The Atypical Cannabinoid Abn-CBD Reduces Inflammation and Protects Liver, Pancreas, and Adipose Tissue in a Mouse Model of Prediabetes and Non-alcoholic Fatty Liver Disease

Abstract

Results: Body weight and triglycerides profiles in blood and liver were comparable between vehicle-and Abn-CBD-treated DIO mice. However, treatment with Abn-CBD reduced hyperinsulinemia and markers of systemic low-grade inflammation in plasma and fat, also promoting white adipose tissue browning. Pancreatic islets from Abn-CBD-treated mice showed lower apoptosis, inflammation and oxidative stress than vehicle-treated DIO mice, and beta cell proliferation was induced. Furthermore, Abn-CBD lowered hepatic fibrosis, inflammation and macrophage infiltration in the liver when compared to vehicle-treated DIO mice. Importantly, the balance between hepatocyte proliferation and apoptosis was improved in Abn-CBD-treated compared to vehicletreated DIO mice. Romero-Zerbo et al. Abn-CBD in Prediabetes and NAFLD Conclusions: These results suggest that Abn-CBD exerts beneficial immunomodulatory actions in the liver, pancreas and adipose tissue of DIO prediabetic mice with NAFLD, thus protecting tissues. Therefore, Abn-CBD and related compounds could represent novel pharmacological strategies for managing obesity-related metabolic disorders.

Abnormal Cannabidiol protects pancreatic beta cells in mouse models of experimental Type 1 diabetes

“…Abn-CBD significantly reduced beta cell apoptosis in both T1D mouse models, in agreement with previous reports in mouse models of type 2 diabetes (Ruz-Maldonado et al, 2018;Vong et al, 2019b;Romero-Zerbo et al, 2020), in which Abn-CBD was shown to reduce cytokine (mix of TNFα, IFNγ and IL-1β)-induced apoptosis in islets in vitro (Ruz-Maldonado et al, 2018). IL-6, which is elevated in T1D (Alnek et al, 2015), plays a very important role at the onset of T1D by activating CD4 + T cell differentiation (Hundhausen et al, 2016).…”

“…We did not find a significant increase in beta cell proliferation in Abn-CBD-treated STZ-induced diabetic mice as compared to vehicle-treated mice that may account for the lack of improved glycemia over the short experimental period time. These results challenge previous reports indicating that Abn-CBD stimulated beta cell proliferation in the STZ-treated Swiss mouse model as well as in a diet-induced mouse model of obesity and prediabetes and isolated human islets (McKillop et al, 2016;Ruz-Maldonado et al, 2018;Romero-Zerbo et al, 2020). Discrepancies may potentially be related to differences in time and via of administration.…”

“…At the molecular level, we found that Abn-CBD repressed activation of both NF-κB (measured as phosphorylation of p65) and the inflammasome (measured as TXNIP staining) in islets from both models of T1D treated with Abn-CBD, that explains a reduced inflammation-mediated beta cell death and fibrosis. Thus, the anti-apoptotic effect of Abn-CBD in beta cells seems to arise from a combination of lower levels of cytokines and chemokines in circulation, decreased inflammation and immune infiltration into the islets, and reduced sensitivity to cytokines by beta cells (Ruz-Maldonado et al, 2018;Vong et al, 2019b;Romero-Zerbo et al, 2020) and this study. The reduced insulitis originates from lower CD4 + T cells polarization to Th1, dampening Th1/Th2 ratio, subsequently decreasing CTL cells maturation and infiltration and lowering the presence of M1 macrophages in the islets.…”

“…Phytocannabinoids and synthetic cannabinoids have been investigated for their antiinflammatory and glucose-lowering properties, but their potential as therapeutic agents for the treatment of insulitis and T1D remains unexplored. Herein we investigated the potential preclinical benefits of the synthetic cannabinoid Abn-CBD in T1D models, as emerging evidence point to its ability in modulating inflammation, insulin secretion as well as beta cell proliferation and apoptosis (McKillop et al, 2013(McKillop et al, , 2016Ruz-Maldonado et al, 2018;Romero-Zerbo et al, 2020). Overall, we found that prophylactic administration of Abn-CBD was able to 1) reduce levels of systemic proinflammatory cytokines, 2) reduce polarization of CD4 + T cells towards proinflammatory Th1 cells, 3) decrease immune infiltration in the islets, the severity of insulitis and intra-islet inflammation and 4) decrease apoptosis of islet cells.…”

Long-Term Low-Dose Delta-9-Tetrahydrocannbinol (THC) Administration to Simian Immunodeficiency Virus (SIV) Infected Rhesus Macaques Stimulates the Release of Bioactive Blood Extracellular Vesicles (EVs) that Induce Divergent Structural Adaptations and Signaling Cues

“…Cannabinoids, the chemical compounds found in the cannabis (marijuana) plant, exhibit pharmacobiological effects in various conditions, including remyelination [ 1 ], hyperthermia [ 2 ], hypothermia [ 3 ], catalepsy [ 4 , 5 ], inflammation and immune activation [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ], analgesia [ 13 ], cellular growth/arrest, apoptosis [ 14 ], as well as alteration in the functions of a variety of immune cells [ 15 , 16 , 17 , 18 ]. Although more than 100 cannabinoids have been identified in cannabis, THC and the non-psychotropic cannabidiol (CBD) are the most widely used and both have the same molecular formula (C 21 H 30 O 2 ) and molecular weight (314.5 g/mol).…”