González Mariscal, IsabelGómez Cañas, MaríaFernández Ruiz, José JavierMuñoz, Eduardo2024-01-182024-01-182021González-Mariscal I, Carmona-Hidalgo B, Winkler M, Unciti-Broceta JD, Escamilla A, Gómez-Cañas M, Fernández-Ruiz J, Fiebich BL, Romero-Zerbo SY, Bermúdez-Silva FJ, Collado JA, Muñoz E. (+)-trans-Cannabidiol-2-hydroxy pentyl is a dual CB1R antagonist/CB2R agonist that prevents diabetic nephropathy in mice. Pharmacol Res. 2021, 169(2021): 105492.1043-661810.1016/j.phrs.2021.105492https://hdl.handle.net/20.500.14352/93737Natural 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 streptozo tocin (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.engjournal articlehttps://doi.org/10.1016/j.phrs.2021.105492https://pubmed.ncbi.nlm.nih.gov/34019978/restricted access577(+)-enantiomersCannabidiolCannabinoid 1 receptorCannabinoid 2 receptorCannabinoidsDiabetic nephropathyType 1 diabetesCiencias Biomédicas24 Ciencias de la Vida