Alpha-phenyl-tert-butylnitrone (PBN) inhibits NF kappa B 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 specie s (ROS) have been implicated in pancreatic beta cell death and the developm ent of insulin-dependent diabetes mellitus (IDDM). We speculate that treatm ent with the PEN, will protect against diabetes development in two distinct chemically induced models fur IDDM. Pretreatment with PEN (150 mg/kg ip) s ignificantly reduced the severity of hyperglycemia in both alloxan- and str eptozotocin (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 allo xan and STZ induced NF kappa B activation in the pancreas 30 min after thei r 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 reduc e hyperglycemia in two distinct diabetogenic compounds. This research indic ates that NF kappa B activation may be a key signal leading to beta cell de ath and IDDM. Understanding the cellular pathways leading to beta cell deat h may help in developing effective preventive or therapeutic targets for ID DM. (C) 2000 Elsevier Science Inc.