Supplementation of N-acetylcysteine inhibits NF kappa B activation and protects against alloxan-induced diabetes in CD-1 mice

Reactive oxygen species (ROS) are involved in the destruction of pancreatic beta cells and the development of insulin-dependent diabetes mellitus (IDD M), However, the cellular mechanism responsible for beta cell death is stil l unclear. We hypothesize that activation of NF kappa B by ROS is the key c ellular signal in initiating a cascade of events leading to beta cell death . Thus, enhancement of pancreatic GSH, a known antioxidant and key regulato r of NF-KB, should protect against IDDM, Weanling CD1 mice (n=5) were injec ted with alloxan (50 mg/kg i.v.) to induce IDDM, Using EPR spin trapping te chniques, we demonstrated that alloxan generated ROS in the pancreas 15 min after administration. Activation of NF kappa B in pancreatic nuclear extra cts was observed 30 min after alloxan injection, as assessed by an electrop horetic mobility shift assay. Fasting blood glucose levels were monitored f or 14 days. Supplementation with N-acetylcysteine (NAC, 500 mg/kg), a GSH p recursor, inhibited alloxan-induced NF kappa B activation and reduced hyper glycemia, Thus, NF kappa B activation by ROS may initiate a sequence of eve nts leading to IDDM, Inhibition of NF-kappa B activation by NAC attenuated the severity of IDDM, This research will contribute to the understanding of the etiology of IDDM and may lead to the development of better strategies for disease prevention.