba, Spain; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, 14004 Córdoba, Spain; Hospital Universitario Reina Sofía, Córdoba, Spain., Muñoz E; Instituto Maimónides de Investigación Biomédica de Córdoba, Spain; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, 14004 Córdoba, Spain; Hospital Universitario Reina Sofía, Córdoba, Spain. Electronic address: fi1muble@uco.es.
Jazyk: angličtina
Zdroj: Pharmacological research [Pharmacol Res] 2021 Jul; Vol. 169, pp. 105492. Date of Electronic Publication: 2021 May 19.
DOI: 10.1016/j.phrs.2021.105492
Abstrakt: Natural cannabidiol ((-)-CBD) and its derivatives have increased interest for medicinal applications due to their broad biological activity spectrum, including targeting of the cannabinoid receptors type 1 (CB 1 R) and type 2 (CB 2 R). Herein, we synthesized the (+)-enantiomer of CBD and its derivative (+)-CBD hydroxypentylester ((+)-CBD-HPE) that showed enhanced CB 1 R and CB 2 R binding and functional activities compared to their respective (-) enantiomers. (+)-CBD-HPE Ki values for CB 1 R and CB 2 R were 3.1 ± 1.1 and 0.8 ± 0.1 nM respectively acting as CB 1 R antagonist and CB 2 R agonist. We further tested the capacity of (+)-CBD-HPE to prevent hyperglycemia and its complications in a mouse model. (+)-CBD-HPE significantly reduced streptozotocin (STZ)-induced hyperglycemia and glucose intolerance by preserving pancreatic beta cell mass. (+)-CBD-HPE significantly reduced activation of NF-κB by phosphorylation by 15% compared to STZ-vehicle mice, and CD3 + T cell infiltration into the islets was avoided. Consequently, (+)-CBD-HPE prevented STZ-induced apoptosis in islets. STZ induced inflammation and kidney damage, visualized by a significant increase in plasma proinflammatory cytokines, creatinine, and BUN. Treatment with (+)-CBD-HPE significantly reduced 2.5-fold plasma IFN-γ and increased 3-fold IL-5 levels compared to STZ-treated mice, without altering IL-18. (+)-CBD-HPE also significantly reduced creatinine and BUN levels to those comparable to healthy controls. At the macroscopy level, (+)-CBD-HPE prevented STZ-induced lesions in the kidney and voided renal fibrosis and CD3 + T cell infiltration. Thus, (+)-enantiomers of CBD, particularly (+)-CBD-HPE, have a promising potential due to their pharmacological profile and synthesis, potentially to be used for metabolic and immune-related disorders.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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