Hypoxia-Induced Injury of Human Islets Is Reduced By Cyclodextrin-Complexed Curcumin.

Purpose: Curcumin is a pluripotent agent with anti-inflammatory, anti-apoptotic and anti-diabetogenic qualities as shown in rodents. The primary molecular target of curcumin is nuclear transcription factor (NFkB) activated in human islets exposed to hypoxia during pancreas procurement, the isolation procedure and after transplantation. Unfortunately, curcumin had to be administered in high doses because of its low bioavailability. This disadvantage has been solved by preparing cyclodextrin-complexed curcumin (CDC) characterized by increased bioactivity and improved long-term stability compared to non-complexed curcumin. The aim of this initial study was to evaluate the capability of CDC to prevent hypoxic injury from isolated human islets. Methods: Human islets isolated from six different donors were incubated with CDC added in a range from 1 to 40 μM and cultured at 37°C in hypoxic atmosphere (2% O2). After 48-72 hours islets were assessed for survival, fragmentation and reactive oxygen species (ROS) production. Islet viability was assessed by FDA-PI staining using a plate reader-based assay to provide unbiased results. All data were related to hypoxia-exposed, vehicle-treated controls considered as 100%. All data are presented as mean ± SD. Results: Forty μM CDC was most effective to increase islet survival (159±40%, p<0.001 by Wilcoxon test) and to reduce islet fragmentation (75±10%, p<0.01) during hypoxia. In contrast, the increase in viability that was observed for all concentrations used was only significant when 5 (107±4%, p<0.05) or 10 μM CDC (108±6%, p<0.05) was applied. When the overall survival of viable cells was calculated the protection of hypoxic islets was only significant when applying concentrations of 10, 20 and 40 μM CDC (157±31%, p<0.05; 155±44%, p<0.05; 167±44%, p<0.001). Overall survival correlated with reduced production of ROS at 10 (62±19%, p<0.05), 20 (52±17%, p<0.01) and 40 μM CDC (46±8%, p<0.01). Conclusions: The present study demonstrated that CDC significantly reduces hypoxic injury in isolated human islets and is well tolerated within the range tested. The high bioactivity of CDC seems to be important for human islet pretransplant treatment and may be relevant for its application during pancreas procurement and the islet isolation process. Studies are ongoing to evaluate the effect of CDC on human islet function. DISCLOSURES:Parkkinen, J.: Employee, Producer of the compound tested.