(+)-trans-Cannabidiol-2-hydroxy pentyl is a dual CB1R antagonist/CB2R agonist that prevents diabetic nephropathy in mice

González-Mariscal, Isabel; Carmona‐Hidalgo, Beatriz; Winkler, Mathias; Unciti-Broceta, Juan D.; Escamilla, Alejandro; Gómez‐Cañas, María; Fernández‐Ruiz, Javier; Fiebich, Bernd L.; Romero-Zerbo, Silvana Y.; Bermúdez‐Silva, Francisco Javier; Collado, Juan A.; Muñóz, Eduardo

doi:10.1016/j.phrs.2021.105492

Cited by 15 publications

(16 citation statements)

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“…Inverse agonists of CB1R have been shown to prevent diabetic nephropathy in rodent models [14]. We have recently described chemical modifications of (−)-CBD that increases the binding of CB1Rs and CB2Rs [20]. In the same way (−)-CBD-2-hydroxy pentyl ((−)-CBD-HPE) had a moderate binding to CB1R but strong for CB2R.…”

Section: Discussionmentioning

confidence: 99%

“…In functional assays (−)-CBD-HPE behaved as an agonist for CB2R and antagonist for CB1R [35]. We synthesized the (+)-enantiomer of CBD and its derivative (+)-CBD hydroxy pentyl ester ((+)-CBD-HPE) and showed that (+)-CBD-HPE exhibited an enhanced CB1R and CB2R binding and CB1R antagonist/CB2R agonist functions compared to it respective (−) enantiomer [20]. Concurrently to CBD and at the same dose, (+)-CBD-HPE prevented STZ-induced lesions in the kidney and avoided renal fibrosis and CD3 + T cell infiltration [20].…”

Section: Discussionmentioning

confidence: 99%

“…We synthesized the (+)-enantiomer of CBD and its derivative (+)-CBD hydroxy pentyl ester ((+)-CBD-HPE) and showed that (+)-CBD-HPE exhibited an enhanced CB1R and CB2R binding and CB1R antagonist/CB2R agonist functions compared to it respective (−) enantiomer [20]. Concurrently to CBD and at the same dose, (+)-CBD-HPE prevented STZ-induced lesions in the kidney and avoided renal fibrosis and CD3 + T cell infiltration [20]. The beneficial effects obtained with (+)-CBD-HPE are likely due to its enhanced affinity and activity over the CB1R and CB2R compared to CBD.…”

Section: Discussionmentioning

confidence: 99%

“…Eight-to-ten-week-old mice were treated intraperitoneally with CBD (10 mg/kg; the same dose used in our concurrent study with (+)-enantiomers of CBD [20]) or vehicle (DMSO:Tween-80:PBS) for 14 days. On day 7, mice were challenged with streptozotocin (STZ) or vehicle (Saline; control group) was initiated and blood glucose was monitored.…”

Section: Cannabidiol Does Not Avert Streptozotocin-induced Hyperglycemia and Glucose Intolerancementioning

confidence: 99%

“…It also alleviates diabetic nephropathy in type 2 diabetic rats [14]. Additionally, we previously showed that a (+)-enantiomer of CBD ameliorated diabetic nephropathy at onset in mice [20]. However, despite the beneficial effects of CBD on T1D NOD mice described 15 years ago, its potential effect on diabetic nephropathy has not been investigated.…”

Section: Introductionmentioning

confidence: 97%

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Detrimental Effect of Cannabidiol on the Early Onset of Diabetic Nephropathy in Male Mice

et al. 2021

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Anti-inflammatory and antidiabetogenic properties have been ascribed to cannabidiol (CBD). CBD-based medicinal drugs have been approved for over a lustrum, and a boom in the commercialization of CBD products started in parallel. Herein, we explored the efficacy of CBD in streptozotocin (STZ)-induced diabetic mice to prevent diabetic nephropathy at onset. Eight-to-ten-week-old C57BL6J male mice were treated daily intraperitoneally with 10 mg/kg of CBD or vehicle for 14 days. After 8 days of treatment, mice were challenged with STZ or vehicle (healthy-control). At the end of the study, non-fasting blood glucose (FBG) level was 276 ± 42 mg/dL in vehicle-STZ-treated compared to 147 ± 9 mg/dL (p ≤ 0.01) in healthy-control mice. FBG was 114 ± 8 mg/dL in vehicle-STZ-treated compared to 89 ± 4 mg/dL in healthy-control mice (p ≤ 0.05). CBD treatment did not prevent STZ-induced hyperglycemia, and non-FBG and FBG levels were 341 ± 40 and 133 ± 26 mg/dL, respectively. Additionally, treatment with CBD did not avert STZ-induced glucose intolerance or pancreatic beta cell mass loss compared to vehicle-STZ-treated mice. Anatomopathological examination showed that kidneys from vehicle-STZ-treated mice had a 35% increase of glomerular size compared to healthy-control mice (p ≤ 0.001) and presented lesions with a 43% increase in fibrosis and T cell infiltration (p ≤ 0.001). Although treatment with CBD prevented glomerular hypertrophy and reduced T cell infiltration, it significantly worsened overall renal damage (p ≤ 0.05 compared to vehicle-STZ mice), leading to a more severe renal dysfunction than STZ alone. In conclusion, we showed that CBD could be detrimental for patients with type 1 diabetes, particularly those undergoing complications such as diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cannabidiol Does Not Avert Streptozotocin-induced Hyperglycemia and Glucose Intolerancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Detrimental Effect of Cannabidiol on the Early Onset of Diabetic Nephropathy in Male Mice

et al. 2021

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Pharmaceutical targeting of the cannabinoid type 1 receptor impacts the crosstalk between immune cells and islets to reduce insulitis in humans

Wreven,

Ruiz de Adana,

Hardivillé

et al. 2024

Diabetologia

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Aims/hypothesis Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. However, functional beta cells can persist even in the face of continuous insulitis. Despite advances in immunosuppressive treatments, maintaining functional beta cells to prevent insulitis progression and hyperglycaemia remains a challenge. The cannabinoid type 1 receptor (CB1R), present in immune cells and beta cells, regulates inflammation and beta cell function. Here, we pioneer an ex vivo model mirroring human insulitis to investigate the role of CB1R in this process. Methods CD4+ T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) from male and female individuals at the onset of type 1 diabetes and from non-diabetic individuals, RNA was extracted and mRNA expression was analysed by real-time PCR. Single beta cell expression from donors with type 1 diabetes was obtained from data mining. Patient-derived human islets from male and female cadaveric donors were 3D-cultured in solubilised extracellular matrix gel in co-culture with the same donor PBMCs, and incubated with cytokines (IL-1β, TNF-α, IFN-γ) for 24–48 h in the presence of vehicle or increasing concentrations of the CB1R blocker JD-5037. Expression of CNR1 (encoding for CB1R) was ablated using CRISPR/Cas9 technology. Viability, intracellular stress and signalling were assayed by live-cell probing and real-time PCR. The islet function measured as glucose-stimulated insulin secretion was determined in a perifusion system. Infiltration of immune cells into the islets was monitored by microscopy. Non-obese diabetic mice aged 7 weeks were treated for 1 week with JD-5037, then euthanised. Profiling of immune cells infiltrated in the islets was performed by flow cytometry. Results CNR1 expression was upregulated in circulating CD4+ T cells from individuals at type 1 diabetes onset (6.9-fold higher vs healthy individuals) and in sorted islet beta cells from donors with type 1 diabetes (3.6-fold higher vs healthy counterparts). The peripherally restricted CB1R inverse agonist JD-5037 arrested the initiation of insulitis in humans and mice. Mechanistically, CB1R blockade prevented islet NO production and ameliorated the ATF6 arm of the unfolded protein response. Consequently, cyto/chemokine expression decreased in human islets, leading to sustained islet cell viability and function. Conclusions/interpretation These results suggest that CB1R could be an interesting target for type 1 diabetes while highlighting the regulatory mechanisms of insulitis. Moreover, these findings may apply to type 2 diabetes where islet inflammation is also a pathophysiological factor. Data availability Transcriptomic analysis of sorted human beta cells are from Gene Expression Omnibus database, accession no. GSE121863, available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM3448161. Graphical Abstract

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Features of (+)-trans-cannabidiol-2-hydroxy pentyl and applications to disease: A focus on usage in diabetic nephropathy

Muñóz

Winkler

Götz

et al. 2023

Medicinal Usage of Cannabis and Cannabinoids

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(+)-trans-Cannabidiol-2-hydroxy pentyl is a dual CB1R antagonist/CB2R agonist that prevents diabetic nephropathy in mice

Cited by 15 publications

References 41 publications

Detrimental Effect of Cannabidiol on the Early Onset of Diabetic Nephropathy in Male Mice

Detrimental Effect of Cannabidiol on the Early Onset of Diabetic Nephropathy in Male Mice

Pharmaceutical targeting of the cannabinoid type 1 receptor impacts the crosstalk between immune cells and islets to reduce insulitis in humans

Features of (+)-trans-cannabidiol-2-hydroxy pentyl and applications to disease: A focus on usage in diabetic nephropathy

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