期刊
PHARMACOLOGICAL RESEARCH
卷 169, 期 -, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2021.105492
关键词
Cannabidiol; (+)-enantiomers; Cannabinoids; Cannabinoid 1 receptor; Cannabinoid 2 receptor; Diabetic nephropathy; Type 1 diabetes
资金
- Consejeria de Salud y Familias of Junta de Andalucia - Proyectos de Investigacion en Salud [PI-0318-2018]
- Nicolas Monardes Program, Spain [C1-0018-2019]
- Ministry of the Economy and Competition, Spain (MINECO) [SAF2017-87701-R]
- Emerald Health Biotechnology Espana SLU
- Symrise AG
- Ministry of Science, Innovation and University, Spain (MICIU) [RTI2018-098885-B-100]
- European Union FEDER funds
Natural cannabidiol and its derivatives, particularly the enantiomer (+)-CBD-HPE, showed enhanced binding and functional activities on cannabinoid receptors CB1R and CB2R. The compound demonstrated potential in preventing hyperglycemia and its complications in a mouse model, with promising pharmacological profile for metabolic and immune-related disorders.
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 (CB1R) and type 2 (CB2R). Herein, we synthesized the (+)-enantiomer of CBD and its derivative (+)-CBD hydroxypentylester ((+)-CBD-HPE) that showed enhanced CB1R and CB2R binding and functional activities compared to their respective (-) enantiomers. (+)-CBD-HPE Ki values for CB1R and CB2R were 3.1 +/- 1.1 and 0.8 +/- 0.1 nM respectively acting as CB1R antagonist and CB2R 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. (+)-CBDHPE significantly reduced activation of NF-kappa B 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-gamma 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.
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