Alpha-Phenyl-tert-butylnitrone (PBN) inhibits NFκB activation offering protection against chemically induced diabetes

Alpha-phenyl-tert-butylnitrone (PBN) is an effective spin trapping agent by reacting with and stabilizing free radical species. Reactive oxygen species (ROS) have been implicated in pancreatic β cell death and the development of insulin-dependent diabetes mellitus (IDDM). We speculate that treatment with the PBN, will protect against diabetes development in two distinct chemically induced models for IDDM. Pretreatment with PBN (150 mg/kg ip) significantly reduced the severity of hyperglycemia in both alloxan- and streptozotocin (STZ) induced diabetes. To determine the mechanism by which PBN prevents hyperglycemia, we examined the ability of PBN to inhibit NFκB activation and to stabilize alloxan- and STZ-induced radicals. Both alloxan and STZ induced NFκB activation in the pancreas 30 min after their injection (50 mg/kg iv). PBN pretreatment inhibited both alloxan- and STZ-induced activation of NFκB and nitric oxide production. EPR studies showed that PBN could effectively trap alloxan-induced free radicals. It is clear that PBN can inhibit NFκB activation in the pancreas and reduce hyperglycemia in two distinct diabetogenic compounds. This research indicates that NFκB activation may be a key signal leading to β cell death and IDDM. Understanding the cellular pathways leading to β cell death may help in developing effective preventive or therapeutic targets for IDDM.