[Introduction and objectives]: Novel treatments to fight against type 2 diabetes (T2D) are needed. In this context, recent findings suggest that targeting inflammation is a promising complementary therapy. Indeed, there is evidence suggesting a link between anxiety/depression and obesity/T2D. Abnormal-cannabidiol (Abn-CBD) and LH-21 are synthetic cannabinoids whose pharmacology and effects are still unclear. Abn-CBD seems to activate GPR18 and/or GPR55, whereas LH-21 has been reported to antagonize CB1, though some recent report also suggest GPR55-mediated actions. Interestingly, these GPCRs have been related to inflammatory response and have indeed been found in the CNS. Despite preliminary anti-obesity and anti-hyperglycaemic activity of these drugs, there is a lack of information on the putative modulation of inflammation and anxiety/depression. In order to address these gaps, the effects of chronic administration of Abn-CBD and LH-21 was investigated in diet-induced obese/diabetic mice. [Material and methods]: 10 weeks-old C57Bl/6J mice were fed a high-fat diet (45% kcal content) for 15 weeks. Animals developed an obese/diabetic phenotype with insulin resistance, glucose intolerance, fatty liver, altered inflammatory markers and anxiety. Then, groups of ten mice were daily injected with LH-21 (3 mg/Kg), Abn-CBD (0.05 mg/Kg) or vehicle for two weeks. Food intake and body weight was monitored on a daily basis, glucose handling was assessed by ipGTT and ipITT and finally mice were sacrificed for tissue collection. Several adipokines were determined by ELISA, and inflammatory citokines were assessed by V-PLEX proinflammatory panel kit. Liver histopathology was studied by oil-red staining and F4/80 immunohistochemistry. Behavioural performance was evaluated by the open field test and the elevated plus maze, before and after treatment. [Results]: Abn-CBD and LH-21 treatment did not alter food intake and body weight gain, with little impact on glucose handling. However, both drugs showed anti-inflammatory effects to varying degrees. While Abn-CBD decreased the pro-inflammatory markers IL-6, IL-5 and KC-GRO with no changes in other inflammatory markers, such as IL-2, IL-12p70, IFN-γ, IL-10 and adiponectin, LH-21 decreased plasma levels of leptin without altering any other inflammatory marker. Abn-CBD and LH-21 did not decrease fat content in the liver, nevertheless both drugs decreased macrophages infiltrate in this tissue, suggesting an intra-hepatic anti-inflammatory effect. Regarding behavioural performance, Abn-CBD did not affect locomotion or anxiety. By contrast, LH-21 promoted an anxiolytic behaviour by increasing number of entries into open arms and reverting the obesity/diabetes-induced decrease in time spent and distance travelled in open arms of plus maze, without affecting locomotion. [Conclusions]: Abn-CBD and LH-21 ameliorate the inflammatory status in an animal model of type 2 diabetes, the latter indeed reverting obesity/diabetes-induced anxiety.

Resumen del póster presentado al XXVIII Congreso Nacional de la Sociedad Española de diabetes, celebrado en Bilbao del 20 al 22 de abril de 2016.

Funded by the ISCIII (PI13/00309 to FJBS) and the Consejería de Salud de la Junta de Andalucía (PI-0574-2012 to SYRZ).

Peer reviewed