A transcriptional inhibitor of TNF-α prevents diabetes induced by multiple low-dose streptozotocin injections in mice

The aim of the present study was to examine the effect of a transcriptional inhibitor of tumour necrosis factor-alpha (TNF-alpha) on the development of diabetes induced by multiple low doses of streptozotocin (STZ) in mice. MDL 201.449A is a novel transcriptional inhibitor of TNF-alpha gene expression and protein production and might therefore be potentially interesting in counteracting diabetes. We have studied the effect of MDL 201,449A on the development of hyperglycaemia and pancreatic insulitis in mice treated with multiple low-dose injections of streptozotocin. It was found that one daily sc injection of MDL 201,449A (25 mg/kg body weight) for 14 days prevented the development of hyperglycaemia following the streptozotocin injections. The mice treated with multiple low-dose injections of streptozotocin became gradually hyperglycaemic, and concomitant treatment with MDL 201,449A significantly reduced this elevation in blood glucose levels. In vitro MDL 201,449A reduced TNF-alpha mRNA levels dose-dependently by 75-80% after ConA stimulation of spleen cells, indicating the efficacy of MDL 201,449A to counteract TNF-alpha mRNA synthesis. These data suggest that transcriptional inhibition of TNF-alpha might be an interesting approach in the prevention of type 1 diabetes. (C) 2001 Academic Press.