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 beta cell death and the development of insulin-dependent diabetes mellitus (IDDM). We speculate that treatment with the PEN, will protect against diabetes development in two distinct chemically induced models fur IDDM. Pretreatment with PEN (150 mg/kg ip) significantly reduced the severity of hyperglycemia in both alloxan- and streptozotocin (STZ) induced diabetes. To determine the mechanism by which PEN prevents hyperglycemia, we examined the ability of PEN to inhibit NF kappa B activation and to stabilize alloxan- and STZ-induced radicals, Both alloxan and STZ induced NF kappa B activation in the pancreas 30 min after their injection (50 mg/kg iv). PEN pretreatment inhibited both alloxan- and STZ-induced activation of NF kappa B and nitric oxide production. EPR studies showed that PEN could effectively trap alloxan-induced free radicals. It is clear that PEN can inhibit NF kappa B activation in the pancreas and reduce hyperglycemia in two distinct diabetogenic compounds. This research indicates that NF kappa B activation may be a key signal leading to beta cell death and IDDM. Understanding the cellular pathways leading to beta cell death may help in developing effective preventive or therapeutic targets for IDDM. (C) 2000 Elsevier Science Inc.