Abnormal cannabidiol ameliorates inflammation preserving pancreatic beta cells in mouse models of experimental type 1 diabetes and beta cell damage

The atypical cannabinoid Abn-CBD improves the inflammatory status in preclinical models of several pathologies, including autoimmune diseases. However, its potential for modulating inflammation in autoimmune type 1 diabetes (T1D) is unknown. Herein we investigate whether Abn-CBD can modulate the inflammatory response during T1D onset using a mouse model of T1D (non-obese diabetic- (NOD)-mice) and of beta cell damage (streptozotocin (STZ)-injected mice). Six-week-old female NOD mice were treated with Abn-CBD (0.1–1 mg/kg) or vehicle during 12 weeks and then euthanized. Eight-to-ten-week-old male C57Bl6/J mice were pre-treated with Abn-CBD (1 mg/kg of body weight) or vehicle for 1 week, following STZ challenge, and euthanized 1 week later. Blood, pancreas, pancreatic lymph nodes (PLNs) and T cells were collected and processed for analysis. Glycemia was also monitored. In NOD mice, treatment with Abn-CBD significantly reduced the severity of insulitis and reduced the pro-inflammatory profile of CD4 T cells compared to vehicle. Concomitantly, Abn-CBD significantly reduced islet cell apoptosis and improved glucose tolerance. In STZ-injected mice, Abn-CBD decreased circulating proinflammatory cytokines and ameliorated islet inflammation reducing intra-islet phospho-NF-κB and TXNIP. Abn-CBD significantly reduced 2 folds intra-islet CD8 T cells and reduced Th1/non-Th1 ratio in PLNs of STZ-injected mice. Islet cell apoptosis and intra-islet fibrosis were also significantly reduced in Abn-CBD pre-treated mice compared to vehicle. Altogether, Abn-CBD reduces circulating and intra-islet inflammation, preserving islets, thus delaying the progression of insulitis. Hence, Abn-CBD and related compounds emerge as new candidates to develop pharmacological strategies to treat the early stages of T1D.
H2020-MSCA-IF-2016, Grant Agreement number: 748749, EU. Consejeria de Salud y Familias, Junta de Andalucia, Spain (PI-0318-2018). Instituto de Salud Carlos III, Ministerio de Sanidad, Gobierno de España, Spain (PI17/01004). Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación and Fondo Europeo de Desarrollo Regional, Spain (BFU2017-83588-P to BRG). We thank all the staff of the animal facility at IBIMA (ECAI de Experimentación Animal) and especially its coordinator Dr. Ricardo González Carrascosa for his excellent work. The authors also gratefully acknowledge all the staff of the bioimaging facility at IBIMA (ECAI de Imagen) and the proteomic (ECAI de Proteómica) facility, especially Dra. Carolina Lobo-García for excellent technical assistance. FJBS and IGM belong to the regional "Nicolás Monardes" research program from Consejería de Salud y Familias (C-0070-2012, RC0005-2016, RC-0001-2021 and C1-0018-2019; Junta de Andalucía, Spain). FJBS, NCV and BRG are members of the pancreatic islets study group from the Spanish Society for Diabetes (SED), Spain. CIBERDEM is an initiative of the Instituto de Salud Carlos III, Spain.